IntroductionIn recent years, the rapid evolution of immunometabolism has fundamentally reshaped our understanding of immune responses.1,2 Emerging evidence reveals that immune cells undergo swift metabolic reprogramming upon infection, stress, or injury to meet bioenergetic and biosynthetic demands, while metabolic intermediates directly modulate immune signaling, inflammatory amplification, and tissue repair.3,4,5,6,7 The bidirectional coupling between metabolism and immunity not only maintains physiological homeostasis but also underlies the pathogenesis of diverse disorders, including infections, metabolic syndromes, autoimmune diseases, ischemia‒reperfusion injury, and cancer.8,9,10,11,12 Balancing antimicrobial defense with the suppression of excessive inflammation remains a central challenge in therapeutic design.Within this context, the itaconate metabolite derived from aconitate decarboxylase 1 (ACOD1), the enzyme encoded by immune-responsive gene 1 (IRG1), has attracted considerable attention.13,14 Originating from the tricarboxylic acid (TCA) cycle intermediate cis-aconitate via IRG1-catalyzed decarboxylation, itaconate represents a critical branch of TCA metabolism.15,16 Initially, regarded as a byproduct of macrophage activation during infection, itaconate has since been recognized as a versatile signaling mediator capable of modulating immune and stress responses through multiple mechanisms, including inhibition of succinate dehydrogenase (SDH), regulation of redox homeostasis, activation of the NRF2 pathway, and interference with inflammasome assembly.17,18,19,20 This molecule exhibits dualistic properties: while attenuating hyperinflammation and protecting tissues from immune-mediated damage, it may, under certain microenvironmental conditions, be exploited by pathogens to evade clearance or promote immune tolerance and tumor immune escape.21,22,23,24,25,26 Consequently, itaconate has emerged as a pivotal metabolic hub that integrates immune signaling and cellular homeostasis, offering a new paradigm for the metabolic regulation of inflammation.Despite significant progress, current research on itaconate remains constrained by notable limitations and controversies. Its biological effects are highly context-dependent—determined by cell lineage, disease stage, and tissue microenvironment—which together dictate whether itaconate exerts anti- or pro-inflammatory functions. Discrepancies between in vitro and in vivo models, coupled with an incomplete understanding of their pharmacokinetics and dose‒response relationships, further complicate interpretation. Moreover, differences in bioavailability and activity profiles between esterified prodrugs (e.g., 4-octyl itaconate, 4-OI) and the free acid form present additional challenges for clinical translation.27,28 Beyond these pharmacological uncertainties, the upstream and downstream regulatory networks of itaconate signaling, its epigenetic consequences, and its metabolic crosstalk with other intermediates, such as succinate and lactate, remain insufficiently integrated.29,30 Establishing a unified mechanistic framework and developing strategies for controlled delivery and spatiotemporal precision are therefore central challenges in this field.31,32,33This review centers on the IRG1/ACOD1-itaconate axis, aiming to construct a multilayered, interdisciplinary framework that connects molecular mechanisms, disease phenotypes, and therapeutic strategies. We first summarize the metabolic origin, structural characteristics, and signaling mechanisms of itaconate, emphasizing its pivotal roles in energy metabolism, redox regulation, and inflammasome activation. We then provide a disease-oriented synthesis of its functional paradigms and regulatory diversity across infectious inflammation, metabolic disorders, ischemia‒reperfusion (I/R) injury, autoimmunity, cancer, and organ-specific inflammatory pathologies. Building on these insights, we discuss recent advances in itaconate derivatives and engineered delivery systems, highlighting their pharmacochemical, pharmacokinetic and translational implications. Finally, we identify key scientific questions and translational bottlenecks that define future research priorities.Through this conceptual structure, we aim to integrate fragmented mechanistic findings into a coherent model that elucidates the systemic significance of itaconate as a metabolic immune interface and to provide a testable theoretical and practical framework for developing next-generation anti-inflammatory and immunomodulatory therapies based on metabolic reprogramming.Biosynthesis, metabolism, and signaling mechanisms of itaconateItaconate as a central hub of inflammatory metabolismItaconate is a key branch metabolite of the TCA cycle and occupies a central position in the regulation of inflammation and immunometabolism. It is produced through the decarboxylation of cis-aconitate catalyzed by ACOD1, the enzyme encoded by IRG1, representing the only known pathway for itaconate biosynthesis in mammalian cells.34 In activated macrophages, this reaction forms a metabolic break point within the TCA cycle, marking the onset of metabolic reprogramming. Recent studies have revealed that itaconate functions not only as a metabolic intermediate but also as a molecular bridge linking energy metabolism and immune signaling. Through redox regulation, protein modification, and signaling network remodeling, itaconate exerts bidirectional immunoregulatory effects across a spectrum of pathological contexts, including infection, autoimmunity, and cancer. Figure 1 provides a systematic summary of the immune-metabolic regulatory network governed by the IRG1-itaconate axis.Fig. 1Full size imageIntegrated overview of the IRG1-itaconate axis in immune-metabolic regulation. a Upstream induction of the IRG1/ACOD1-itaconate axis; b metabolic remodeling and downstream regulatory network of itaconate. Created with BioRender.comUpstream induction of Irg1/ACOD1The expression of Irg1/ACOD1 is tightly regulated by immune signaling, metabolic state, and epigenetic modulation and is markedly induced in various immune cell types, particularly macrophages and monocytes. During infection and inflammation, pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) and bacterial lipopeptides, cytokines, including TNF and interferons, and damage-associated molecular patterns (DAMPs), collectively drive ACOD1 expression. Its upstream network involves multiple immune receptors (e.g., TLRs, IFNAR), adaptors (MYD88), ubiquitin ligases (A20), and transcriptional regulators such as NF-κB, IRFs, STATs, C/EBPβ, and PKC, forming a multilayered signaling system that finely tunes ACOD1 transcriptional activity. Among these, the canonical TLR pathway serves as a principal induction mechanism: upon inflammatory stimulation by LPS, bacterial lipoproteins, or infection, it activates IRF1/9, STAT1/3, C/EBPβ, and PKC, which in turn promote Irg1 transcription and itaconate production, thereby shaping immunometabolic responses and downstream functional outcomes.1,35,36In the context of infection and inflammation, the IRF1-mediated signaling axis constitutes one of the core mechanisms driving Irg1 induction. In human macrophages infected with, TNF-α and IL-6 promote IRF1 nuclear translocation through autocrine and paracrine signaling, leading to upregulation of the mitochondrial enzyme IRG1 and enhanced itaconate production that restricts bacterial growth.37 Similarly, certain chemical stimuli can induce Irg1 expression through IRF1 activation. For instance, thimerosal triggers the ROS-RIPK3-IRF1 pathway, strongly inducing IRG1 expression in tumor cells but only weakly in macrophages, indicating a cell type-specific regulatory pattern.38 In addition, within cardiovascular inflammation models, scavenger receptor A1 (SR-A1) interacts with Lyn kinase to promote STAT3 phosphorylation and nuclear translocation, which in turn enhances Irg1 transcription.39Notably, metabolic cues and transcriptional regulatory networks play equally critical roles in controlling Irg1 expression. Studies have shown that the metabolic transcription factor TFEB is activated under infectious conditions, directly binds to the Irg1 promoter, and enhances its transcription, thereby increasing itaconate synthesis.40,41 Conversely, itaconate itself promotes TFEB nuclear translocation and activation, which in turn stimulates the autophagy‒lysosome pathway (ALP) and mitigates metabolic and infectious tissue injury42,43 This TFEB-Irg1/itaconate-TFEB positive feedback loop maintains lysosomal homeostasis and reinforces host antibacterial immunity.In contrast, certain signaling molecules negatively regulate the Irg1/itaconate axis. In metabolic-associated steatohepatitis (MASH), β-arrestin 2 is markedly upregulated in hepatic macrophages and peripheral monocytes, promoting IRG1 ubiquitination and degradation, thereby reducing itaconate production and weakening metabolic anti-inflammatory defense.44 Epigenetic mechanisms also contribute to fine-tuning this pathway. The histone deacetylase (HDAC) inhibitor valproic acid (VPA) enhances H3K27 acetylation, upregulates IRG1 expression, increases itaconate production, and activates the Nrf2-HO-1/SOD1 antioxidant cascade, highlighting the involvement of epigenetic modulation in regulating this axis.45Intercellular metabolic communication further shapes Irg1-itaconate activity. Extracellular vesicles or exosomes derived from skeletal muscle cells or mesenchymal stem cells have been shown to enhance IRG1 expression and itaconate synthesis in macrophages, promoting their polarization toward an anti-inflammatory phenotype.46,47Additionally, several natural bioactive compounds and endogenous metabolites can upregulate the IRG1-itaconate axis. Quercetin, in a respiratory syncytial virus (RSV) infection model, suppresses glycolysis and TCA cycle flux while increasing IRG1 expression and itaconate production, thereby inhibiting SDH and alleviating inflammation.48 Dihydrotanshinone I (DHTS) upregulates IRG1, activates the Nrf2 pathway, suppresses NLRP3, and ameliorates hepatic inflammation and fibrosis in MASLD mice.49 The plant-derived compound pubescenoside C (PBC) binds to HSP90 and inhibits GSK3β activity, resulting in activation of the Acod1-itaconate axis.50 The endogenous lipid mediator lipoxin A4 (LXA4) also activates the IRG1-itaconate-Nrf2/HO-1-IRAK-M axis to inhibit TLR4-TRAF6 signaling and reduce inflammatory injury in renal I/R models.51Collectively, Irg1/ACOD1 induction integrates immune, metabolic, and epigenetic signals, forming the systemic regulatory foundation of the itaconate pathway (Fig. 1a). However, emerging evidence indicates that ACOD1 may also exert itaconate-independent functions. In polymicrobial sepsis, ACOD1 amplifies cytokine storms and TNF-associated signaling largely independent of itaconate,52 suggesting that ACOD1- and itaconate-mediated effects are not always equivalent.Synthesis and transmembrane transport of itaconateIn inflammation-activated macrophages, ACOD1 in the mitochondrial matrix decarboxylates cis-aconitate to generate itaconate, creating a citrate to itaconate branch point. Notably, itaconate production varies across species and individuals; human macrophages produce lower levels than their murine counterparts, partly due to the reduced catalytic activity of human ACOD1, and naturally occurring ACOD1 variants can further modulate enzymatic activity.53 The anionic itaconate, which resembles malate, is exported across the inner mitochondrial membrane via the dicarboxylate carrier, the citrate carrier, and the oxoglutarate carrier to the cytosol.54Under exogenous stimulation, such as LPS, these transport activities are upregulated, promoting cytosolic accumulation of itaconate. For extracellular trafficking, ABCG2 functions as an ATP-dependent efflux transporter; its loss causes intracellular itaconate buildup and enhances TFEB-dependent lysosome biogenesis and antibacterial responses.55 Conversely, SLC13A3 serves as a principal uptake transporter that governs the cellular import of itaconate and downstream signaling.43Together, itaconate production and transport maintain intracellular homeostasis and are prerequisites for its signaling functions.Itaconate derivatives and isomersThe chemical scaffold of itaconate gives rise to a broader “itaconate family”, including the naturally occurring isomers mesaconate and citraconate, as well as synthetic esterified derivatives such as 4-octyl itaconate (4-OI) and dimethyl itaconate (DMI). These related molecules are highly relevant experimentally and mechanistically, but they should not be considered interchangeable with endogenous itaconate.Natural isomers have attracted increasing attention because they extend the metabolic and signaling landscape of the ACOD1/itaconate axis. Mesaconate has been shown to be generated from itaconate in activated macrophages in an ACOD1-dependent context, and tracing studies further suggest that mesaconate can arise from itaconate in vitro and can be detected across multiple tissues in vivo. However, endogenous mesaconate levels are much lower than those of itaconate, approximately 1-10% of itaconate in macrophages, indicating that mesaconate is likely a minor but biologically relevant branch metabolite rather than a major end product.56,57,58 Functionally, mesaconate shares part of the immunoregulatory profile of itaconate, including suppression of inflammatory cytokine output and inhibition of glycolytic remodeling, but appears to be less potent than itaconate in inhibiting succinate dehydrogenase (SDH), the TCA cycle, and glycolysis.56,57In contrast, citraconate remains much less understood. Although citraconate is a structural isomer of itaconate, current evidence indicates that it is not generated endogenously by macrophages but can be readily taken up by these cells.57,59 Importantly, the tissue distribution, physiological source, and biosynthetic route of citraconate are still poorly defined, and this knowledge gap should be explicitly acknowledged when discussing the biology of itaconate isomers. In particular, the production pathway of citraconate remains unknown, making it premature to regard citraconate as a routine downstream metabolite of the canonical ACOD1-itaconate pathway.58,59 Mechanistically, citraconate is the most electrophilic of the three isomers, is a stronger activator of Nrf2-associated antioxidant responses, and competitively inhibits ACOD1 catalysis, thereby reducing endogenous itaconate synthesis; on this basis, it has been proposed as the first natural inhibitor of ACOD1.57,59Synthetic derivatives were developed largely to overcome the high polarity and limited passive membrane permeability of itaconate. Among them, DMI and 4-OI are the most widely used tools. Both derivatives are more electrophilic than endogenous itaconate and can reproduce many anti-inflammatory and antioxidant phenotypes, including activation of Nrf2 signaling and suppression of inflammatory cytokines.19,57,60 Nevertheless, increasing evidence indicates that these compounds are not simple surrogates of endogenous itaconate. DMI is not metabolized into intracellular itaconate and instead exerts strong electrophilic effects, including conjugation with glutathione (GSH).19,57,61 For 4-OI, some studies support intracellular hydrolysis to itaconate, whereas others suggest that this conversion may be incomplete or context dependent; accordingly, its biological effects likely reflect both partial itaconate delivery and derivative-specific electrophilic reactivity.19,57 Therefore, conclusions drawn from DMI- or 4-OI-treated systems should be interpreted with caution, especially when inferring the actions of endogenous itaconate.Beyond differences in cell permeability, members of the itaconate family also diverge in metabolic output. Itaconate itself directly inhibits SDH and dampens TCA cycle flux, whereas mesaconate is less effective in this regard, and DMI/4-OI often shows stronger electrophile-driven signaling effects than metabolic mimicry.19,57 In some models, 4-OI promotes metabolic rewiring toward aerobic glycolysis or fatty acid oxidation depending on the cellular context, while DMI more prominently perturbs thiol redox balance through GSH adduct formation.19,61 Moreover, compared with dimethyl fumarate (DMF), which primarily rescues mitochondrial complex I activity, itaconate more effectively restrains hyperactivation of complexes I and II and mitigates oxidative stress in inflammatory microglia.62Taken together, itaconate, its endogenous isomers, and its synthetic derivatives constitute a mechanistically related but functionally nonidentical family of metabolites. Their shared anti-inflammatory and immunomodulatory properties make them valuable experimental and therapeutic candidates; however, important distinctions in endogenous production, tissue distribution, electrophilicity, intracellular conversion, and metabolic targets must be considered. In particular, the biosynthesis and tissue distribution of mesaconate and especially citraconate remain incompletely defined, representing an important unresolved area in itaconate biology.57,58Metabolism of itaconate and remodeling of energy pathwaysItaconate is a central metabolite in inflammatory metabolic reprogramming, influencing energy metabolism, mitochondrial function, and epigenetic regulation.Intracellular itaconate can re-enter the TCA cycle through a degradation route. It is first converted to itaconyl-CoA by itaconate-CoA transferase, then hydrated to citramalyl-CoA by itaconyl-CoA hydratase, and finally cleaved by citramalyl-CoA lyase (encoded by CLYBL) to yield pyruvate and acetyl-CoA, thus reintegrating into the TCA cycle. This pathway is evolutionarily conserved in mammals and many bacteria. Several pathogens, including Yersinia pestis and Pseudomonas aeruginosa, harbor this three-enzyme-encoding gene cluster, enabling them to metabolize itaconate as an energy substrate and detoxify it, which is essential for intracellular survival.63,64,65,66,67During inflammatory stress or infection, activation of pyruvate dehydrogenase kinase (PDK) leads to phosphorylation and inhibition of the pyruvate dehydrogenase complex (PDC), blocking pyruvate conversion to acetyl-CoA. This diverts carbon flux from the citrate branch toward the itaconate-generating pathway, marking a key feature of metabolic reprogramming under inflammatory conditions.68 In parallel, itaconate and its derivatives, 4-OI and DMI, covalently modify key glycolytic enzymes (GAPDH, ALDOA, ENO1, PKM2, LDHA), strongly suppressing their enzymatic activity and glycolytic flux, thereby limiting hyperglycolysis in inflammatory cells.50,69,70,71,72,73,74,75 Beyond glucose metabolism, itaconate also binds noncovalently to the mitochondrial branched-chain aminotransferase (BCAT2), inhibiting its catalytic activity and reshaping LPS-induced branched-chain amino acid metabolism.76 Thus, itaconate not only restricts glucose-derived energy output but also redirects carbon allocation through amino acid pathways, fine-tuning the metabolic state of inflammatory cells.Furthermore, itaconate can induce posttranslational modifications of cysteine or lysine residues on multiple metabolic enzymes and signaling proteins, thereby modulating their function and downstream signaling.28,57 Table 1 summarizes the known protein targets, modification mechanisms, and biological effects of itaconate and its derivatives.50,54,70,71,73,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96Table 1 Target proteins, post-translational modification sites, and functional mechanisms of ITA and its derivativesFull size tableItaconate competitively inhibits multiple mitochondrial pathways. It suppresses the reductive carboxylation activity of mitochondrial isocitrate dehydrogenase 2 (IDH2), blocking the reverse conversion of α-ketoglutarate to isocitrate and citrate, thereby reducing the supply of cis-aconitate to the ACOD1 pathway and creating negative feedback that limits its own synthesis. This mechanism is linked to shifts in the NADP⁺/NADPH ratio and competitive inhibition of complex II (SDH), revealing a self-regulatory strategy by which itaconate preserves metabolic homeostasis during inflammation.97Itaconate is a competitive and reversible inhibitor of mitochondrial complex II/SDH. By suppressing succinate oxidation, itaconate decreases electron transfer to coenzyme Q (CoQ), prevents reverse electron transport from CoQH₂ to complex I, and lowers mitochondrial ROS generation, which in turn attenuates HIF-1α stabilization and the expression of IL-1β and other inflammatory mediators.58,98,99,100,101 In addition, the conversion of itaconate to itaconyl-CoA by itaconate-CoA transferase can sequester mitochondrial CoA pools (“CoA trap”), limiting available CoA, decreasing substrate-level phosphorylation efficiency, and constraining ATP and GTP synthesis, thereby further suppressing complex II function.102 Dose-dependent studies also show that itaconate inhibits the respiratory activities of complexes II and II + III, reduces ADP- and DNP-stimulated respiration, suppresses complex IV, and promotes calcium-dependent opening of the mitochondrial permeability transition pore with cytochrome c release, culminating in mitochondrial dysfunction.103Beyond metabolic enzymes, itaconate is also a potent inhibitor of the TET family of DNA dioxygenases. It competitively binds to the α-ketoglutarate (α-KG) active site of TET2, thereby blocking the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC)—a key epigenetic mark—thus impairing active DNA demethylation. TET enzymes utilize α-KG as a cosubstrate, converting it to succinate through a “nuclear bypass oxidation” distinct from the mitochondrial TCA route in which α-KG is converted to succinyl-CoA via OGDC. By targeting TET2, itaconate reduces 5-hmC levels and downregulates genes associated with the NF-κB and STAT signaling pathways, thereby suppressing inflammatory responses.91,104,105,106Under inflammatory stress, itaconate not only remodels cellular energy metabolism through regulation of glycolysis and the TCA cycle but also directly modulates fatty acid oxidation. Its derivative, itaconyl-CoA, competes with methylmalonyl-CoA for the vitamin B₁₂ cofactor binding site of methylmalonyl-CoA mutase (MUT), leading to MUT inactivation and blockade of the conversion of methylmalonyl-CoA to succinyl-CoA, thereby restricting the entry of branched-chain amino acid and fatty acid carbon flux into the TCA cycle.63,98 In addition, itaconate covalently modifies and irreversibly inactivates the mitochondrial inner-membrane carnitine-acylcarnitine translocase (CACT, encoded by SLC25A20). Because CACT mediates the import of long-chain acylcarnitines and the export of free carnitine, its inactivation blocks mitochondrial uptake of long-chain fatty acids, suppresses β-oxidation, and disrupts mitochondrial energy supply.88,107,108Thus, by targeting key metabolic nodes across glycolysis, the TCA cycle, and fatty acid oxidation, itaconate systemically limits the energy acquisition and metabolic activity of inflammatory cells, underscoring its central role in immunometabolic reprogramming (Fig. 1b).Signaling pathways and inflammation-protective mechanismsIn LPS-induced inflammatory diseases such as sepsis, acute lung injury (ALI), acute kidney injury (AKI), myocarditis, and sepsis-associated multiple organ dysfunction syndrome (MODS), the Irg1-itaconate axis has been widely recognized for its strong protective effects. Loss of Irg1 aggravates tissue inflammation and organ injury, whereas treatment with exogenous 4-OI or DMI significantly alleviates pathological damage and improves disease outcomes.The underlying mechanisms involve multiple signaling cascades. On the one hand, itaconate activates the Keap1-Nrf2-HO-1 pathway, enhancing antioxidant defense and autophagic clearance to mitigate oxidative stress and inflammatory damage. On the other hand, itaconate and its derivatives modulate key proinflammatory signaling networks, including TLR4/NF-κB, MAPK (p38, ERK), PI3K/Akt, NF-κB, and STAT3, thereby suppressing the expression of cytokines such as IL-1β and TNF-α. In addition, itaconate derivatives, particularly DMI, have been shown to regulate the IκBζ-ATF3 axis, whereas evidence supporting the direct activation of ATF3 by endogenous itaconate remains limited and context-dependent.109,110,111,112,113,114,115,116,117,118,119,120At the level of cell death and immune regulation, itaconate inhibits NLRP3 inflammasome activation and gasdermin D (GSDMD) modification through Nrf2-dependent mechanisms, thereby blocking caspase-1-mediated pyroptosis.93,121,122 Itaconate derivatives, particularly 4-OI, have been shown to suppress STING activation and inhibit GPX4 degradation and lipid peroxidation via NRF2-dependent and -independent mechanisms, thereby reducing ferroptosis and tissue injury, whereas evidence for similar effects of unmodified itaconate remains limited.114,123 The ACOD1/itaconate axis also plays a pivotal role in neutrophil regulation by enhancing the activity of the E3 ubiquitin ligase UBR5, which promotes PAD4 ubiquitination and degradation, thus inhibiting NETosis.79 Furthermore, itaconate reduces HIF-1α expression while activating the HO-1 pathway, limiting NET formation and protecting tissues from excessive neutrophil-mediated damage.124 In addition, itaconate promotes reverse migration of polymorphonuclear neutrophils and reduces ICAM-1-dependent adhesion at inflamed sites, thereby accelerating inflammation resolution and restoring tissue homeostasis.125Collectively, the Irg1-itaconate axis orchestrates a multifaceted metabolic protection network that integrates antioxidant, anti-inflammatory, and cell death-regulatory mechanisms to preserve immune balance and tissue integrity.Summary and outlookOverall, the Irg1/itaconate axis serves as a central hub that links cellular metabolism to immune responses. Inflammatory stimuli induce ACOD1, divert tricarboxylic acid cycle flux toward itaconate, and initiate signaling cascades that include KEAP1-NRF2, NF-κB, and TET2, thereby driving anti-inflammatory, antioxidant, and immunoregulatory programs. Future studies should define tissue-specific regulation, clarify the pharmacology of itaconate derivatives, and evaluate translational potential, with the goal of applying this metabolic-immune network to precise interventions for infectious and inflammation-related diseases.Itaconate in infectious inflammatory diseasesInfectious inflammatory diseases impose a major health burden, and the host immunometabolic network is pivotal in determining pathogen clearance and inflammatory homeostasis.126 IRG1 and its metabolite itaconate constitute a key nexus between metabolism and immunity. IRG1 catalyzes the decarboxylation of cis-aconitate to generate itaconate within mitochondria. Itaconate then constrains the growth of bacteria, viruses, fungi, and parasites by targeting multiple metabolic nodes in pathogens, such as isocitrate lyase and methylmalonyl-CoA mutase, and it modulates host responses to limit hyperinflammation and tissue injury. Some pathogens have evolved strategies to detoxify or exploit itaconate, producing a complex host‒ interplay. Thus, the IRG1-itaconate axis functions both as a metabolic barrier to infection and as a critical node in pathogen adaptation and immunopathology.This section synthesizes the organism-specific roles of the axis (Figs. 2, 3, Supplementary Table 1). For bacteria, coverage includes Mycobacterium tuberculosis (Mtb), nontuberculous mycobacteria (NTM), Salmonella, Legionella, Brucella, Staphylococcus aureus, and Pseudomonas aeruginosa (Fig. 2). For viruses, we focused on influenza virus, respiratory syncytial virus, and SARS-CoV-2. We also considered parasites such as Plasmodium, Toxoplasma, and Leishmania and fungi such as Aspergillus and Mycoplasma (Fig. 3). Comparative analysis across these pathogens aims to define common and context-specific mechanisms of the IRG1-itaconate axis in infectious inflammation and to evaluate its potential for host-directed therapy.Fig. 2Full size imageAntibacterial mechanisms and bacterial adaptation-host tolerance mediated by the IRG1-itaconate axis during bacterial infection. This figure summarizes the antibacterial functions of the IRG1-itaconate axis across multiple bacterial pathogens discussed in Section “Bacterial infections” and reorganizes them into four mechanistic modules rather than assigning individual pathogens to separate panels. a Upstream induction and transport; b Direct antimicrobial action and metabolic inhibition; c Bacterial adaptation and tolerance; d Immune regulation and inflammatory balance. The central circle highlights representative bacterial species covered in this section, including Mycobacterium tuberculosis, Salmonella, Legionella pneumophila, Coxiella burnetii, Brucella spp., Francisella tularensis, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Vibrio spp., Veillonella parvula, and Klebsiella pneumoniae. Created with BioRender.comFig. 3Full size imageDual roles of the IRG1-itaconate axis in host defense and pathogen exploitation across viral, fungal, mycoplasmal, and parasitic infections. This figure illustrates the dual, context-dependent roles of the IRG1-itaconate axis across viral, fungal, parasitic, and mycoplasma infections discussed in Sections “ Viral infections” and “Mycoplasma infections”. Pathogens are organized according to their predominant outcomes but may exhibit overlapping effects depending on infection stage and host context. a Protective mechanisms: Pathogens predominantly associated with protective host responses include IAV, RSV, SARS-CoV-2, VSV, ZIKV, HIV, fungi, Toxoplasma gondii, and Schistosoma japonicum. b Pathogenic or exploited mechanisms: In contrast, RSV, VSV, IAV, Plasmodium spp., Leishmania spp., and Mycoplasma pneumoniae exemplify contexts in which the IRG1-itaconate axis is hijacked or becomes maladaptive. Created with BioRender.comBacterial infectionsAt the bacterial level, the actions of the IRG1-itaconate axis can be reorganized into four interconnected mechanistic modules: upstream induction and transport, direct antimicrobial action and metabolic inhibition, bacterial adaptation and tolerance, and immune regulation with inflammatory balance (Fig. 2a–d). Importantly, these panels do not correspond to specific bacterial species one-to-one; rather, they summarize shared and context-dependent mechanisms derived from multiple pathogens discussed in this section.Intracellular bacteriaMtb lineageDuring infection with Mtb and NTM, host monocytes and macrophages induce IRG1 (ACOD1) and produce itaconate, linking metabolic restriction with control of inflammatory pathology. Early studies identified Irg1 as the enzyme-encoding generating itaconate from cis-aconitate; Irg1 deficiency reduces antimicrobial activity and exacerbates infection.127 In vivo, itaconate accumulation limits bacterial growth and dampens immunopathology, whereas Irg1-deficient mice show increased bacterial burden and excessive inflammation, highlighting its dual role in host defense and immune regulation.128 Irg1 induction requires coordinated signaling via ESX-1-mediated cytosolic access and STING-IFNAR activation, together with TLR2-MyD88-NF-κB signaling and phagolysosomal processing.129 In human systems, macrophage lineage strongly influences this response: alveolar-like macrophages generate less itaconate and are more permissive to infection than M-CSF-derived macrophages, indicating that microenvironmental context determines antimicrobial capacity.130Itaconate restricts mycobacterial metabolism through multitarget inhibition. It irreversibly modifies isocitrate lyase (ICL1/2), disrupting the glyoxylate and methylcitrate cycles,94 and its derivative itaconyl-CoA inhibits methylmalonyl-CoA mutase, blocking propionate utilization.131 In addition, itaconate suppresses glycolysis-purine coupling by targeting aldolase and IMP dehydrogenase.132 Related compounds such as DMI further target fatty acid synthesis enzymes (e.g., AccD6),133 although these effects should not be directly attributed to endogenous itaconate.To counteract this metabolic pressure, Mtb has evolved an itaconate degradation pathway. Rv2498c functions as a β-hydroxyacyl-CoA lyase involved in itaconate metabolism, and its deletion attenuates virulence.134 Additional enzymes, including Rv2503c, Rv3272, Rv2499c, and Rv3389c, mediate itaconate catabolism, and disruption of this pathway impairs bacterial growth in vitro and in vivo.132Beyond antimicrobial effects, itaconate contributes to immunometabolic and epigenetic regulation. The infection-driven accumulation of TCA intermediates, including itaconate, promotes DNA hypermethylation and immune tolerance, which can be reversed by targeting metabolic pathways or TCA cycle enzymes. Clinical data further support this link, as everolimus reduces hypermethylation in tuberculosis patients.135In NTM infection, the antimicrobial activity of itaconate is strongly pH dependent, with greater efficacy under acidic conditions, while derivatives such as 4-OI enhance macrophage bactericidal function.136 In Mycobacterium avium infection, cytokine-driven IRF1 activation promotes IRG1 expression and relocalization of itaconate to phagosomes, enabling localized antimicrobial activity.37Because of the strong polarity of itaconate, esterified derivatives are used to improve membrane permeability. DMI exhibits multifaceted host-directed effects both in vitro and in vivo, including restoration of IL-6/IL-10 balance, promotion of autophagy and phagosome maturation, suppression of STAT3 signaling, and enhanced intracellular clearance of Mtb and related pathogens. Importantly, DMI is not metabolized into itaconate and displays distinct biological properties; thus, these effects cannot be assumed to reflect those of endogenous itaconate, and similar effects have not been directly demonstrated for unmodified itaconate. These findings support the potential of targeting itaconate-related immunometabolic pathways as host-directed therapeutic strategies against mycobacterial infections.137In summary, itaconate plays a dual role in Mtb and NTM infections by integrating antimicrobial and immunomodulatory functions. It primarily restricts mycobacterial growth through multitarget metabolic inhibition while mitigating hyperinflammation and immunopathology but also imposes metabolic pressure that drives pathogen adaptation and detoxification mechanisms. Moreover, itaconate contributes to the coupling of metabolic and epigenetic regulation, shaping a state of immune tolerance or reversible homeostasis.SalmonellaItaconate, produced by IRG1 in activated macrophages, links metabolic remodeling to antimicrobial defense by targeting bacterial energy metabolism. As noted above, it inhibits isocitrate lyase within the glyoxylate shunt, restricting intracellular pathogens such as Salmonella enterica.127 During infection, a spatiotemporally coordinated mechanism enhances this effect: Rab32 recruits mitochondrial IRG1 to Salmonella-containing vacuoles, enabling localized itaconate delivery, while TFEB promotes IRG1 expression and Rab32-BLOC3-dependent lysosomal biogenesis, amplifying bactericidal activity.40,92,138At the metabolic level, itaconate further disrupts bacterial growth through S-itaconation of enzymes involved in de novo purine biosynthesis (e.g., PurF, GuaA/B/C), thereby limiting nucleotide production and imposing additional metabolic stress.139 In parallel, transmembrane transport contributes to systemic antimicrobial coordination. The efflux transporter ABCG2 regulates intracellular itaconate levels in macrophages; its loss enhances TFEB-dependent lysosomal biogenesis and bactericidal capacity.55 Conversely, hepatocytes import extracellular itaconate via SLC13A3, activating TFEB and reinforcing hepatic innate immunity.43Beyond direct antimicrobial activity, itaconate modulates host responses by promoting the pentose phosphate pathway, enhancing NADPH oxidase-dependent ROS production, and inducing the anti-inflammatory regulator A20, thereby suppressing IL-6, IL-1β, and TNF-α while preserving effective bacterial clearance.140On the pathogen side, Salmonella has evolved strategies to withstand host itaconate pressure. By inhibiting the glyoxylate shunt enzyme isocitrate lyase, itaconate disrupts bacterial energy and carbon utilization and functions as a key macrophage-derived metabolic weapon; acidic phagosomal conditions further potentiate this effect. However, Salmonella carries an itaconate-degradation operon under the control of the adjacent regulator RipR, enabling metabolic adaptation.141 Structural and biochemical studies indicate that isocitrate is the native ligand of RipR, while small molecules such as 3-phenylpropionate competitively bind RipR and weaken its regulatory function, supporting bacterio-modulation as a potential anti-infective strategy.142,143In summary, the role of itaconate in Salmonella infection spans multiple layers: metabolic origin and organelle coordination, transmembrane transport and tissue adaptation, pathogen tolerance, and host resensitization.Legionella pneumophilaDuring Legionella infection, IFN-I/II signaling dominates the host response, remodels the proteome of the Legionella-containing vacuole (LCV), and induces mitochondrial IRG1 in macrophages, leading to itaconate production. Notably, IRG1-expressing mitochondria closely associate with LCVs, enabling localized delivery of itaconate into the vacuolar niche, where it directly exerts bactericidal activity against intravacuolar Legionella.144 Itaconate also displays broad antimicrobial activity against extracellular multidrug-resistant pathogens. Mechanistically, this effect is integrated within a redundant IFN-γ-induced defense network, including iNOS, CASP11, IRGM1/3, and NOX2, in which combined deficiencies—rather than single-gene loss—are required to impair bacterial restriction.145 These findings indicate that itaconate-mediated killing involves both localized targeting of intracellular bacteria and coordinated metabolic and immune effector functions.Coxiella burnetii (agent for Q fever)The ACOD1/IRG1-itaconate axis is crucial for defense against Q fever. ACOD1-deficient mice display increased bacterial burden, weight loss, and upregulation of inflammatory genes, whereas exogenous itaconate restores macrophage control and directly suppresses Coxiella burnetii growth.146 Notably, itaconate isomers have divergent effects in macrophages: only itaconate itself is bactericidal, while citraconate and mesaconate undermine host defense by inhibiting endogenous itaconate synthesis or uptake.147 These findings highlight isomer-specific metabolic regulation as a determinant of pathogen control.Brucella sppBrucellosis is a prevalent zoonotic disease in which alveolar macrophages serve as the primary early host cells. Transcriptomic analyses revealed a marked upregulation of ACOD1 within 24 hours post-infection, and Acod1-deficient mice exhibited substantially higher pulmonary bacterial burdens, underscoring the pivotal role of itaconate in pulmonary defense. In vitro, both DMI and itaconate inhibit Brucella growth in a dose-dependent manner by targeting isocitrate lyase.148 Moreover, MyD88 signaling enhances antimicrobial activity by promoting glycolysis and itaconate metabolism, enabling bacterial restriction even in the absence of IFN-γ, whereas MyD88 deficiency facilitates Brucella exploitation of host glucose metabolism. These findings highlight the central role of MyD88-dependent metabolic reprogramming and itaconate production in host resistance to Brucella infection.149Francisella tularensisIn host defense against this cytosolic pathogen, IFN-γ-induced itaconate inhibits mitochondrial complex II, attenuating mitochondrial activity and thereby restricting bacterial replication within the cytosol.150 This mechanism represents an indirect, metabolism-driven form of antimicrobial control that alters the host energy landscape rather than targeting the pathogen directly. Interestingly, Acod1-deficient mice are more susceptible to primary infection, but display enhanced T-cell-dependent protection upon secondary challenge with virulent F. tularensis, including elevated numbers and effector functions of both CD4⁺ and CD8⁺ T cells.151 These findings suggest that itaconate influences antigen-presenting cell metabolism and thereby shapes adaptive immune responses in the context of prior exposure rather than directly promoting vaccine-induced immunity.Extracellular bacteriaStaphylococcus aureus (S. aureus)S. aureus is a major human pathogen with a remarkable capacity to adapt to host immunity. The IRG1-itaconate axis shapes infection dynamics, immune evasion, and host defense at multiple levels.In airway infection, S. aureus elicits mitochondrial stress, induces IRG1, and drives robust itaconate production. Itaconate suppresses bacterial glycolysis, rerouting carbon toward exopolysaccharide (EPS) biosynthesis and promoting biofilm formation—an adaptive shift that favors antibiotic tolerance and chronicity, consistent with clinical isolates from chronic respiratory infection that exhibit high EPS and strong biofilm phenotypes.152 Under acidic phagolysosomal conditions, sublethal itaconate provokes oxidative, electrophilic, and acid stress and triggers extensive S-thiolation and S-itaconation, acting as an effective anti-MRSA agent.153 These findings indicate that itaconate functions both as a potent metabolic antimicrobial and as a driver of bacterial persistence.On the host side, dual effects are also evident. DMI induces trained immunity in mice, producing durable transcriptional and metabolic reprogramming that enhances resistance to S. aureus.154 Conversely, itaconate can transiently suppress bacterial energy metabolism and slow growth in vitro, conferring tolerance to aminoglycosides.155 In pulmonary infection, host-derived fumarate cooperates with itaconate to support bacterial adaptation via staphylococcal fumarate hydratase FumC; ΔfumC mutants are markedly attenuated in fumarate/itaconate-rich environments.156In immune cells, itaconate exhibits both protective and compromising effects. In neutrophils, S. aureus selectively induces IRG1 expression, suppressing glycolysis and oxidative bursts, which weakens bactericidal activity and facilitates immune evasion.157 Conversely, in cutaneous infection, local γδ T-cell-derived GM-CSF and hypoxic cues cooperatively drive macrophages toward an IRG1-dependent inflammatory metabolic program, enhancing bacterial clearance and establishing a memory-like secondary immune response.158Tissue-specific studies further underscore its therapeutic potential in S. aureus infection. In endophthalmitis, metabolomic and transcriptomic analyses revealed marked upregulation of IRG1 and itaconate following infection, which was validated in vitreous samples from patients. Irg1⁻/⁻ mice show exacerbated pathology, whereas intravitreal administration of itaconate reduces inflammation and bacterial load, synergizes with antibiotics, and preserves retinal architecture and vision. Mechanistically, these protective effects depend on NRF2/HO-1 pathway activation and suppression of NLRP3 inflammasome signaling.159 Similarly, in intracerebral hemorrhage and peritonitis models, Irg1 deficiency impairs macrophage clearance of erythrocytes and S. aureus, whereas 4-OI activates Nrf2 by alkylating Keap1 and upregulating Cd36, thereby restoring phagocytosis and improving outcomes, indicating potential therapeutic value across infectious and sterile inflammatory contexts.83Collectively, itaconate occupies a central and bidirectional role in S. aureus infection. On the one hand, it functions as a metabolic weapon that enhances host defense via antimicrobial and immunoreprogramming effects; on the other hand, it fosters bacterial metabolic adaptation, antibiotic tolerance, and immune evasion within specific host cell niches. This complex immunometabolic interplay highlights itaconate as a promising yet double-edged target for antimicrobial and immunomodulatory therapy, necessitating careful evaluation of pathogen adaptation and resistance risks.Pseudomonas aeruginosa (PA)PA is a prototypical opportunistic pathogen that commonly causes chronic airway infections, with pathogenesis tightly intertwined with host immunometabolism.As a key host immunometabolite, itaconate acts at multiple levels in defense against PA. As an orthosteric agonist of OXGR1, itaconate stimulates OXGR1-dependent mucin secretion and mucociliary clearance, strengthening barrier defense.160 The IRG1-itaconate axis directly kills PA under acidic and ROS-rich conditions and contributes to monophosphoryl lipid A-induced innate immune training.161 Itaconate also synergizes with aminoglycosides such as tobramycin by enhancing biofilm penetration, thereby improving antibacterial efficacy.162 In atypical infection settings, loss of Acod1 compromises host defense; in diabetic mouse keratitis, reduced Acod1 expression exacerbates disease, whereas exogenous 4-OI ameliorates infection and inflammation, underscoring translational potential.163However, IRG1-itaconate-mediated antimicrobial and anti-inflammatory effects are not universally protective and may be co-opted to promote persistent colonization. PTEN, a tumor suppressor that complexes with CFTR, is deficient in cystic fibrosis. Combined PTEN-CFTR deficiency augments mitochondrial activity and drives excess succinate and ROS release, creating a niche favorable to succinate-preferring PA and inducing an IRG1-itaconate-dominated anti-inflammatory program. Despite extensive myeloid recruitment, bacterial clearance is inefficient, yielding a low-inflammation, high-burden microenvironment that fosters long-term colonization.164More complexly, PA can directly use host-derived itaconate as a carbon source, thereby promoting exopolysaccharide (EPS) production and biofilm formation while dampening host inflammation to establish chronic infection.165,166 In the lung, hepatically produced ketone bodies selectively support the survival of LPS-deficient strains that rely on fatty acid metabolism and oxidative phosphorylation; pulmonary PA further exploits host itaconate to stimulate ketogenesis, fostering host‒ coexistence.167 Itaconate also drives alginate synthesis and channels glutamine metabolism to suppress inflammasome activation and limit immunopathology, stabilizing a tolerant chronic state.168 At the population level, itaconate decreases acetylation of the small RNA-binding protein CspC, relieving repression of rsaL and activating quorum sensing (QS) and virulence gene expression.169 In parallel, PA counters itaconate pressure through an efficient degradation pathway; structural and functional studies of the key enzymes itaconyl-CoA hydratase and citramalyl-CoA lyase elucidate catalytic mechanisms that underlie metabolic adaptation and offer targets for intervention.66,67Taken together, the IRG1-itaconate axis in PA infection exemplifies a double-edged effect: a host defense metabolite that can be coopted to drive bacterial metabolic adaptation, QS activation, and maintenance of chronic tolerance. Therapeutic strategies targeting this axis should therefore account for pathogen metabolic plasticity and compensatory pathways.Other extracellular and opportunistic pathogensDuring Escherichia coli (E. coli) infection, itaconate exhibits stage-dependent regulatory effects within the host‒ interface. Early in infection, itaconate may transiently increase the intracellular bacterial burden but subsequently enhance macrophage phagocytic and bactericidal capacity by upregulating MARCKS, RhoB, and CDC42 and reshaping the cytokine milieu, ultimately limiting infection progression.170 In E. coli-induced endometritis, the protective effects of DMI depend on the gut microbiota, mediated by increased Muribaculaceae abundance, elevated guanosine levels, and activation of the CXCL14 axis.171 Clinically, treatment of urinary tract infections with the traditional Chinese medicine Polygonum bistorta root significantly elevates urinary itaconate, suggesting that its efficacy may stem from modulation of host immunometabolism.172In intestinal ecology and Vibrio-associated infections, itaconate broadly acts as a suppressive metabolite, regulating host metabolism and microbial homeostasis to prevent colonization while directly interfering with bacterial core carbon pathways to restrict growth and virulence. In murine models, intestinal bacterial infection induces hepatic transcriptional remodeling of the bile acid metabolome, accompanied by elevated itaconate, increased tuft cell abundance, and altered microbiota composition that together inhibit Vibrio cholerae colonization.173 In marine pathogenic Vibrio sp. DO1, itaconate disrupts the glyoxylate shunt and central carbon metabolism, forcing metabolic rerouting and suppressing bacterial proliferation.174 In Hirschsprung-associated enterocolitis, Veillonella parvula activates macrophages via LPS-TLR4 signaling, triggering barrier breakdown and dysbiosis; itaconate effectively blocks this pathway, highlighting its therapeutic potential in microbiota imbalance-driven inflammation.175In hypervirulent Klebsiella pneumoniae (hvKP) infection, itaconate primarily mitigates immune pathology. hvKP activates the IRG1-itaconate axis via SYK rather than STING signaling, while exogenous itaconate alkylates and inhibits the critical Lys593 residue of SYK, suppressing excessive M1 macrophage activation and cell death. This alleviates intestinal inflammation, restores microbiota balance, and markedly reduces mortality.176Collectively, in infections caused by E. coli, Vibrio, and Klebsiella, itaconate exerts both anti-infective and immunoregulatory effects by enhancing phagocytosis and maintaining microbiota homeostasis while simultaneously reducing excessive inflammation. These coordinated actions highlight its pivotal role and translational potential in host‒ metabolic interactions.Viral infectionsIn viral infection, the IRG1-itaconate axis exerts bidirectional control. On the one hand, it reshapes cellular metabolism, activates Nrf2-dependent antioxidant defenses, and suppresses NF-κB and NLRP3 inflammasome signaling, thereby limiting viral replication, dampening inflammation, and preserving tissue homeostasis. On the other hand, some viruses co-opt this pathway or exploit its anti-inflammatory tone to promote immune suppression and persistence. Itaconate can also modify viral or host proteins and perturb bioenergetics and redox balance to achieve antiviral effects, yet excessive activation may provoke metabolic dysregulation and tissue injury. Thus, the axis functions as both an immunometabolic barrier and a potential point of vulnerability, with net effects dictated by viral species, stage of infection, and host immune context (Fig. 3a, b).Influenza A virus (IAV)Among viral models, IAV is the best studied. Monocytes and macrophages are major targets and sources of itaconate during infection. Acod1-deficient mice display aggravated lung inflammation and body weight loss, whereas treatment with exogenous DMI or 4-OI alleviates inflammation by limiting ROS production, inhibiting STAT1 phosphorylation, and downregulating IFN signaling and chemotactic pathways without increasing viral load. Notably, 4-OI directly suppresses viral transcription and replication in peripheral blood mononuclear cells and A549 cells.177 Mechanistically, 4-OI covalently modifies CRM1 at Cys528 to block nuclear export of viral RNPs,89 and synthetic itaconate derivatives directly target influenza nucleoprotein to inhibit its function.178 The natural isomers mesaconate and citraconate also show anti-inflammatory and antiviral activity; citraconate is both a potent NRF2 activator and a natural ACOD1 inhibitor, offering additional levers for host-directed metabolic modulation.59Respiratory syncytial virus (RSV)During RSV infection, treatment with quercetin elevates IRG1-itaconate, inhibits SDH, downregulates the HIF-1α/NLRP3 axis, and promotes M2 polarization, thereby alleviating lung inflammation.48In SARS-CoV-2/COVID-19, itaconate derivatives also show therapeutic promise. 4-OI and DMF suppress Ifnb1 expression and block type I IFN-caspase-11-mediated macrophage pyroptosis, reducing tissue factor release, limiting immunothrombosis, and lowering mortality.179 Urine proteomics indicate CLYBL upregulation in patients, favoring conversion of itaconate to acetyl-CoA and potentially depleting anti-inflammatory itaconate, suggesting supplementation of itaconate or inhibition of CLYBL as therapeutic strategies.180 Metabolomics further shows that itaconic acid combined with LYM, IL-6, PCT, and CRP predicts early mortality in older severe COVID-19 cases with high accuracy, highlighting both therapeutic and prognostic utility.181Neurotropic virusesIn neurotropic infection, itaconate also plays distinctive roles. During Zika virus (ZIKV) infection of neurons, ZBP1-RIPK1/3 signaling induces IRG1 and itaconate, suppressing SDH and creating a metabolic state unfavorable for viral genome replication.182 In models of HIV-associated neurocognitive disorders, particularly with cocaine exposure, 4-OI remodels microglial morphology, attenuates inflammation, and activates NRF2-driven transcription, indicating neuroprotective and anti-inflammatory potential.183Viral exploitation of itaconate and its derivativesAlthough itaconate generally benefits the host during viral infection, it can be co-opted under specific conditions. In RSV infection, IRG1 induction and the resulting accumulation of itaconate have been reported to enhance ROS production, promote inflammatory cell infiltration, and aggravate lung injury. In contrast, quercetin-induced activation of the IRG1-itaconate pathway suppresses the SDH-HIF-1α-NLRP3 signaling cascade, facilitates M2 macrophage polarization, and alleviates inflammation.48,184 These divergent outcomes suggest dependence on cell type, timing, and signal strength. During VSV and IAV infection, neutrophil-derived itaconate alkylates key cysteines on the Rab GDP-dissociation inhibitor GDI2 (Cys203, Cys335, Cys414), blocking recycling of Rab GTPases from membranes to the cytosol, which enhances membrane retention of Rabs and facilitates viral trafficking and replication.81 Viruses may also suppress the demethylase ALKBH5 to increase m6A modification of OGDH mRNA, lowering OGDH and itaconate levels and reshaping metabolism to favor replication.185 Even in the absence of a specific virus, 4-OI reduces poly(I:C)-induced IFN-β expression partly via NRF2, underscoring the inherent tension between its anti-inflammatory and antiviral effects.186Fungal, parasitic, and mycoplasma infectionsIn fungal, parasitic, and mycoplasma infections, the IRG1-itaconate axis exerts a characteristic dual effect (Fig. 3a, b). On the one hand, it enhances host defense and tissue protection through metabolic reprogramming, redox regulation, and anti-inflammatory signaling. On the other hand, certain pathogens, such as Leishmania and Mycoplasma pneumoniae, can exploit or subvert this pathway to promote immune tolerance, persistence, or impaired antimicrobial responses.Fungal infectionsIn fungal infections, itaconate-related responses are generally protective but largely driven by derivative-based evidence. In Aspergillus keratitis, DMI reduces fungal burden and inflammation while activating NRF2 signaling and limiting neutrophil infiltration.187 Metabolomic analyses further show that fungal stimulation reshapes dendritic cell metabolism, reducing citrate, itaconate, and α-ketoglutarate while increasing succinate and lactate, with cytokine production linked to pyruvate dehydrogenase activity.188 These findings suggest that itaconate participates in infection-associated metabolic remodeling, although direct antifungal mechanisms remain incompletely defined.Parasitic infectionsIn parasitic infections, the role of itaconate varies across pathogens and disease stages. In Toxoplasma gondii infection, disruption of ACOD1-itaconate signaling is associated with metabolic imbalance and neuroinflammation, while DMI restores synaptic function and reduces inflammation.189,190 In helminth infection, itaconate inhibits Schistosoma japonicum egg hatching via ROS-dependent mechanisms.140 However, in malaria, the effects vary by disease stage: protective in mild infection but detrimental in severe forms, where IFN-γ-driven metabolic remodeling impairs mitochondrial function, triggers mtDNA release, activates STING-IRF3/7 signaling, and upregulates PD-L1, suppressing CD8⁺ T-cell activity and exacerbating parasitemia.191,192 In Leishmania infection, early Acod1 induction promotes lipid metabolism and M2 polarization, creating a permissive niche for parasite persistence.193Mycoplasma infectionsIn Mycoplasma pneumoniae infection, itaconate is associated with impaired host defense. Neutrophils serve as a major source, and Irg1 deficiency reduces bacterial burden and inflammation. Mechanistically, itaconate suppresses mitochondrial ROS production, weakening neutrophil bactericidal function. Clinically, serum itaconate correlates with neutrophil counts, supporting its role in disease progression rather than protection.194SummaryTaken together, across viral, fungal, parasitic, and mycoplasma infections, the IRG1-itaconate axis functions as a context-dependent immunometabolic regulator that can be broadly conceptualized into two outcome-oriented categories: protective effects that restrict pathogen replication and limit immunopathology and pathogenic (or exploited) effects that promote immune suppression, persistence, or tissue injury (Fig. 3a, b). Importantly, these categories are not mutually exclusive, and certain pathogens, such as RSV and IAV, exhibit dual roles depending on the stage of infection and host immune context.Overall, the IRG1-itaconate axis acts as a double-edged sword in infectious inflammation. On the one hand, it directly inhibits pathogen metabolism, activates anti-inflammatory and antioxidant pathways, and modulates inflammasome activity and cell death to preserve host defense and tissue integrity. On the other hand, diverse pathogens can adapt by degrading, evading, or exploiting itaconate, and excessive host accumulation may exacerbate inflammation or induce immune tolerance. This dynamic equilibrium underscores the context-dependent nature of its function.Future research should focus on pathogen-specific and immune-state-dependent mechanisms, exploring precision modulation of the IRG1-itaconate axis through small-molecule derivatives (e.g., DMI, 4-OI), metabolic reprogramming, and integrated epigenetic–immune interventions to advance host-directed therapies for infection and inflammation.Itaconate in noninfectious inflammatory diseasesThe progression of noninfectious inflammatory diseases generally follows a continuum from metabolic stress and inflammatory amplification to cellular injury and tissue remodeling. As an immunometabolic regulator, itaconate and its biosynthetic enzyme ACOD1/IRG1 have emerged as important modulators across this pathological axis. Under inflammatory conditions, IRG1 induction and itaconate production are closely associated with broad changes in cellular metabolism, inflammatory responses, and tissue adaptation.Rather than acting through a single pathway, the effects of itaconate span multiple levels of regulation, ultimately influencing cell fate and disease progression across diverse pathological contexts (Fig. 4, Supplementary Table 2). This integrative framework highlights the central role of the IRG1-itaconate axis in linking metabolic adaptation to inflammatory outcomes and supports its potential as a therapeutic target.Fig. 4Full size imageBroad regulatory effects of the IRG1-itaconate axis in noninfectious inflammatory diseases. This schematic summarizes the disease spectrum in which itaconate and its commonly used cell-permeable derivatives, 4-OI and DMI, have been implicated as immunometabolic regulators. The central region highlights itaconate, 4-OI and DMI as modulators of noninfectious inflammation. The inner ring organizes the field into six major pathological modules: metabolism-associated inflammation, toxic and mechanical injury, ischemia-reperfusion injury, degenerative disorders, fibrosis, and skin, ovarian and periodontal diseases. The outer ring lists representative conditions within these modules, including obesity, insulin resistance and diabetes, metabolic liver disease, atherosclerosis, hematoinflammation, neurotoxicity, lung injury, digestive injury, bone and connective tissue injury, ischemia-reperfusion injury of the CNS, heart, liver, kidney and lung, neurodegeneration, osteoarticular degeneration, pulmonary, hepatic and renal fibrosis, skin diseases, ovarian diseases and periodontitis. Created with BioRender.comMetabolism-associated inflammationObesity, insulin resistance, fatty liver disease, and atherosclerosis share common pathophysiological features characterized by low-grade chronic inflammation and disrupted energy metabolism. Targeting both the metabolic and inflammatory axes may, in theory, enable disease reversal (Fig. 5).Fig. 5Full size imageThe IRG1-itaconate axis in metabolism-associated inflammatory diseases. This figure depicts the roles of the IRG1-itaconate axis and its derivatives across major metabolism-associated conditions, including obesity and insulin resistance/diabetes (a), metabolic liver disease (b), atherosclerosis and vascular inflammation (c), and hematopoietic inflammation (d). Created with BioRender.comHigh-fat diet, obesity, insulin resistance, and diabetesUnder conditions of obesity and a high-fat diet, the Acod1-itaconate axis functions as a key endogenous regulator of glucose and lipid homeostasis. Acod1-deficient mice exhibit aggravated glucose intolerance and insulin resistance without changes in body weight, accompanied by enhanced inflammatory signaling and impaired lipid metabolism, with long-term studies showing earlier metabolic dysfunction.195Metabolomic analyses further identified TCA-derived metabolites, including itaconate, citraconate, and mesaconate, as microbiota-regulated mediators of metabolic homeostasis. These metabolites enhance insulin signaling, promote fatty acid oxidation, and suppress lipogenesis and gluconeogenesis, thereby improving insulin resistance, hepatic steatosis, and mitochondrial dysfunction in vivo. Notably, plasma citraconate levels negatively correlate with fasting glucose in humans, supporting translational relevance.196Exogenous itaconate supplementation exerts robust anti-obesity and metabolic benefits. In diet-induced obesity models, itaconate significantly limits weight gain, ameliorates hyperlipidemia, and improves glucose tolerance independently of leptin signaling while enhancing energy expenditure and thermogenesis in brown adipose tissue. Proteomic analyses reveal metabolic reprogramming from anabolic to oxidative states in liver and adipose tissue through upregulation of β-oxidation proteins and downregulation of lipogenic pathways, underscoring its therapeutic promise against obesity.197 Classical biochemical studies further demonstrate that itaconate, as a phosphoenolpyruvate analog, inhibits fructose-6-phosphate-2-kinase (F6P2K), thereby reducing fructose-2,6-bisphosphate (F26BP) levels, suppressing glycolysis and lipogenesis, and preventing visceral fat accumulation.198The protective effects of itaconate extend beyond peripheral metabolism to the central nervous system. In palmitate-induced lipotoxicity models, the cell-permeable derivative DMI restores insulin signaling markers such as IRS-1 and Akt phosphorylation and attenuates inflammatory responses mediated by NFκB and IκB. Mechanistically, DMI enhances AMPK phosphorylation and upregulates PPARδ and the myokine FGF21, thereby alleviating insulin resistance in skeletal muscle.199 Similar mechanisms operate in obesity-related pulmonary vascular pathology, where ACOD1 expression is suppressed in pulmonary microvascular endothelial cells. Overexpression of ACOD1 or treatment with 4-OI mitigates free-fatty-acid-induced inflammation and mitochondrial oxidative stress via Nrf2 activation, while Nrf2 silencing abolishes this protection, establishing the ACOD1/itaconate-Nrf2 axis as a systemic defense mechanism maintaining metabolic and organ homeostasis.200Short-term high-fat feeding rapidly induces microglial metabolic reprogramming, channeling fatty acid carbon flux toward protective metabolites such as itaconate, thereby improving metabolic and cognitive outcomes.201 Systemic administration of DMI also restores synaptic ultrastructure, suppresses microglial activation and neuroinflammation, and remodels the gut barrier and microbiota, reversing diet-induced cognitive impairment through a potential gut-brain axis mechanism.202Overall, ACOD1, itaconate, and their derivatives act as both endogenous regulators of metabolic homeostasis and potential therapeutic targets for obesity and its complications. They exert multilayered effects across the continuum of energy metabolism reprogramming, insulin signaling improvement, and peripheral and central organ protection. Interestingly, some studies suggest that their actions are not unidirectional. Under high-fat diet conditions, ACOD1 can promote gut microbiota dysbiosis, thereby aggravating obesity and metabolic disturbances. Oral administration of exogenous itaconate has been reported to exacerbate microbial imbalance and the obese phenotype, indicating a complex bidirectional interaction between the gut and metabolic systems.203In diabetes, pancreatic β-cells are highly susceptible to oxidative stress, leading to accelerated functional decline. The itaconate derivative 4-OI alleviates hypoxia-induced β-cell injury by inhibiting LDHA activity and reducing ROS generation.74 In type 1 diabetes models, 4-OI significantly attenuates insulitis, restricts macrophage M1 polarization, and suppresses MAPK signaling, resulting in improved glycemic control and restored β-cell function. In human PBMCs, 4-OI similarly suppresses LPS-induced IL-1β production.204In diabetic nephropathy, loss of IRG1 markedly worsens tubular injury and renal dysfunction. Exogenous 4-OI activates the Nrf2-PGC1α pathway, enhances mitochondrial biogenesis, and mitigates oxidative stress, tubular damage, and fibrosis.205 Moreover, 4-OI inhibits TGF-β production in a dose-dependent manner, preventing hyperglycemia- and TGF-β-induced renal fibrosis by limiting excessive ROS generation.206 In high glucose-exposed HUVECs, 4-OI functions as an Nrf2 activator by disrupting Keap1-Nrf2 binding, promoting Nrf2 accumulation and nuclear translocation, and inducing Nrf2-ARE-dependent genes such as HO-1, NQO1, and GCLM. These effects reduce ROS levels and protect against high glucose-induced cell death, apoptosis, lipid peroxidation, and mitochondrial depolarization.207 Collectively, these findings highlight the therapeutic potential of itaconate in modulating inflammation and oxidative stress throughout the course of diabetes (Fig. 5a).Metabolism-associated liver diseaseUnder metabolic stress, such as nutrient deprivation or fasting, hepatic itaconate increases and enhances glucagon-driven gluconeogenesis. This effect depends on NRF2 and is independent of insulin and CREB.208 In chronic settings, including obesity-related fatty liver and MASH, the IRG1-itaconate pathway is suppressed or imbalanced, which amplifies oxidative stress and inflammation. In patients and mouse models of MASH, β-arrestin 2 is upregulated in hepatic macrophages and monocytes. Promoting IRG1 ubiquitination reduces itaconate production, leading to excessive SDH activity, increased mitochondrial ROS, M1 polarization, and disease exacerbation. Deletion of β-arrestin 2 restores itaconate and alleviates MASH progression.44Similarly, in obesity-related metabolic dysfunction-associated steatotic liver disease (MASLD) models, IRG1 expression is reduced, and genetic loss further aggravates obesity, dyslipidemia, insulin resistance, and liver injury. Mechanistically, itaconate activates NRF2 and prevents oxidative stress-mediated inhibition of AKT. The derivative 4-OI improves steatosis and oxidative stress in these models.209In human MASH and mouse MASLD, elevated hepatic itaconate suggests an early compensatory response. Male mice lacking Irg1 show greater hepatic lipid accumulation and glucose intolerance, whereas exogenous 4-OI reduces hepatocellular lipid storage by promoting fatty acid oxidation and oxidative phosphorylation, supporting a model in which macrophage-derived itaconate cross-regulates hepatocyte lipid metabolism.210 Plant-derived small molecules exhibit similar actions. The tanshinone component dihydrotanshinone I improves diet-induced MASLD by activating IRG1-itaconate, enhancing NRF2 antioxidant signaling, and suppressing NLRP3 inflammasome activation. This reduces hepatic inflammation, oxidative stress, and fibrosis, and the effect is lost with IRG1 deficiency, indicating a central role for the itaconate pathway.49Collectively, itaconate and its derivatives confer multiple benefits in metabolism-associated liver disease (Fig. 5b). They reinforce gluconeogenesis during fasting-related stress, and in obesity and MASLD, they exert antioxidant and anti-inflammatory effects through NRF2 and fatty acid oxidation pathways. Downregulation of this axis is associated with disease worsening, whereas exogenous 4-OI or activators such as dihydrotanshinone I partially restore hepatic homeostasis, positioning the IRG1-itaconate pathway as a promising therapeutic target.Atherosclerosis and vascular inflammationAtherosclerosis is driven by lipid-induced chronic inflammation. Single-cell analyses and histology show that IRG1 and itaconate are upregulated in human and mouse plaques, primarily in monocytes, macrophages, and neutrophils. In experimental settings, these findings are largely derived from hypercholesterolemia-driven models, including Ldlr⁻/⁻ mice fed a Western diet and PCSK9-AAV-induced atherosclerosis models.211,212 Irg1 deficiency increases plaque burden, lipid deposition, and IL-1β, with enhanced lipid accumulation, neutrophil extracellular trap formation, and hyperactivation of the NLRP3 inflammasome. In contrast, 4-OI remodels advanced plaques and attenuates inflammation, indicating therapeutic potential.211 In a complementary study, myeloid-specific deletion of Acod1 aggravated plaque inflammation and increased aortic M1 macrophages, while ACOD1 expression in human lesions inversely correlated with luminal obstruction, supporting a protective role. Mechanistically, itaconate restrains oxidized lipid-driven macrophage activation via an Nrf2-dependent anti-inflammatory program, thereby limiting lesion formation.212The impact of ACOD1 is model- and sex dependent. In Ldlr knockout mice, Acod1 loss did not change the overall plaque area but increased body weight and plasma cholesterol in males. In Apoe knockout mice, female Acod1 knockout animals had reduced plaque in the aortic arch.213 These differences may reflect sex-dependent variability in metabolic and inflammatory responses, although the underlying mechanisms remain incompletely defined. In addition, some studies predominantly used male mice or did not systematically compare both sexes, which may further contribute to variability across findings. Single-cell profiling of human carotid plaques found that low ACOD1 expression was restricted to rare macrophages, suggesting context specificity in humans. Adding further complexity, transplantation of Acod1-deficient bone marrow into Ldlr knockout recipients yielded plaques with smaller necrotic cores that were nonetheless enriched for monocyte recruitment, macrophage lipid loading, and metabolic reprogramming toward purine and glycerol pathways, raising the possibility that ACOD1 inhibition can promote plaque stability in select settings.214 Thus, the IRG1-itaconate axis in atherosclerosis likely diverges by sex, genetic background, and lesion milieu.In abdominal aortic aneurysm, the protective role of IRG1 and itaconate is more consistent. Irg1 deficiency worsens angiotensin II-induced aneurysm formation, whereas exogenous itaconate suppresses disease by alkylating Keap1, activating Nrf2, and transcriptionally repressing inflammatory genes.215 Macrophage scavenger receptor scavenger receptor A1 (SR-A1) sustains IRG1 transcription through Lyn and STAT3, maintaining itaconate levels. Loss of SR-A1 exacerbates inflammation and aneurysm, while bone marrow reconstitution with SR-A1 competent cells or treatment with 4-OI ameliorates disease, defining a protective SR-A1-STAT3-IRG1 pathway.39During endothelial activation, the proinflammatory lipid lysophosphatidylcholine triggers an acute response via mitochondrial reactive oxygen species. The anti-inflammatory cytokines IL-35 and IL-10 blunt mtROS and reverse cytokine and adhesion molecule induction but do not engage the itaconate pathway, suggesting a limited role in this context.216 In contrast, 4-OI is effective in vascular calcification. It suppresses osteogenic differentiation of vascular smooth muscle cells and aortic ring calcification by inducing HMOX-1 and dampening inflammation and oxidative stress. Knockdown or pharmacologic inhibition of HMOX-1 abrogates these effects, identifying HMOX-1 as a key mediator.217Overall, the role of IRG1 and itaconate in vascular pathology is context dependent and disease specific (Fig. 5c). In atherosclerosis, most evidence supports anti-inflammatory protection through Nrf2, although opposing outcomes emerge with differences in genotype and sex. In abdominal aortic aneurysms, the protective effects are consistent. In vascular calcification, 4-OI shows anti-inflammatory and anti-calcific activity. Taken together, itaconate functions as an immunometabolic hub that confers multidimensional protection during vascular inflammation and remodeling, while its dual roles in complex atherosclerotic lesions underscore the need to account for individual variation and disease stage in translational strategies.Inflammatory diseases of the hematopoietic systemItaconate also exhibits distinct functions in hematopoiesis (Fig. 5d). Under inflammatory conditions, itaconate is highly expressed in the hematopoietic niche and can be secreted by central macrophages of erythroblastic islands to erythroid progenitors. It competitively inhibits ALAS2 and blocks the synthesis of heme and protoporphyrin IX, thereby suppressing erythropoiesis and hemoglobinization and ultimately promoting anemia of chronic inflammation. These findings reveal that beyond iron restriction, itaconate directly impairs hemoglobin synthesis through ALAS2 inhibition.218,219SummaryCollectively, the IRG1-itaconate axis functions far beyond classic immunometabolic regulation. Across diverse organs and pathological contexts, itaconate can limit necroptotic cell death, recalibrate systemic metabolism, influence hematopoietic differentiation, and alleviate neuroinflammation, thereby representing a promising therapeutic target in inflammation-related diseases.Itaconate in toxic and mechanical injuryToxic injuries caused by drugs, oxides, and chemicals, as well as mechanical insults such as trauma, stretch, or ventilation, amplify oxidative stress and inflammation. As a stress-inducible immunometabolic node, the IRG1/itaconate axis activates NRF2, suppresses the NLRP3 inflammasome and several programmed cell death pathways, including ferroptosis, necroptosis, and pyroptosis, and in certain contexts enhances TFEB-mediated autophagy and mitochondrial quality control. These coordinated effects achieve anti-inflammatory, antioxidant, cytoprotective, and reparative outcomes (Fig. 6).Fig. 6Full size imageProtective mechanisms of the IRG1-itaconate axis in toxic and mechanical injuries. This schematic shows the roles of the IRG1-itaconate axis and its derivatives across diverse toxic and mechanical injury contexts, including neurotoxicity (a), lung injury (b), liver injury (c), pancreatic injury (d), intestinal injury (e), and bone and connective tissue injury or wound healing (f). Created with BioRender.comNeurotoxicity and neurotraumaIn neurotoxic injury, itaconate exerts neuroprotective effects (Fig. 6a). Corticosterone induces hippocampal neuronal inflammation and necroptosis, whereas itaconate upregulates Menin, decreases pRIP1, pRIP3, pMLKL, and inflammatory mediators, and restores neuronal viability.220In traumatic brain injury, microglial Irg1 expression is elevated, but endogenous itaconate decreases, aggravating metabolic disturbance and inflammation. Treatment with 4-OI reprograms glucose, glutamine, and fatty acid oxidation, reduces proinflammatory activation and neurodegeneration, and improves long-term neurological function.221In spinal cord injury, Irg1 overexpression or treatment with itaconate derivatives mitigates microglial inflammation and promotes motor recovery.222 ACOD1 also interacts with phosphorylated p62 to enhance NRF2, forming an ACOD1 p62 NRF2 positive feedback loop. Loss of ACOD1 exacerbates inflammation and motor dysfunction, whereas exogenous or endogenous itaconate, including 4-OI, reduces p62 phosphorylation, indicating that ACOD1 also possesses itaconate-independent neuroprotective activity.223In traumatic optic neuropathy, IRG1 and its product itaconate suppress microglial overactivation, preserve retinal ganglion cell survival, and improve visual function.224 In febrile seizure models, DMI increases the seizure threshold, improves cognition and motor performance, and attenuates oxidative stress.225In sensory injury and pain, 4-OI prevents cisplatin-induced ototoxic ferroptosis via the NRF2/HO-1/SLC7A11/GPX4 axis and protects cochlear hair cells.226 In inflammatory pain models, dimethyl or diethyl itaconate alleviates hyperalgesia by suppressing spinal c-fos or inhibiting the NLRP3 IL-1β signaling pathway, supporting its potential in pain management.227,228Following nerve injury, 4-OI upregulates IL-10 and activates the STAT3 and beta-endorphin pathways to relieve neuropathic pain.229 Diethyl itaconate enhances Nrf2 expression in dorsal root ganglia and spinal cord, inhibits ERK1 and ERK2 phosphorylation and proinflammatory cytokines, and produces sustained analgesia.230 It also reduces NGFI-A, NGFI-B, IL-1β, TNF-α, and IL-6 while increasing IL-10 in the spinal cord.231Regarding glial trophic function, diethyl itaconate restores astrocytic NGF, BDNF, and GDNF and their receptors under inflammatory stress, protecting astrocytes from injury.232 Combined treatment with itaconate and mesaconate attenuates microglial reactivity and rescues synaptic plasticity.233Respiratory toxicity and mechanical injuryIn pulmonary injury, itaconate shows protective activity (Fig. 6b). In ventilator-induced lung injury, 4-OI activates Nrf2 and HO-1, suppresses the NLRP3 inflammasome, lowers reactive oxygen species and lipid peroxidation, and mitigates tissue damage.234 In a hyperoxia model of bronchopulmonary dysplasia, itaconate promoted TFEB nuclear translocation, enhanced autophagic flux, cleared mitochondrial injury, reduced apoptosis of type II alveolar cells, and improved lung development.235 The systemic toxicology of cigarette smoke places itaconate within an immune oxidative stress network, supporting a modulatory role in pulmonary toxic responses.236Gastrointestinal toxicity and mechanical injuryIn acute hepatic injury (Figs. 6c), 4-OI stabilizes SLC7A11 via OTUB1-mediated deubiquitination, restores glutathione synthesis, and activates Nrf2 to coordinately increase proteins governing glutathione metabolism and iron homeostasis, including GPX4, FTH1, FTL1, and FPN1. These changes suppress ferroptosis and protect against acetaminophen hepatotoxicity.237 Additional studies have shown that 4-OI activates the AKT/ERK/Nrf2/Sirt3 pathway to attenuate oxidative injury in L02 and HepG2 cells and to reduce acetaminophen-induced liver damage in mice.238 In carbon tetrachloride injury, protection depends on NRF2 and involves reduced oxidative stress, inhibition of HMGB1/NF-kB signaling, and diminished inflammatory infiltration.239In acute pancreatitis (Fig. 6d), itaconate derivatives directly modulate cell death pathways. Dimethyl itaconate dose-dependently inhibits RIPK1/RIPK3/MLKL-mediated necroptosis, promotes Nrf2 nuclear translocation, decreases reactive oxygen species and mitochondrial oxidative stress, and lessens caerulein-induced disease in mice.240 Similarly, 4-OI limits lipid peroxidation and ferroptosis, alleviating pancreatitis and associated lung injury induced by caerulein and LPS.241In intestinal injury (Fig. 6e), itaconate counters perfluorooctanoic acid-induced oxidative stress and barrier disruption by lowering Keap1, activating the NRF2/HO-1 axis, restoring tight junctions and the mucus barrier, and reshaping the microbiota with enrichment of Lactobacillus and reduction of pathobionts.242 Metabolomics in premature infants suggests that enteral feeding elevates metabolites, including itaconic acid, which may hold diagnostic value for necrotizing enterocolitis, although this association is correlative and may reflect transient protective upregulation.243 More recent data show that itaconate is reduced in necrotizing enterocolitis samples, correlating with increased proinflammatory macrophages, while 4-OI corrects mitochondrial metabolism, limits M1 polarization, and markedly improves disease in mice.244 Mechanistically, itaconate engages the TFEB autophagy lysosome axis to mitigate pathology.42Bone and connective tissue toxicity or mechanical injuryIn bone and connective tissue injury as well as wound healing (Figs. 6f), 4-OI provides multilayered protection centered on NRF2 activation. In osteoblasts, it disrupts the Keap1-Nrf2 complex and promotes Nrf2 nuclear translocation, inducing HO-1, NQO1, and GCLC expression. This prevents mitochondrial depolarization and the formation of the cyclophilin D-ANT1-p53 complex, thereby suppressing apoptosis and necrosis.245In a postextraction alveolar bone loss model, 4-OI activates NRF2, inhibits RANKL-driven osteoclastogenesis, reduces inflammatory infiltration, and promotes bone regeneration.246 During tendon injury, metabolomic and single-cell analyses identify mature neutrophils as the primary endogenous source of itaconate. These cells release itaconate at high levels at injury sites and recirculate to the bone marrow, influencing hematopoiesis and local fibrosis. Exogenous itaconate further suppresses inflammation and enhances tenogenic differentiation and tissue repair.247In chronic wounds, 4-OI inhibits p38 MAPK, downregulates TNF-α and COX-2, reduces collagen uptake, and activates NRF2, promoting macrophage polarization toward an anti-inflammatory reparative phenotype and optimizing extracellular matrix remodeling.248 In diabetic patients with iatrogenic laryngotracheal stenosis, scar fibroblasts display elevated itaconate and CD90 expression, suggesting that metabolic reprogramming contributes to fibrotic phenotypes.249SummaryOverall, the IRG1/itaconate axis broadly confers antioxidative, anti-inflammatory, anti-cell-death (apoptosis, pyroptosis, and ferroptosis), and pro-repair effects in toxic and mechanical injuries. Across the nervous, respiratory, digestive, skeletal, and connective systems, itaconate consistently demonstrates multitarget protective activity. These findings suggest that itaconate functions not only as a metabolic stress buffer but also as an emerging therapeutic molecule for managing toxic and mechanical tissue injury.Itaconate in ischemia and reperfusion injuryIschemic and hemorrhagic injury and ischemia‒reperfusion injury are major drivers of multisystem organ damage characterized by intertwined oxidative stress, inflammatory amplification, cell death, and tissue repair. IRG1 and its metabolite itaconate act as central regulators in these noninfectious inflammatory settings. By inhibiting succinate dehydrogenase, buffering redox stress, modulating ferroptosis and necroptosis, and activating pathways such as Nrf2/HO-1 and PINK1/Parkin mitophagy, they improve outcomes in intracerebral hemorrhage, cerebral ischemia, myocardial infarction, hepatic and renal ischemia‒reperfusion, lung transplantation injury, and peripheral limb ischemia. Tissue context shapes responsiveness to itaconate, and in select settings, proinflammatory or antiangiogenic effects have been observed, underscoring context dependence. System-level synthesis across the brain, cardiovascular system, liver and kidney, lung, and soft tissues clarifies metabolic mechanisms of sterile inflammation and informs targeted interventions (Fig. 7).Fig. 7Full size imageProtective mechanisms of the IRG1-itaconate axis in ischemia‒reperfusion injury across multiple organs. This figure provides a system-level overview of the roles of the IRG1-itaconate axis and its derivatives across ischemic, hemorrhagic, and ischemia‒reperfusion injuries in multiple organs, including the central nervous system (a), heart (b), liver and kidney (c), lung (d), and peripheral limb and soft tissues (e). Created with BioRender.comCentral nervous system ischemic and hemorrhagic injuryMicroglia are resident macrophages with neuroprotective or neurotoxic phenotypes. During early inflammation, microglia can shift from a mildly reactive state associated with complex II inhibition and itaconate to a nitric oxide-driven complex IV inhibition state with oxidative stress. Itaconate restrains this transition and confers neuroprotection.250In intracerebral hemorrhage, IRG1 deficiency impairs macrophage and microglial erythrophagocytosis, delays hematoma clearance, and worsens outcomes, whereas exogenous itaconate or 4-OI alkylates Keap1 Cys155, promotes Nrf2 nuclear translocation, and activates CD36-dependent phagocytosis, improving hemorrhage and peritonitis models.83 Itaconate can also alkylate Keap1 at Cys151 to release Nrf2 inhibition upstream96 and alkylate GPX4 at Cys66 to enhance GPX4 activity downstream, thereby limiting neuronal ferroptosis and providing potent neuroprotection after hemorrhage.82In subarachnoid hemorrhage, the IRG1/itaconate axis activates PINK1/Parkin-mediated mitophagy, suppresses neuronal ferroptosis, and attenuates early brain injury.251 In ischemic stroke and cerebral ischemia‒reperfusion, IRG1 is strongly induced. Loss of IRG1 enlarges infarcts and disrupts the blood brain barrier, whereas DMI restores HO-1 expression and improves motor function and survival.252 Exogenous itaconate limits SDH activity and redox stress, improves hemodynamics, and reduces leukocyte adhesion and neuronal injury in rat and mouse models.253 Dimethyl itaconate also mitigates neurological deficits and inflammation in transient middle cerebral artery occlusion.254 In neonatal hypoxic ischemic encephalopathy, 4-OI suppresses microglial and astrocytic activation, lessens cognitive deficits and neuronal death, and requires astrocytic Nrf2 signaling.255 In neonatal hypoxia-induced seizures, DMI reduces oxidative stress and inflammation and improves neurological and behavioral outcomes.256 Together, these findings highlight the IRG1-itaconate axis as a central immunometabolic regulator that orchestrates neuroprotection across diverse CNS injury contexts (Fig. 7a).Cardiovascular I/R and myocardial injuryIn myocardial infarction and drug-induced cardiotoxicity, loss of IRG1 aggravates inflammation and fibrosis, whereas 4-OI reverses these effects through the NRF2-ATF3 pathway, suppressing IL-6 and IL-1β and improving cardiac remodeling.257 TREM2⁺ macrophages contribute to postinfarct repair via SYK-SMAD4 signaling, which downregulates SLC25A53—a mitochondrial NAD transporter. Reduced SLC25A53 expression lowers mitochondrial NAD levels and reprograms the TCA cycle, leading to itaconate accumulation. Secreted itaconate, in turn, limits cardiomyocyte apoptosis and promotes fibroblast proliferation, thereby facilitating tissue repair.258During donor heart preservation, valproic acid (VPA) enhances H3K27 acetylation and epigenetically induces IRG1 expression, thereby increasing itaconate availability, upregulating NRF2 target genes such as HO-1 and SOD1, and reducing succinate accumulation, which prolongs graft viability and improves transplant outcomes; notably, these antioxidant and cardioprotective effects were markedly blunted in Irg1-deficient mice, supporting a functional requirement for Irg1 in this process.45 In myocardial I/R models, 4-OI promotes angiogenesis and myocardial regeneration through MAPK/ERK activation.259 Likewise, the natural product pubescenoside C (PBC) from Ilex pubescens increases macrophage Acod1 expression and intracellular itaconate, drives M2 polarization, and reduces infarct size. Mechanistically, itaconate modifies PKM2 at Cys474, Cys424, and Lys151, promoting its mitochondrial translocation and stabilizing Bcl-2, thereby suppressing cardiomyocyte apoptosis.50 Collectively, the IRG1-itaconate axis protects against myocardial injury by limiting inflammation and cell death while promoting cardiac repair and remodeling (Fig. 7b).Hepatic and renal I/R injuryIn hepatic I/R, IRG1 is upregulated in hepatocytes and confers cytoprotection via NRF2-mediated antioxidant defense—administration of 4-OI markedly attenuates injury.260 Preoperative aerobic exercise enhances itaconate metabolism through HMGB1-driven signaling, reprogramming Kupffer cells toward a trained anti-inflammatory phenotype that provides sustained protection against I/R.261 Methane exposure also augments the itaconate-NRF2 axis and alleviates hepatic injury.262 In fulminant hepatic failure induced by LPS/D-galactosamine, IRG1 deficiency activates the AMPK/JNK apoptotic pathway and exacerbates liver damage, whereas 4-OI significantly reverses this process.263In both sublethal and lethal renal I/R, IRG1-deficient mice display exaggerated inflammation and tissue injury. Exogenous itaconate or DMI promotes NRF2 nuclear translocation, reduces oxidative stress and macrophage activation, and improves survival.264 In renal I/R models, 4-OI alleviates endoplasmic reticulum stress in an NRF2-dependent manner—preserving renal structure and function.265 Furthermore, the endogenous lipid mediator LXA4 induces the IRG1/itaconate-NRF2 pathway and upregulates IRAK-M, which competitively binds TRAF6 to suppress TLR4 downstream signaling. This metabolic and immune coupling markedly reduces IRI-associated acute kidney injury, and the protection is abolished in IRG1- or IRAK-M-deficient models, defining a causal link between metabolism and innate immune regulation.51 Collectively, the IRG1-itaconate axis protects against hepatic and renal I/R injury by limiting oxidative stress and inflammation while preserving tissue function (Fig. 7c).Pulmonary IR injuryAlveolar macrophages (AMs) exhibit a distinct reversal of metabolic responsiveness. Unlike bone marrow-derived macrophages (BMDMs), endogenous itaconate in resident AMs paradoxically enhances proinflammatory cytokine expression and activates NLRP3, thereby aggravating acute lung injury. In contrast, its ester derivatives, DMI and 4-OI, suppress AM inflammation. Airway transfer of BMDMs can reprogram the local response to itaconate, suggesting that immune-metabolic interventions targeting the alveolar niche require cautious evaluation before clinical translation.266Notably, in donor lung preservation and airway organoid models, 4-OI serves as an effective preservation additive. By activating NRF2, it reduces ROS accumulation, apoptosis, and inflammation while enhancing epithelial barrier integrity and ciliary function, leading to significantly improved posttransplant outcomes.267 In acute respiratory distress syndrome (ARDS), 4-OI clears mitochondrial ROS and prevents mtDNA release, thereby suppressing NLRP3-mediated pyroptosis and downregulating the cGAS/STING-IRF3 amplification loop, ultimately reducing pulmonary edema and inflammation.268 Collectively, the IRG1-itaconate axis exerts context-dependent effects in pulmonary I/R injury, with its derivatives predominantly conferring anti-inflammatory and lung-protective benefits (Fig. 7d).Limb ischemia, revascularization, and soft tissue repairIn peripheral arterial ischemia models, miR-93 has been shown to promote M2 macrophage polarization and enhance angiogenesis and reperfusion recovery by suppressing IRF9 and downregulating the IRG1/itaconate pathway. Conversely, activation of the IRF9-IRG1-itaconate axis correlates with reduced endothelial angiogenic capacity.269 These findings contrast with the generally protective role of itaconate in most ischemia‒reperfusion contexts, suggesting that its effects on vascular regeneration are context-dependent and cell type specific. Further studies are needed to clarify the precise mechanisms underlying its dual influence on angiogenesis.In ischemic skin flap models, itaconic acid activates NRF2 and autophagy pathways, upregulates VEGF and CD31 expression, and inhibits apoptosis through increased Bcl-2 and decreased Bax levels, thereby improving flap survival.270 Under hypoxic-ischemic stress, DMI reduces endothelial ROS production, maintains mitochondrial membrane potential and ATP levels, stabilizes cytoskeletal architecture, and promotes migration and angiogenesis.271 Together, the IRG1-itaconate axis exerts context- and cell type-dependent effects on angiogenesis, while its derivatives generally promote vascular repair and tissue regeneration (Fig. 7e).SummaryCollectively, the IRG1/itaconate axis exerts broad antioxidant, anti-inflammatory, and cytoprotective effects across multiple organs—including the brain, heart, liver, kidney, and lung—during ischemia‒reperfusion injury. However, its actions remain highly context dependent; in certain microenvironments, itaconate may even display proinflammatory or antiangiogenic properties. This duality underscores the need for careful therapeutic evaluation that accounts for tissue context and cellular heterogeneity. Overall, IRG1/itaconate has emerged as a central metabolic regulator in ischemia‒reperfusion-associated inflammation with substantial therapeutic potential.Itaconate in degenerative diseaseDegeneration typically unfolds under persistent low-grade inflammation that drives oxidative stress and mitochondrial dysfunction, disrupts cell fate decisions, including apoptosis, ferroptosis, and senescence, and culminates in failed tissue repair and remodeling. The IRG1/itaconate axis serves as a central metabolic hub. It mitigates chronic inflammation and tissue degeneration through the NRF2, STING/NF-κB, and AMPK-mTOR-ULK1 pathways, and it directly targets regulatory nodes such as the GPX4 catalytic site, ZNF598-Nrf2 ubiquitination, and the HRD1-Nrf2 axis. Across multiple lineages, including microglia, astrocytes, chondrocytes, osteolineage cells, fibroblast-like or mesenchymal cells, and valvular interstitial cells, it orchestrates organ-specific coupling of metabolism, immunity, and regeneration. Overall, this axis exerts predominantly protective effects in neurodegeneration, osteoarticular degeneration and bone disorders, organ fibrosis or calcification, and age-related structural remodeling (Fig. 8).Fig. 8Full size imageProtective mechanisms of the IRG1-itaconate axis in degenerative diseases. This figure presents the roles of the IRG1-itaconate axis and its derivatives across major degenerative conditions, including neurodegeneration and cognitive impairment (a), osteoarticular degeneration and bone disorders (b), and calcific or structural remodeling diseases such as calcific aortic valve disease and myopia (c). Created with BioRender.comNeurodegeneration and cognitive impairmentIn aging-related cognitive decline, 4-OI improves postoperative cognitive dysfunction, suppresses microglial and astrocytic activation, lowers hippocampal IL-1β and IL-6, and promotes neurogenesis through remodeling of the gut microbiota and metabolites. The effect depends on Nrf2/ERK and is reversed by Nrf2 inhibition.272In Alzheimer’s disease, characterized by Aβ deposition, neuroinflammation, and neuronal loss, 4-OI activates AMPK-mTOR-ULK1 to enhance autophagy and reduce Aβ burden and inflammation.273 Dimethyl itaconate attenuates Aβ pathology and inflammatory signaling via Nrf2/HO-1 and improves memory.274In β2-microglobulin-induced cognitive impairment, 4-OI upregulates the hippocampal ACMSD/PIC pathway, reflected by increased ACMSD expression, higher PIC, and reduced 3-HAA, thereby restoring neurogenesis and cognition.275In Parkinson’s disease-related neuroinflammation, 4-OI activates microglial Nrf2, suppresses inflammatory mediators, and indirectly protects neurons.276 Itaconate also inhibits NLRP3, limiting dopaminergic neuronal loss and motor deficits.277 These findings are summarized schematically in Fig. 8a.Osteoarticular degeneration and bone mass disordersIn osteoarthritis (OA), exogenous itaconate activates Nrf2 and suppresses STING-dependent NF-κB signaling, thereby alleviating extracellular matrix degradation, inflammation, and chondrocyte senescence while promoting macrophage M2 polarization. Intra-articular injection of itaconate in vivo attenuates cartilage degeneration and synovitis.278 4-OI restores autophagy by inhibiting the PI3K/AKT/mTOR pathway and protects cartilage in destabilization of the medial meniscus (DMM) models both in vitro and in vivo.279 It also prevents ferroptosis by suppressing GPX4 methylation and maintaining GPX4 expression, showing efficacy comparable to that of ferrostatin-1,280 and stabilizes and promotes Nrf2 nuclear translocation to confer anti-inflammatory and antiapoptotic effects.281 Endogenously, IRG1 is upregulated in OA cartilage; its knockdown amplifies IL-1β-induced apoptosis, extracellular matrix degradation, and NLRP3 activation, whereas itaconate reverses these effects.282 In posttraumatic OA (PTOA), 4-OI reduces M1 accumulation, fibrosis, and synovitis, suggesting modulation of the Th17/IL-17 pathway as a mechanism for pain and inflammation relief.283In spinal degeneration, 4-OI suppresses endplate cartilage breakdown and macrophage-driven inflammation during intervertebral disc degeneration, acting through inhibition of ZNF598-mediated Nrf2 ubiquitination to stabilize Nrf2 activity.284Regarding bone mass regulation, preosteoclasts induce Irg1 and produce itaconate during differentiation. Although itaconate is not essential for osteoclastogenesis, it markedly promotes osteoblast differentiation and bone formation. Irg1⁻/⁻ mice exhibit bone loss, while itaconate supplementation restores bone formation.285 In osteoporotic models, 4-OI prevents BMSC ferroptosis and promotes osteogenesis via Nrf2 activation, alleviating bone loss in ovariectomized mice.286 Conversely, Irg1 deletion amplifies NLRP3 signaling, enhances RANKL-dependent osteoclastogenesis, and accelerates bone loss, whereas exogenous itaconate counteracts these effects.287 With inflammaging, macrophage itaconate levels increase, but responsiveness to RANKL decreases; exogenous itaconate still suppresses osteoclast activity and rescues bone mass in LPS-induced bone loss models.288Clinically, hydrogen-rich water upregulates ACOD1/itaconate, improves local perfusion, promotes M2 polarization, and mitigates glucocorticoid-associated osteonecrosis; DMI mimics this protection in a dose-dependent manner.289 Moreover, 4-OI inhibits Hrd1-mediated Nrf2 ubiquitination, thereby enhancing Nrf2 activity, suppressing osteoclastogenesis in vitro, and preventing bone loss in ovariectomized mice, linking the itaconate pathway to postmenopausal osteoporosis through metabolic-inflammatory regulation.290 These findings are summarized schematically in Fig. 8b.Other degenerative diseasesIn calcific aortic valve disease (CAVD), 4-OI activates Nrf2, upregulates Hmox1 and NQO1, suppresses ROS, and limits mitochondrial and endoplasmic reticulum stress, thereby blocking osteogenic transdifferentiation of valvular interstitial cells and calcium deposition; in vivo, it mitigates wire injury-induced aortic valve stenosis.291 In myopia-related scleral remodeling, hypoxia downregulates NRF2 and NQO1, increases HIF-1A and MMP2, and lowers COL1A1. Dimethyl itaconate promotes NRF2 nuclear translocation, restores COL1A1, and suppresses MMP2, indicating NRF2-mediated correction of scleral ECM dynamics.292 Marine-derived screening further identifies itaconate derivatives that inhibit ectopic calcification of mesenchymal stem cells, providing leads for degenerative calcific disorders.293 These findings are summarized schematically in Fig. 8c.FibrosisFibrotic diseases of the lung, liver, and kidney are driven by chronic inflammation, oxidative stress, and fibroblast activation. The IRG1/itaconate axis counteracts these processes by engaging Nrf2-dependent antioxidant defense, modulating TGF-β/Smad signaling, and tuning regulated cell death pathways, thereby exerting broad antifibrotic and tissue-protective effects that inform metabolic therapeutic strategies (Fig. 9).Fig. 9Full size imageProtective mechanisms of itaconate and its derivatives in organ fibrosis. This figure integrates the roles of the IRG1-itaconate axis and its derivatives in fibrotic diseases of the lung (a), liver (b), and kidney (c). Created with BioRender.comIn pulmonary fibrosis (Fig. 9a), 4-OI acts via Nrf2 to directly suppress epithelial–mesenchymal transition and indirectly reduce macrophage M2 polarization and TGF-β1 production, producing dual antifibrotic control.294 Dimethyl itaconate similarly limits TXNIP through Nrf2, lowers ROS, and restrains fibroblast-to-myofibroblast differentiation.295 In idiopathic pulmonary fibrosis, airway macrophages are central. Itaconate levels in bronchoalveolar lavage fluid and ACOD1 expression in macrophages are reduced; Acod1-/- mice develop persistent fibrosis that is alleviated by the transfer of wild-type macrophages. In vitro, itaconate inhibits lung fibroblast proliferation and repair capacity, and aerosolized itaconate confers protection in vivo.296In hepatic fibrosis (Fig. 9b), CCl₄ models indicate that IRG1 upregulation is protective. IRG1 deficiency augments TGF-β1/Smad3 signaling, α-SMA and collagen deposition and weakens Nrf2 antioxidation, whereas 4-OI activates Nrf2, suppresses TGF-β1 signaling, and reduces fibrosis.297 In thioacetamide-induced fibrosis, the IRG1/itaconate pathway modulates SLC39A14 to restrain ferroptosis in hepatic stellate cells, thereby limiting fibrogenesis.298In renal fibrosis (Fig. 9c), 4-OI inhibits TGF-β/Smad and NF-κB signaling, decreases ROS, and curbs excessive autophagy, improving outcomes in UUO and adenine models.299 The SGLT2 inhibitor dapagliflozin increases itaconate metabolism, suppresses NLRP3 inflammasome activation, and protects against renal fibrotic injury.300The itaconate axis in skin, ovarian, and oral diseasesWithin the broader spectrum of noninfectious inflammatory disorders, itaconate and its derivatives have emerged as key regulators beyond classical immunometabolic contexts. These molecules modulate epithelial, endocrine, and mucosal homeostasis through convergent mechanisms involving oxidative stress, inflammatory signaling, and regulated cell death. Such actions link metabolic control to tissue-specific pathophysiology, providing a mechanistic foundation for therapeutic exploration in skin, ovarian, and oral diseases (Fig. 10).Fig. 10Full size imageRegulatory mechanisms of the IRG1-itaconate axis in skin, ovarian, and oral diseases. This figure illustrates the roles of the IRG1-itaconate axis and its derivatives in noninfectious inflammatory conditions involving the skin (a), ovary (b), and oral tissues (c). Created with BioRender.comIn a Vohwinkel syndrome model driven by GJB2 mutation, octyl itaconate activates the KEAP1-NRF2-GCLC/HO-1 pathway and restores keratinocyte viability-apoptosis balance under oxidative stress, with NRF2 dependence confirmed by knockdown.301 In melanogenesis, DMI suppresses the NRF2-dependent MC1R-ERK1/2-MITF axis, and MITF targets TYR, TRP-1, and TRP-2, thereby reducing melanin synthesis. Its inhibitory effect exceeds that of itaconic acid and involves p38 MAPK and AKT signaling.302,303 In psoriasis, keratinocyte oxeiptosis is suppressed, whereas octyl itaconate inhibits KEAP1 and activates PGAM5 to restore oxeiptosis, reduce lesions, and limit inflammatory cytokines, suggesting a tractable cell death target.304 These findings are summarized schematically in Fig. 10a.In a rat model of polycystic ovary syndrome, DMI at 50 mg/kg improves insulin resistance, lowers TNF-α and IL-1β, and promotes steroidogenesis and follicular development, with efficacy comparable to metformin.305 In diminished ovarian reserve, itaconic acid activates NRF2 and suppresses GSDMD-mediated pyroptosis, increasing follicle number, improving hormone profiles, enhancing granulosa cell viability, and reducing ROS. NRF2 inhibition abrogates protection, underscoring pathway centrality.306 These findings are summarized schematically in Fig. 10b.In experimental periodontitis, 4-OI reduces alveolar bone loss and local inflammation by disrupting the KEAP1-NRF2 complex and inducing downstream antioxidant enzymes. Genetic or siRNA suppression of Nrf2 eliminates protection, demonstrating strict NRF2 dependence.307 These findings are summarized schematically in Fig. 10c.Across dermatologic, reproductive endocrine, and oral settings, itaconate derivatives follow a shared logic. By pivoting on the KEAP1-NRF2 axis and coordinating oxidative stress control, inflammatory restraint, and regulated cell death, they preserve tissue function and improve disease phenotypes, highlighting broad translational potential.The itaconate axis in autoimmune and immune-mediated diseasesAutoimmune and immune-mediated diseases arise from loss of immune tolerance and uncontrolled inflammation, spanning demyelinating disorders of the eye and central nervous system, hepatobiliary and intestinal autoinflammation, arthritides and connective tissue diseases, systemic lupus erythematosus and scleroderma. Advances in immunometabolism highlight the central role of inflammatory cells in energy and metabolic reprogramming. Within this framework, the ACOD1/IRG1-itaconate axis functions as an inflammatory metabolic brake that shapes the fate of macrophages, dendritic cells, and T cells.Extensive preclinical evidence shows that itaconate and its derivatives, including 4-OI and DMI, attenuate proinflammatory signaling and restore immune balance through electrophilic modifications, Nrf2 activation, and suppression of inflammasome and interferon pathways. These effects are not disease-restricted but recur across organs and clinical phenotypes, positioning itaconate as a key connector between metabolic regulation and immune dysregulation.This section synthesizes molecular mechanisms, animal models, and patient-based data across organ systems and outlines the translational opportunities and clinical implications of targeting the itaconate pathway in autoimmune and immune-mediated disease (Fig. 11, Supplementary Table 3).Fig. 11Full size imageRegulatory mechanisms of the IRG1-itaconate axis in autoimmune and immune-mediated diseases. This figure integrates the roles of the IRG1-itaconate axis and its derivatives across a broad spectrum of autoimmune and immune-mediated diseases involving multiple organ systems. The panels illustrate representative disease contexts, including ocular and central nervous system autoimmunity (a), autoimmune hepatitis (b), primary sclerosing cholangitis (c), inflammatory bowel disease (d), rheumatoid arthritis and juvenile idiopathic arthritis (e), systemic connective tissue diseases (f), hematologic and transplant-related disorders (g), allergic airway inflammation (h), genitourinary autoimmunity (i), and autoinflammatory diseases (j). Created with BioRender.comOcular and central nervous system autoimmune or immune-mediated diseasesThe eye and central nervous system (CNS) are both immune-privileged organs, where inflammation is often driven by Th17 cells and accompanied by barrier disruption. In these disorders, itaconate and its derivatives, such as DMI and 4-OI, exert protective effects through integrated immunometabolic mechanisms. Their key actions include inhibition of Th17/STAT3 signaling, activation of the NRF2-HO-1 antioxidant pathway, and suppression of NLRP3 inflammasome activity and ROS generation, collectively restoring the Th17/Treg balance and attenuating aberrant microglial or dendritic cell activation.In experimental autoimmune uveitis (EAU), DMI selectively suppresses antigen-specific Th17 responses without affecting Th1 cells. Mechanistically, it inhibits dendritic cell secretion of IL-1β, IL-6, and IL-23, blocks p-STAT3 nuclear translocation, and activates the NRF2/HO-1 pathway to limit Th17 differentiation, thereby reducing inflammation and tissue injury.308 Endogenous itaconate similarly ameliorates EAU by reducing ROS and oxidative stress, reversing Th17-driven pathology. Transcriptomic analyses have revealed that itaconate downregulates heat shock protein genes—particularly DNAJA1—and disrupts the DNAJA1/CDC45 axis, thereby restraining abnormal CD4⁺ T-cell proliferation and restoring Th17/Treg equilibrium.309 Recent studies have extended these findings by showing that itaconate and its derivatives regulate Th17 responses through coordinated metabolic reprogramming, including modulation of mitochondrial function, mitophagy, and epigenetic remodeling, thereby reinforcing immune homeostasis rather than acting through a single pathway.310,311 In PBMCs from Behçet’s uveitis, 4-OI enhances NRF2 expression and suppresses IL-17, TNF-α, and IL-6 while upregulating IL-10, which translates into reduced ocular inflammation and Th1/Th17 activity in EAU mice, underscoring its translational promise.312In CNS autoimmunity, itaconate derivatives also confer neuroprotection. In experimental autoimmune encephalomyelitis (EAE), DMI reduces blood‒brain barrier disruption and MMP3/MMP9 expression, inhibits microglial hyperactivation, and limits peripheral Th1/Th17 infiltration into the CNS. In relapsing-remitting EAE, DMI mitigates relapse severity, suggesting sustained benefit across disease phases.313 Similarly, 4-OI activates the NRF2/HO-1 axis while downregulating IRG1 expression and suppressing proinflammatory responses in BV2 and spinal microglia, thereby alleviating demyelination and neurological deficits.314 This negative feedback indicates that itaconate derivatives act as both metabolic mimetics and self-limiting immunoregulators. In neuromyelitis optica spectrum disorder (NMOSD), PBMCs exhibit upregulated IRG1 and NLRP3 activation; 4-OI effectively inhibits the IRG1-itaconate-NLRP3 pathway, reducing proinflammatory cytokine release both in vitro and in patient-derived cells.315Overall, although ocular and CNS autoimmune diseases differ clinically, they share a Th17-driven inflammatory axis and barrier breakdown as core pathologies. Itaconate and its derivatives exert multilevel immune modulation—suppressing Th17/STAT3 signaling in adaptive immunity while activating NRF2 and inhibiting NLRP3 in innate immunity. These findings highlight their unique immunometabolic regulatory roles in immune-privileged organs and support their potential as cross-organ therapeutic targets in autoimmune inflammation (Fig. 11a).Hepatobiliary and intestinal autoimmune and inflammatory diseasesThe liver and intestine are metabolically active barrier and detoxification organs in which autoimmune and inflammatory diseases feature metabolic reprogramming of antigen-presenting cells, disruption of effector-tolerance balance in T cells, and loss of epithelial barrier integrity. Growing evidence indicates that the IRG1-itaconate axis confers protection by rewiring dendritic cell and macrophage metabolism, modulating tissue-resident memory T-cell fate, and limiting epithelial programmed cell death.In S-100 or concanavalin A models, the itaconate pathway is protective. Endogenous itaconate increases with IRG1 induction, and exogenous supplementation mitigates S-100-induced liver injury and transaminase elevation by dampening glycolysis, restraining dendritic cell maturation, and inhibiting autophagy through PI3K-AKT-mTOR, thereby improving the Th17/Treg balance and limiting CD4⁺ T-cell proliferation.316 In ConA-induced acute hepatitis, IRG1 deficiency exacerbates inflammation and pyroptosis, whereas 4-OI suppresses hepatocyte apoptosis and oxidative stress via Nrf2/HO-1 and inhibits NF-κB/MAPK signaling in macrophages, reducing tissue damage.317,318 Tripterygium glycosides and celastrol elevate hepatic itaconate and, through the PXR-TFEB autophagy pathway, ameliorate injury; 4-OI phenocopies these effects, suggesting crosstalk between drug metabolism and itaconate signaling.319 In addition, 4-OI restores macrophage efferocytosis and promotes M2 polarization via NRF2-TIM4,320 while IRG1/itaconate inhibits JAK3-STAT3 and activates p53 to drive apoptosis of CD69⁺CD103⁺CD8⁺ tissue-resident memory T cells, attenuating inflammation.321Patients show reduced serum itaconate with pathological expansion of hepatic CD103⁺ TRM cells that correlates with disease severity. 4-OI blocks RUNX3 demethylation, limits TRM induction and effector function, and alleviates cholangitis and liver injury in mouse models.322In dextran sulfate sodium colitis, Acod1 is upregulated; Acod1⁻/⁻ mice develop worse inflammation, barrier disruption, and elevated cytokines. Exogenous 4-OI rescues disease even on the Acod1⁻/⁻ background, confirming a protective Acod1-itaconate axis.323 Mechanistically, 4-OI reduces KEAP1, promotes NRF2 nuclear translocation, induces antioxidant enzymes such as GST and NQO1, limits ROS and epithelial apoptosis, and enhances tight junction proteins to restore barrier function. The benefits are NRF2 dependent and synergize with mesalamine or the iNOS inhibitor 1400 W.324 Beyond antioxidation, itaconate suppresses pyroptosis. IRG1 deficiency augments NF-κB/MAPK signaling and activates caspase-1-GSDMD and caspase-3-GSDME pathways, whereas 4-OI blocks these cascades and lowers cytokine release.325 4-OI also modifies granzyme A at Cys54, Cys148, and Ser212 to prevent cleavage of the GSDMB linker, thereby inhibiting GSDMB-dependent pyroptosis and reducing acute colitis.84 Epithelium-targeted delivery using butyrate-modified liposomes achieves efficient uptake, suppresses GSDME-mediated pyroptosis, repairs the barrier, and normalizes the microbiota.326 Translationally, the herbal formula Xianglian Pill elevates colonic itaconate, limits M1 polarization, and blocks TET2/STAT1 and TET2/NF-κB signaling, suggesting indirect activation of the itaconate axis through metabolic-immune crosstalk.106 Population genetics further links higher M-CSF and elevated plasma aconitate/itaconate to reduced ulcerative colitis risk.327Across hepatobiliary and intestinal autoimmunity, itaconate shows shared mechanisms. In the liver, it acts by reprogramming dendritic cells, tuning autophagy and TRM fate, and restoring macrophage efferocytosis. In the gut, it sustains barrier homeostasis through NRF2-dependent antioxidation and inhibition of GSDMD/GSDME-mediated pyroptosis. These data define IRG1-itaconate as a central immunometabolic hub and outline metabolic intervention strategies for AIH, PSC, and IBD (Fig. 11b-d).Joint and bone-related autoimmune diseasesIn immune-mediated arthritides such as rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), the inflammatory microenvironment is orchestrated not only by T cells and macrophages but also by fibroblast-like synoviocytes (FLS), chondrocytes, and osteoclasts. The IRG1-itaconate axis functions as a key metabolic checkpoint that restrains synovitis and bone erosion by suppressing inflammation-driven metabolic reprogramming, alleviating oxidative stress, and modulating epigenetic activity.In RA, serum and synovial itaconate levels are elevated, primarily derived from inflammatory macrophages. Itaconate inhibits TET2 to prevent excessive osteoclast activation, while exogenous itaconate or 4-OI supplementation alleviates disease severity and preserves bone integrity.105 Endogenous itaconate directly limits FLS proliferation and migration by reducing oxidative phosphorylation and glycolysis, causing succinate and citrate accumulation and interrupting aberrant metabolism. Intra-articular administration of itaconate attenuates inflammation and bone erosion in collagen-induced arthritis (CIA), whereas Irg1-deficient mice develop more severe disease.328 The Acod1-itaconate axis also restrains osteoclast differentiation by suppressing the SDH-ROS and HIF1α-glycolysis pathways, and 4-OI inhibits bone destruction both in vitro and in vivo.329Clinical metabolomics confirms its relevance: plasma itaconate and its derivatives correlate inversely with DAS44 and CRP in early RA patients treated with DMARDs, identifying itaconate as a potential biomarker of inflammation resolution.330 In Tg197 transgenic RA mice, disease progression parallels rising itaconate, while TNF-α blockade with infliximab normalizes levels, reflecting its association with inflammatory burden and therapeutic response.331 More broadly, the macrophage metabolites succinate and itaconate form a pro- versus anti-inflammatory balance, with succinate promoting and itaconate suppressing inflammation through NRF2—a shared mechanism in both RA and OA.332 Upstream regulation studies show that the branched-chain aminotransferase BCAT1 is the major isoform in human macrophages; its inhibitor ERG240 reduces IRG1 expression and itaconate synthesis, ameliorating CIA and crescentic glomerulonephritis.333In JIA, metabolic dysregulation is also evident. Synovial CD4⁺ T cells exhibit increased mitochondrial mass, glucose and fatty acid uptake, and oxidative stress, alongside reduced NRF2/NQO1 expression. Treatment with 4-OI restores NRF2 activity, lowers oxidative stress, and suppresses IFN-γ secretion, suggesting therapeutic potential to correct T-cell metabolic imbalance and inflammation.334Collectively, itaconate serves as an anti-inflammatory metabolite in macrophages while also protecting joint and bone tissues by suppressing FLS hypermetabolism, preventing osteoclast overactivation, and mitigating T-cell oxidative stress. This establishes itaconate as a key regulator of the joint-bone-immune axis and highlights its potential as both a biomarker and therapeutic target in RA and JIA (Fig. 11e).Systemic connective tissue diseasesSystemic lupus erythematosus (SLE) and systemic sclerosis (SSc) represent prototypical connective tissue diseases. SLE is characterized by immune complex deposition and aberrant type I interferon signaling, whereas SSc involves immune-driven fibroblast activation and progressive fibrosis. Despite distinct clinical phenotypes, both diseases exhibit downregulation or dysfunction of the ACOD1-itaconate axis, suggesting that this metabolic pathway serves as a critical link between inflammation and tissue injury.Multiple experimental and clinical studies have consistently demonstrated the protective role of itaconate in SLE. In NZB/W F1 lupus mice, 4-OI markedly reduces proteinuria, renal immune complex deposition, and splenomegaly, accompanied by decreased JAK1 phosphorylation, downregulation of type I interferon-related and proinflammatory gene clusters, and upregulation of Treg-associated markers.335 Itaconate restrains NF-κB activation through dual mechanisms: the derivative 4-OI alkylates Keap1 to activate the NRF2-HO-1/NQO1 pathway, thereby suppressing NF-κB activity and the production of TNF-α, IL-1β, and IL-6 in SLE PBMCs and THP-1 macrophages336; meanwhile, endogenous itaconate directly modifies IRAK4 at cysteine 13, blocking its autophosphorylation and promoting NF-κB degradation, whereas loss of itaconate leads to hypersecretion of inflammatory cytokines.85Metabolomic analyses revealed markedly reduced plasma itaconate in active SLE,337 consistent with impaired ACOD1 function. In TLR7-induced lupus, Acod1 deficiency exacerbates renal immune complex deposition, proteinuria, and anti-dsDNA antibody production, while 4-OI partially reverses these changes; patient plasma levels of itaconate are likewise reduced and correlate inversely with disease activity and cardiometabolic risk.338 Glucocorticoids, a mainstay of SLE therapy, exert part of their anti-inflammatory effects via this axis: the glucocorticoid receptor interacts with the pyruvate dehydrogenase complex to enhance TCA turnover and itaconate synthesis, thereby suppressing inflammatory cytokines; this effect is lost when the TCA cycle is blocked or ACOD1 is deleted.339 Together, these findings indicate that disruption of the itaconate pathway in SLE exacerbates immune dysregulation and organ injury while contributing to systemic metabolic complications.SSc is a chronic autoimmune disease characterized by localized or diffuse skin thickening and fibrosis. Itaconate also exhibits antifibrotic potential in SSc. In dermal fibroblasts from SSc patients, 4-OI activates NRF2 signaling, induces HO-1 and NQO1, and reduces collagen accumulation as well as IL-6 and MCP-1 expression; these effects are abolished in Nrf2-deficient cells.340 Metabolic profiling shows that TGF-β1-activated fibroblasts display enhanced glycolysis and glutaminolysis with concurrent succinate accumulation, correlating with a profibrotic phenotype, while itaconate treatment significantly suppresses collagen synthesis, suggesting antagonism of the TGF-β1-glycolysis/glutaminolysis-succinate axis.341 Thus, the itaconate pathway functions as both a negative regulator of metabolic reprogramming and an intrinsic brake on fibrotic signaling in SSc.In both SLE, driven by immune complexes and type I interferons, and SSc, dominated by TGF-β1-mediated fibrosis, itaconate exerts protective effects through NRF2 activation, suppression of inflammatory signaling, and metabolic counterregulation. The consistent reduction in circulating itaconate in patients further supports its potential as a biomarker and therapeutic target in systemic autoimmune disorders (Fig. 11f).Hematologic, renal, and transplant-related autoimmune diseasesAcross hematologic disorders, renal immune inflammation, and transplant rejection, the itaconate axis functions as an immunometabolic counterregulatory signal. By suppressing glycolysis, restraining M1 macrophage polarization, and promoting Treg differentiation, itaconate exerts cross-disease protective effects in diverse immune contexts.In immune thrombocytopenia models, 4-OI markedly alleviates thrombocytopenia by inhibiting M1 macrophage polarization, downregulating CD80/CD86 and TNF-α/IL-6 expression, and concurrently reducing CD4⁺ T-cell proliferation while enhancing Treg differentiation, thereby restoring immune balance and increasing platelet counts.342In immune-mediated renal injury, acute iron deprivation induces an ATF4-dependent Warburg program in macrophages, characterized by reduced oxidative phosphorylation, enhanced glycolysis, lipid droplet accumulation, and moderate itaconate production. Under LPS stimulation, this reprogramming elevates the itaconate/succinate ratio and suppresses proinflammatory cytokine release. In crescentic glomerulonephritis, iron deprivation via this pathway mitigates glomerular lesions and cortical inflammation.343 In the transplant setting, metabolomic profiling of renal grafts reveals elevated itaconate and kynurenine during acute cellular rejection, representing compensatory counterregulatory metabolic signals in response to heightened immune activation.344Whether in immune thrombocytopenia, nephritis, or transplant rejection, itaconate acts through metabolic reprogramming to mediate anti-inflammatory and tissue-protective effects. Its dynamic modulation across disease states highlights its potential as a shared therapeutic target for cross-organ immunometabolic regulation (Fig. 11g).Respiratory allergy and immune-mediated airway inflammationAllergic airway diseases such as asthma are driven by Th2-dominant responses and eosinophilic infiltration, traditionally regarded as archetypal “type II inflammation.” Emerging evidence identifies the Irg1-itaconate axis as a pivotal metabolic regulator restraining this process across macrophages, T cells, epithelial cells, and eosinophils, forming a systemic anti-inflammatory network.In ovalbumin (OVA) and house dust mite-induced asthma models, pulmonary Acod1/Irg1 expression and itaconate levels are markedly upregulated, whereas Acod1-deficient mice exhibit exacerbated type II inflammation, including elevated IL-5/IL-13, increased serum IgE, enhanced eosinophil infiltration, and worsened airway hyperreactivity. Bone marrow chimera and macrophage-specific knockout studies confirm that protection is mediated by alveolar macrophage-derived itaconate. Mechanistically, itaconate directly inhibits Th2 differentiation by downregulating GATA3 and its downstream cytokines.345,3464-OI exerts multicellular anti-inflammatory effects by broadly suppressing cytokine and chemokine production. In M1/M2 macrophages, Th2 cells, and airway epithelial cells, 4-OI reduces eosinophil-attracting chemokines, partly via NRF2 activation. In vivo, 4-OI administration significantly decreases airway resistance and eosinophilic infiltration, interferes with IL-5 signaling, and directly inhibits eosinophil differentiation.347The Irg1-itaconate axis establishes a metabolic negative-feedback loop across macrophages, Th2 cells, epithelial cells, and eosinophils, effectively restraining type II inflammatory amplification. From exacerbated pathology in Acod1 deficiency to substantial inflammation relief with 4-OI treatment, convergent evidence supports itaconate as a promising therapeutic target in allergic airway disease (Fig. 11h).Autoimmune diseases of the genitourinary systemWithin the genitourinary tract, experimental evidence for the protective role of itaconate remains limited to experimental autoimmune prostatitis (EAP). In this model, 4-OI activates the NRF2/HO-1 signaling pathway, suppressing NLRP3 inflammasome-mediated pyroptosis and oxidative stress. Consequently, 4-OI reduces IL-1β, IL-6, TNF-α, and lipid peroxidation levels while enhancing antioxidant enzyme activity in prostatic tissue. These effects are abolished by NRF2 inhibition, confirming that the protective action is NRF2-dependent.348 This finding provides preliminary metabolic evidence for targeting autoimmune inflammation in the genitourinary system, although current research remains scarce (Fig. 11i).Autoinflammatory and immune-mediated diseasesUnlike classical autoimmune diseases primarily driven by adaptive immune dysregulation, autoinflammatory diseases (AIDs) arise from intrinsic activation of innate immune pathways. They are commonly associated with aberrant inflammasome or nucleic acid-sensing mechanisms, leading to excessive IL-1β, IL-18, or type I interferon production. Recent studies have revealed that itaconate and its derivatives serve as key immunometabolic regulators in these disorders.In cryopyrin-associated periodic syndromes (CAPS), gain-of-function mutations in NLRP3 cause constitutive inflammasome activation and uncontrolled IL-1β release. 4-OI inhibits this process at multiple levels by suppressing caspase-1 activation, preventing gasdermin D cleavage, and reducing IL-18 and IL-1β secretion.349 Mechanistically, itaconate modifies NLRP3 at Cys548 via 2,3-dicarboxypropylation, disrupting its interaction with NEK7 and thereby blocking inflammasome assembly. Functionally, 4-OI suppresses IL-1β release in CAPS patient PBMCs and alleviates inflammation in a urate-induced peritonitis model, identifying itaconate as an endogenous metabolic brake on inflammasome activation.95Beyond inflammasome regulation, itaconate also modulates nucleic acid-sensing pathways. NRF2 acts as a negative regulator of STING by destabilizing its mRNA and dampening type I interferon responses. Through NRF2 activation, 4-OI downregulates STING expression and IFN-I production, suppressing inflammation in cells from patients with STING-dependent interferonopathies.350 Independently, 4-OI can alkylate STING at Cys91, inhibiting its palmitoylation and polymerization, thereby specifically blocking the cGAS-STING pathway and attenuating autoinflammation.87In the rare ISG15-deficiency autoinflammatory syndrome, characterized by systemic interferon elevation with neurologic and cutaneous involvement, iPSC-derived ISG15⁻/⁻ cells exhibit metabolic disruption and heightened oxidative stress. Treatment with itaconate and its derivatives (DMI, 4-OI) reduces inflammation and apoptosis, restores mitochondrial gene expression and redox homeostasis, and shows a distinct advantage in antioxidant gene induction,351 underscoring its therapeutic potential in interferonopathies.Across autoinflammatory diseases such as CAPS, STING-related interferonopathies, and ISG15 deficiency, pathological activation of innate immune pathways is a shared hallmark. Itaconate exerts broad suppressive effects by directly modifying inflammasome or interferon pathway components or indirectly via the NRF2-antioxidant axis. These findings expand the functional scope of the itaconate pathway beyond classical autoimmune regulation, providing a promising metabolic strategy for targeting innate immunity-driven inflammation (Fig. 11j).The dual roles of itaconate and its derivatives in tumorsTumor initiation and progression depend on metabolic reprogramming and dynamic crosstalk within the immune microenvironment, where metabolic intermediates act as regulators of oncogenic signaling and immunity.352,353,354,355,356 Itaconate and its derivatives, including 4-OI and DMI, have emerged as central nodes in cancer metabolism and immune regulation. Depending on the cellular origin and exposure context, itaconate can directly suppress tumor cells or reshape immunity in ways that may favor tumor growth. This antitumor versus protumor duality positions itaconate at the intersection of metabolic homeostasis, regulated cell death, and antitumor immunity (Fig. 12, Supplementary Table 4).Fig. 12Full size imageRegulatory mechanisms of the IRG1-itaconate axis in cancers. This schematic summarizes the antitumor and pro-tumorigenic effects of itaconate and its derivatives, 4-OI and DMI. The left side shows antitumor actions, including metabolic inhibition of cancer cells, enhanced immunogenicity, induction of cell death, and modulation of TAM polarization toward antitumor immunity. The right side shows pro-tumorigenic actions. In specific tumor microenvironments, TAMs, TINs and MDSCs can produce or secrete itaconate, and cancer cells can take up itaconate, thereby suppressing CD8⁺ T-cell function and promoting immune escape, tumor progression and therapy resistance. Created with BioRender.comAntitumor actions of itaconate and its derivativesAcross multiple cancers, itaconate and its derivatives exert antitumor effects by directly killing tumor cells through metabolic inhibition and redox stress and by remodeling the immune microenvironment to enhance antitumor responses.Direct tumor cell killing by itaconate and its derivativesItaconate disrupts key metabolic enzymes to curtail energy and substrate supply, increase oxidative stress, and trigger death pathways. In ER-positive breast cancer, itaconate inhibits succinate dehydrogenase, elevates reactive oxygen species, activates AMPK, halts DNA synthesis, and induces apoptosis.101 In colorectal cancer, 4-OI inhibits the glycolytic enzyme GAPDH and potentiates copper-dependent cell death induced by elesclomol-Cu.72 In retinoblastoma, 4-OI eliminates chemoresistant clones through the ferritinophagy-ferroptosis axis.357 In pancreatic cancer, supraphysiologic itaconate activates NCOA4-mediated ferritinophagy, drives iron overload and lipid peroxidation, and engages an NRF2-tuned ferroptotic balance.358Accumulated ROS and disrupted glutathione metabolism amplify mitochondrial injury. In melanoma, 4-OI weakens glutathione-dependent antioxidant defenses and inhibits mitochondrial respiration, leading to cell death.359 In hepatocellular carcinoma, DMI activates eNOS- or iNOS-dependent NF-κB signaling, destabilizes Bcl-2 family control, promotes cytochrome c release and caspase-3 or caspase-9 activation, and induces mitochondrial apoptosis with efficacy comparable to that of 5-fluorouracil.360In hematologic malignancy, itaconate derivatives show selective metabolic cytotoxicity. In chronic lymphocytic leukemia, inflammatory signaling upregulates IκBζ to support survival and metabolic activation. DMI targets IκBζ, blocks this metabolic program, and reduces CLL cell viability while sparing healthy leukocytes, remaining effective under strong TLR stimulation.361Beyond metabolism, itaconate can modify signaling proteins to induce tumor cell death. In breast cancer, itaconate alkylates ERK2 at Cys254 and enforces aberrant activation, conferring cytotoxicity even in tamoxifen resistance.80 These findings indicate that itaconate can bypass resistance by coupling metabolic interference with covalent signaling rewiring.Itaconate-mediated remodeling of the tumor immune microenvironment and its antitumor effectsBeyond direct cytotoxicity, itaconate exerts potent immunomodulatory effects by reshaping the tumor immune microenvironment. The primary mechanisms involve regulation of macrophage polarization, modulation of inflammatory signaling, and enhancement of tumor immunogenicity.In ovarian cancer, 4-OI suppresses peritoneal macrophage activation, downregulates proinflammatory cytokines, and inhibits HIF-1α signaling, thereby reducing angiogenesis and metastatic potential and markedly limiting peritoneal dissemination.362 In colorectal cancer liver metastasis, the STING-IRG1 axis promotes TFEB nuclear translocation and reprograms macrophages toward an antimetastatic phenotype.363 In cholangiocarcinoma, IRG1 overexpression inhibits M2 polarization, lowers CCL18 secretion, and blocks STAT3 phosphorylation, collectively restraining tumor proliferation and migration; conversely, IRG1 suppression enhances M2 polarization and accelerates progression.364 In hematologic malignancy, inhibition of the pentose phosphate pathway activates the UDPG-STAT1-IRG1-itaconate axis, driving proinflammatory macrophage polarization and metabolic activation, thereby enhancing macrophage phagocytosis of chronic lymphocytic leukemia cells.365Itaconate also enhances tumor immunogenicity. Thimerosal induces IRG1 expression through the ROS-RIPK3-IRF1 pathway, increasing itaconate production, promoting TFEB nuclear translocation, and augmenting antigen presentation, which strengthens T-cell responses and sensitizes tumors to immune checkpoint blockade.38SummaryCollectively, itaconate and its derivatives exert antitumor activity through a dual mechanism. On the one hand, they disrupt metabolic equilibrium and redox homeostasis, inducing ferroptosis, cuproptosis, and mitochondrial apoptosis. On the other hand, they remodel the immune microenvironment by regulating macrophage polarization, inflammatory signaling, and antigen presentation, thereby amplifying immune responses and therapeutic sensitivity. Together, these mechanisms establish itaconate as a pivotal metabolic-immune integrator in cancer biology.Pro-tumorigenic roles of itaconate and its derivativesIn contrast to its antitumor effects, itaconate can promote tumor progression when produced by immune cells such as macrophages, neutrophils, or myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment. Its function is highly context dependent, governed by the producing cell type and target pathway, and it can drive immune suppression, metastasis, and therapeutic resistance through metabolic and signaling reprogramming. Current evidence indicates that macrophages, neutrophils, MDSCs, and even tumor cells themselves can exploit the itaconate axis to facilitate cancer progression.Macrophage-derived itaconate is a dominant contributor to tumor-promoting activity. In melanoma and ovarian cancer peritoneal metastasis, tumor-associated macrophages overexpress ACOD1/IRG1 and generate itaconate, which enhances ROS production and MAPK signaling, markedly promoting metastasis.366 In early-onset colorectal cancer, obesity-related hormones activate the NOTCH4-GATA4-IRG1 axis in M2 macrophages, upregulating itaconate synthesis and driving tumor progression, correlating with poor prognosis.367 In hepatocellular carcinoma (HCC), macrophage-derived itaconate activates a succinate-dependent H3K4me3-Eomes pathway that upregulates PD-1 and TIM-3, inducing CD8⁺ T-cell exhaustion and facilitating tumor growth.368 In nasopharyngeal carcinoma, itaconate released from macrophages enhances tumor cell proliferation, migration, and invasion while impairing CD8⁺ T-cell cytotoxicity, reducing phagocytosis, and promoting M2 polarization. Mechanistically, itaconate binds and suppresses TET2, driving immune evasion and tumor progression.104Furthermore, IRG1 expression in TAMs can be induced by NF-κB and IFNγ-STAT1 signaling, promoting itaconate synthesis that establishes an epigenetic barrier through TET inhibition, reduces proinflammatory gene expression, and limits CD8⁺ T-cell infiltration. Irg1 deficiency enhances antitumor immunity and improves responses to PD-(L)1 blockade, whereas PD-1 therapy itself can paradoxically induce this pathway. Itaconate and its derivative 4-OI further inhibit dendritic cell cross-presentation, promoting immune escape.369,370 These findings underscore the macrophage-itaconate axis as a central driver of immunosuppression and immune checkpoint resistance.Neutrophil-derived itaconate also contributes to metastasis. In metastatic breast cancer, tumor-infiltrating neutrophils (TINs) upregulate ACOD1 through the GM-CSF-JAK/STAT5-C/EBPβ pathway, producing itaconate, which activates an NRF2-dependent antiferroptotic program, sustaining TIN survival and immunosuppression. ACOD1 deletion reduces neutrophil infiltration, enhances antitumor immunity, and improves the response to immunotherapy.371MDSC-derived itaconate suppresses cytotoxic immunity. MDSCs secrete itaconate, which is taken up by CD8⁺ T cells, inhibiting proliferation, cytokine release, and cytotoxicity by blocking aspartate and serine/glycine biosynthesis. Irg1 deficiency enhances anti-PD-1 efficacy, while high IRG1 expression predicts poor prognosis.372Beyond immune cell secretion, tumor cells can import itaconate via the transporter SLC13A3. In HCC, intracellular itaconate activates the NRF2-SLC7A11 pathway, conferring ferroptosis resistance and reducing immunotherapy sensitivity.373 In non-small cell lung cancer, itaconate similarly enters via SLC13A3 and alkylates PD-L1 at Cys272, preventing ubiquitin-mediated degradation, stabilizing PD-L1, and promoting immune escape.77 Metabolomic analyses confirm that elevated itaconate levels in lung tumors correlate with disease progression, while high ACOD1 expression predicts immune checkpoint resistance and poor survival in HCC, melanoma, and glioma.374Itaconate derivatives can likewise promote chemoresistance. In colorectal cancer, 4-OI activates NRF2 and attenuates oxaliplatin cytotoxicity. Conversely, NRF2 inhibition enhances ferroptosis by downregulating GPX4 and GSH and increasing MDA while promoting GSDME-mediated pyroptosis and restoring chemosensitivity.375 These findings suggest that NRF2 serves as a molecular “switch” determining whether itaconate acts in an antitumor or protumor manner.Overall, the ACOD1-itaconate axis functions not only as a protumor metabolic pathway but also as a potential therapeutic target. Deletion of ACOD1 in engineered CAR macrophages enhances inflammatory phenotypes and boosts antitumor efficacy.376 Structural studies of ACOD1 and the discovery of small-molecule inhibitors such as citraconate provide promising avenues for precise metabolic intervention.374 When driven by immune cells, itaconate acts as a “metabolic immune checkpoint” that dampens immune clearance, promotes metastasis, and accelerates therapeutic resistance, highlighting its potential as a next-generation target in cancer immunometabolism.Unifying logic and translational implicationsTumor biology is marked by pronounced heterogeneity: lineage of origin, mutational landscape, and metabolic state jointly shape diverse tumor behaviors.353,355,377,378,379,380,381,382,383,384,385,386,387 In parallel, cancer cells and their microenvironment exhibit substantial contextual plasticity, dynamically reprogramming signaling networks and phenotypic states in response to external cues, immune pressure, and metabolic flux.388,389,390,391,392,393,394,395,396,397,398 Consequently, the same signaling molecule or metabolic intermediate can exert opposing effects across cell types, microenvironmental niches, or disease stages—constraining growth in one context while promoting progression in another.399 This context-dependent duality has become a general principle in cancer metabolism and immune regulation.400,401,402,403,404,405,406,407,408,409,410Within this conceptual framework, the dual roles of itaconate offer a paradigmatic example. As a single metabolite, itaconate can rewire metabolic and immune signaling networks to produce either tumor-suppressive or tumor-promoting outcomes, depending on context. Such divergence arises from differences in its cellular provenance, molecular targets, and surrounding metabolic and signaling milieu.When itaconate is generated within tumor cells—or introduced pharmacologically into the intracellular compartment—it primarily engages metabolic enzymes and redox pathways, precipitating energetic collapse and accumulation of reactive oxygen species. These perturbations trigger noncanonical cell death programs, including ferroptosis and cuproptosis. In this setting, itaconate functions as a metabolic toxin, disrupting cellular homeostasis to exert direct antitumor activity.In contrast, when itaconate is produced mainly by immune cells, including macrophages, neutrophils, or MDSCs, and accumulates in the tumor microenvironment, its role shifts. Itaconate modulates immune signaling and metabolic balance to weaken antitumor immunity, for example, by stabilizing PD-L1, promoting M2 polarization, suppressing T-cell cytotoxicity, or enhancing antioxidant defenses. This establishes an immunosuppressive niche that supports tumor growth and therapeutic resistance. In this context, itaconate behaves as a metabolic immune checkpoint and can underlie the failure of immunotherapy.These dualities inform therapeutic strategies. Within tumor cells, derivatives such as 4-OI or DMI can be used to intensify metabolic collapse and overcome apoptosis resistance for direct cytotoxicity. In immunosuppressive milieus, inhibition of the ACOD1/IRG1 biosynthetic pathway or blockade of SLC13A3 transport may limit itaconate-driven immune escape and drug resistance. Circulating or intratumoral itaconate and its regulators may serve as biomarkers of immunotherapy response and prognosis. Future work should define dose dependence, temporal dynamics, and tissue specificity and develop precision delivery with spatiotemporal control to achieve dual modulation—enhancing itaconate within tumor cells while restraining it in the microenvironment—to open new avenues for cancer therapy.Engineered itaconate delivery and immunometabolic interventionItaconate and its derivatives, including 4-OI, 4-methyl itaconate (4-MI), and DMI, combine chemical reactivity with immunometabolic activity. The α,β-unsaturated carboxylate enables polymerization or grafting, and the Michael acceptor supports reversible covalent interactions. Biologically, these agents inhibit SDH, modulate NRF2-Keap1 and STING, and reshape glycolysis and mitochondrial homeostasis.Materials science leverages these features along two parallel axes. First, controlled release of itaconate or its derivatives is achieved via prodrug modification, polyester backbones, and degradable polymers. Second, material-immune cell interactions induce systems-level reprogramming across metabolism, epigenetics, and inflammation.This strategy has progressed stepwise: from molecular prodrugs and hybrid chemistries to precision nanocarriers such as nanoparticles, liposomes, and micelles, to hydrogels and injectable depots for local homeostasis control, and finally to surface coatings and device integration for clinical use. Each engineering tier targets defined immunometabolic circuits, including NRF2-ROS, glycolysis-STING, SDH-TCA-lipid metabolism, and cfDNA clearance with quorum-sensing blockade. Applications span osteoarthritis and bone repair, atherosclerosis and endovascular therapy, acute cardiac and hepatic injury, infection and wound healing, tuberculosis and oral protein delivery, and cancer therapy with immune modulation. Together, itaconate enables a vertical pipeline from material design to mechanistic intervention and a horizontal portfolio across organs and disease indications (Fig. 13, Supplementary Table 5).Fig. 13Full size imageEngineered itaconate delivery and immunometabolic intervention. This figure outlines engineering strategies and translational applications of the IRG1-itaconate axis and its derivatives across multiple therapeutic platforms. a highlights small-molecule and prodrug-based design strategies, including structural optimization and hybridization. b presents nanoplatforms and vesicular systems enabling targeted and multiresponsive delivery. c illustrates hydrogels and injectable systems for in situ delivery, sustained release, and microenvironmental modulation. d depicts surface engineering and device integration approaches, including vascular grafts, implants, and biomaterial-based therapies. Created with BioRender.comSmall-molecule prodrugs and hybrid modifications: foundations for itaconate medicinal chemistryItaconate and its derivatives face a fundamental barrier to conventional administration, namely, very low oral and transdermal bioavailability due to high polarity, high aqueous solubility, and poor membrane permeability. Two complementary approaches address this limitation. One improves exposure and stability through prodrugging and scaffold modification. The other embeds itaconate’s immunometabolic functions into small-molecule backbones to enable controlled release and signal amplification.Multiple oral prodrug families have been created, including pivaloyloxymethyl (POM), isopropyloxycarbonyloxymethyl (POC), (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL), and 3-(hexadecyloxy)propyl (HDP). POC designs such as P2, P9, and P13 show superior permeability and pharmacokinetics, efficiently releasing itaconate or 4-MI and suppressing poly(I:C)/IFN-γ-induced inflammation in keratinocytes, establishing the principle of preserving the Michael acceptor while improving permeability and stability.411 NRF2 activators, including dimethyl fumarate and DMI, are being explored for dry age-related macular degeneration, with Tecfidera in clinical testing, supporting their potential as systemic immunoantioxidant interventions.412For transdermal delivery, the lipophilic 4-MI prodrug SCD-153 markedly increases skin penetration and promotes hair regrowth, outperforming free 4-MI, DMI, and tofacitinib in alopecia areata models.413 The itaconate-derived anionic surfactants C12-OPK and C18-OPK enhance hydrocortisone permeation at very low concentrations without irritation, highlighting itaconate chemistry as a penetration-enhancer toolkit.414Hybridization further widens the pharmacologic window. Conjugation of itaconate to esterase-triggered CO-releasing motifs yields ItaCORMs that suppress inflammation at low micromolar concentrations, combining itaconate and CO functions.415 Itaconate derivatives have also been extended into anti-infective and anticancer spaces, for example, 1,2,4-triazoles active against gram-positive bacteria416 and fused aromatic hybrids with activity across tumor cell lines and potential against Zika and coxsackie viruses.417Beyond host immunoregulation, itaconate can directly modulate pathogens. Itaconate-based molecularly imprinted polymers capture Pseudomonas aeruginosa AHL quorum-sensing signals,418 and linear itaconate-containing polymers suppress QS phenotypes in Vibrio and Aeromonas with low toxicity.419Together, prodrug and hybrid strategies preinstall mechanistic modules into the molecular scaffold, including Michael addition-Keap1 engagement, SDH inhibition, and CO-mediated mitochondrial protection, creating a robust delivery base for subsequent nanoplatforms, hydrogels, and device integration (Fig. 13a).Nanoplatforms and multifunctional systems: organ and organelle targeting with mechanistic synergyBuilding on prodrug foundations, itaconate and its derivatives have been integrated into nanoparticles, liposomes, and micelles to enhance pharmacokinetics, delivery efficiency, and coordinated immunometabolic control with organ or organelle selectivity. Metal-organic supercontainers encapsulating 4-OI clear ROS, activate NRF2, and inhibit NF-κB to attenuate synovitis and bone erosion.420 Triphenylphosphonium-bearing polysaccharide-polymer hybrids achieve macrophage and mitochondrial cotargeting, delivering 4-OI or dexamethasone to reduce ROS and iNOS, induce M2 polarization, and protect cartilage.421 A theranostic construct with a 4-OI liposomal core, metal-polyphenol layer, and immune-cell membrane coating suppresses pyroptosis and inflammation, activates AMPK, promotes angiogenesis, and improves cardiac function after myocardial infarction.422 PCL/DMI nanofibers balance early anti-inflammation with late repair,423 while acid-triggered OI-FFG-ss-SS31 coactivates NRF2 and releases a mitochondrial protective peptide to mitigate ischemia‒reperfusion injury.424 Itaconate lipid nanoparticles accumulate in atherosclerotic plaques and myeloid cells, suppress inflammation via H3K27ac deacetylation and stabilize ABCA1 to enhance cholesterol efflux, thereby reducing plaque burden.425,426 In bone metabolism, mesoporous silica loaded with 4-OI and coated with Ce-TA restores osteoimmune balance by jointly modulating oxidative stress and epigenetic marks, alleviating osteoporosis.427 For rheumatoid arthritis, 4-OI@PPTP/PLM combines acid-triggered charge reversal with ROS-amplified cationic effects to clear cfDNA, achieve mitochondrial-targeted release, and suppress macrophage inflammation, synovial hyperplasia, and bone destruction.428Cancer-directed platforms emphasize multistimuli responsiveness and targeting: pH-sensitive PEG-PMMI-CholC6 liposomes increase rapamycin selectivity in colorectal cancer,429 and SBA-15-poly(MPC-co-IA) systems improve cisplatin control (IA refers to itaconate).430 Micelles such as PIA-PEG-FA-PHIS exploit folate receptor uptake and acid-triggered release to enhance DOX cytotoxicity,431 and PIAThydCA liberates cinnamaldehyde and TPGS in acidic niches to induce mitochondrial apoptosis.432 Fe₃O₄-based magneto/acid-responsive systems integrate release, separation, and imaging.433,434 Chitosan-hybrid micelles and nanocapsules extend circulation, increase loading and tumor selectivity, and maintain immunocompatibility.435,436 Immuno-oncology applications include lowering TAM-derived endogenous itaconate while combining PD-L1 blockade to boost CD8⁺ T-cell infiltration, cytotoxicity, and durable memory with reduced recurrence and metastasis.437 Heparin-mimetic itaconate polymers inhibit hypercoagulability and metastasis without heparin-associated immunotoxicity and display nanoscale behavior through self-assembly.438In inflammatory disease, butyrate-modified liposomes carrying 4-OI preferentially accumulate in inflamed colonic epithelium, inhibit GSDME-dependent pyroptosis, restore barrier function, and rebalance microbiota in ulcerative colitis.326 Itaconate liposomes selectively target the liver in acute hepatic failure, reprogram macrophage metabolism, activate NRF2/STING, and blunt inflammation and oxidative stress.439 A self-assembled dual modulator, LDO (lonidamine-S-S-4-OI), concurrently blocks glycolysis and STING to curb cytokine storms and improve survival in sepsis.440For infection and tuberculosis delivery, PLA-itaconate nanoparticles release mainly lactate oligomers with pH-tunable trace itaconate via bulk erosion, providing a mechanistic basis for itaconate-based anti-TB materials.441 PVP/PIA smart nanogels enable pH-responsive isoniazid release, lowering the MIC approximately eightfold,442 while inhalable chitosan-hybrid microparticles loaded with PVP/PIA nanoparticles increase lung deposition and enhance mycobacterial killing by 63-fold versus free isoniazid.443 HA-g-poly(AM-co-IA) nanogels extend acyclovir release and improve oral bioavailability.444To overcome humoral barriers in gene therapy, RAPA-itaconate tolerogenic nanoadjuvants reprogram Tfh-germinal center circuits and, together with rapamycin, induce Treg, substantially reducing anti-AAV antibodies.445 A metabolic delivery approach using polydecyl itaconate microspheres (~1.5 μm) enables macrophage phagocytosis and intracellular itaconate release that inhibits SDH and redirects metabolism with low toxicity.446 Carrier materials themselves can shape immunometabolism: GO-PEG increases NO, succinate, and itaconate in macrophages with an LPS-like profile, whereas flavin-stabilized graphene minimizes metabolic load.447Collectively, nano, liposomal, and micellar platforms transform itaconate from a hard-to-deliver metabolite into a programmable therapeutic module characterized by organ and organelle targeting, mechanistic synergy, and material adaptability, enabling integrative delivery-regulation amplification and supporting cross-disease precision translation (Fig. 13b).Hydrogels and injectables: in situ longevity and microenvironmental reprogrammingUnlike nanoparticle or liposomal systems that primarily support systemic delivery, hydrogels and injectable depots emphasize in situ administration, sustained release, and microenvironmental remodeling. The design embeds itaconate or its derivatives within three-dimensional crosslinked networks and uses pH, temperature, or redox responsiveness for controlled release, while material-immune cell crosstalk rebalances local immunometabolic pathways. For oral protein and insulin delivery, dual-responsive NiPAAm-IA hydrogels contract in gastric acid to protect cargo and swell in intestinal fluid to release active protein.448 pH-sensitive semi-interpenetrating networks based on microcrystalline cellulose with itaconic acid and MMA/IA nanogels achieve gastric protection and intestinal release with glucose-lowering efficacy in diabetic models.449,450 Loading and release depend on crosslink density, protein size, and pH-driven swelling kinetics.451,452 IA-based microgels also improve the oral bioavailability of proton-pump inhibitors and bisphosphonates.453,454,455 In tumor-localized control, pH and redox dual-sensitive platforms such as Salecan-IA-HEMA disulfide hydrogels and chitosan/PNIAAm-co-IA injectables accelerate DOX release and cytotoxicity in acidic or high-ROS niches.456,457 PITAU-IA hybrid gels demonstrate tunable NSAID release and biocompatibility, supporting oncology and inflammation applications.458,459,460 In infected and diabetic wounds, FIA self-healing hydrogels provide broad-spectrum antibacterial activity against Staphylococcus aureus, E. coli, and MRSA and promote angiogenesis and repair.461 4OI@PEG gels activate Keap1-NRF2 and accelerate diabetic wound closure.462 A composite 4OI-BP hydrogel embeds 4-OI-modified black phosphorus nanosheets to couple on-demand photothermal or photodynamic sterilization with sustained antioxidant and proangiogenic release, enabling stage-specific care of infected wounds.463 Electrospun P/G-CS-OI nanofibers release 4-OI to drive NRF2-dependent M2 polarization, reduce inflammation, and enhance angiogenesis and re-epithelialization.464 In diabetic infected bone defects, Ag@PEG-4OI/EXO self-healing gels integrate 4-OI, silver ions, and exosomes to combine antibacterial, antioxidant, neurogenic, and osteogenic effects.465 HA-grafted AM/IA nanogels provide strong adhesion, antibacterial and antioxidant activity, and proangiogenic benefits for chronic wounds, while MXene deep eutectic hydrogel microneedles copolymerized with IA enable photothermal-controlled release and robust adhesion, achieving 94.9% closure on day 10 with enhanced vascularization and bacterial suppression.466,467In arthritis and bone repair, IA-based hydrogels enable in situ anti-inflammation with concurrent regeneration. 4-OI/alginate gels suppress inflammatory mediators and improve joint structure.468 OSA/GEL-4-OI accelerates early M2 polarization and cartilage regeneration.469 To extend residence and improve permeability, IA-ZIF-8 nanoparticles immobilized within hydrogel microspheres provide sustained release and superior anti-inflammatory and antioxidant efficacy compared to IA-ZIF-8 alone.470 4-OI@Cu@Gel implements staged release for rapid anti-inflammation followed by pro-osteogenesis, expediting fracture healing.471 Chitosan-based injectables (CS-OI) couple sustained OI release with intrinsic antibacterial activity to deliver dual benefits in vivo.472 Notably, PVA-IA hydrogels induce osteogenesis of amniotic fluid stem cells via matrix elasticity, while ECM-peptide grafting maintains an undifferentiated state, indicating that mechanics and surface cues can antagonize or synergize to determine stem cell fate.473 For ocular surface inflammation, HA-IA-DEX crosslinked films offer mechanical stability, prolonged residence, and reduced corneal IL-6, outperforming eye drops for chronic management.474 IA-grafted polysaccharide networks provide acid-triggered release of penicillins effective against S. aureus and E. coli.475,476,477 IA-modified hyaluronan films, dual-responsive hydrogels, and PLA/MPEG/IA pH-sensitive gels further support mucoadhesive delivery, safety evaluation, and material baselines.478,479,480 Collectively, IA-based hydrogels and injectables unite controllable release with immunometabolic reprogramming, extending from oral protein delivery to local tumor control and from infected wounds to bone and joint repair. Their hallmark is in situ administration with long-acting release and tissue integration, marking a transition from passive carriers to active therapeutic platforms (Fig. 13c).Surface and device integration: engineering translation toward clinical applicationAt the translational interface, itaconate derivatives have progressed beyond nanocarriers and hydrogels into surface engineering, vascular devices, and biodegradable polymers—realizing a “material-as-medicine” paradigm in biomedical design.In interface modulation, zwitterionic itaconate-based monomers can be copolymerized and photocrosslinked into polyzwitterionic networks that remain antifouling at neutral pH but undergo charge reorganization in acidic environments to generate amphiphilic cations mimicking synthetic antimicrobial peptides. These surfaces achieve contact-dependent bactericidal activity while maintaining cytocompatibility,481 offering a dual-mode “antifouling-antibacterial” solution for long-term implant stability.In vascular remodeling, localized 4-OI delivery shows distinct advantages. Poly-L-lactic acid substrates with a “sponge-skin” architecture enable high-capacity and controlled OI release, suppressing smooth muscle cell proliferation and phenotypic switching while preventing restenosis.482 PLCL/OI@REDV small-diameter grafts integrate anti-inflammatory molecules with endothelial-adhesive peptides, simultaneously inhibiting M1 polarization and ROS accumulation while promoting endothelial regeneration and vessel patency.483For cardiac repair, poly(itaconate-co-citrate-co-octanediol) (PICO) elastomers undergo rapid radical crosslinking to form hydrogels with tunable mechanical strength (36–1476 kPa), matching myocardial tissue.484 Upon degradation, PICO releases itaconate and citrate, mitigating inflammation and protecting the ischemic myocardium more effectively than conventional materials.485In barrier-crossing delivery, pressure-mediated microinjection coupled with interventional balloons enables subendothelial transport up to 150 μm within 60 s, where 4-OI effectively reduces intimal hyperplasia,486 offering a precise strategy for vascular and airway wall drug deposition.In dental applications, IA-modified composites enhance both mechanical and biological properties. IA-containing BG/ZnO resin capping materials improve compressive strength, adhesion, and odontogenic gene expression while reducing cytotoxicity.487 PNIPAAm-IA-GO-chitosan thermosensitive hydrogels promote osteogenic differentiation and mineralization of dental pulp stem cells,488 illustrating how IA modification directly modulates cell fate in addition to material performance.Finally, self-therapeutic polyesters embedding IA within the polymer backbone can hydrolytically release IA, intrinsically inducing macrophage M2 polarization, inhibiting acetate-dependent bacterial growth, and accelerating inflammation resolution—without external drug loading.489 This “inherently bioactive polymer” approach exemplifies immune-responsive material design.Collectively, itaconate-derived materials, including advanced antifouling and antibacterial coatings, multifunctional vascular grafts, cardioprotective elastomers, barrier-targeted delivery systems, dental scaffolds, and self-active polyesters, demonstrate broad engineering adaptability and strong clinical potential, representing a significant advancement toward fully integrated therapeutic devices (Fig. 13d).Conclusion and perspectiveAlthough the IRG1/ACOD1-itaconate axis has been established as a central regulator of immunometabolism, the current literature remains fragmented and highly context dependent. Itaconate participates in energy metabolism, redox balance, inflammatory signaling, cell death regulation, and tissue remodeling, yet its reported effects vary across studies. In many inflammatory and tissue-injury settings, it exhibits anti-inflammatory and cytoprotective activities; under specific microenvironmental conditions, however, it may suppress host immunity, facilitate pathogen adaptation, or reinforce tumor-associated immunosuppression. A major conclusion emerging from this review is therefore not that itaconate has a single fixed biological function but that it acts as a context-sensitive metabolic checkpoint. Its functional output is shaped by cell lineage, tissue microenvironment, disease stage, metabolic flux, species-specific biology, and the chemical form being studied. Future work in this field should move beyond cataloging disease associations and individual study findings toward defining generalizable principles, evidence hierarchies and unresolved controversies.Several mechanisms are consistently supported across experimental systems. In inflammatory macrophages and related myeloid cells, induction of IRG1/ACOD1 diverts cis-aconitate from the tricarboxylic acid cycle toward itaconate production, thereby establishing a metabolic brake on excessive inflammatory activation. The best-supported downstream processes include inhibition of succinate oxidation through SDH/complex II, reduction of mitochondrial ROS production, modulation of the succinate-HIF-1α-IL-1β axis, activation of antioxidant programs such as KEAP1-NRF2 signaling, restraint of NLRP3 inflammasome activity, and suppression of excessive glycolytic and cytokine output. These mechanisms recur across models of infection, sterile inflammation, ischemia‒reperfusion injury, metabolic inflammation, and tissue damage. They support one of the clearest general principles in itaconate biology: endogenous itaconate most consistently functions as a protective metabolic brake when inflammatory or metabolic stress threatens to amplify tissue injury.An equally important principle is that endogenous itaconate, synthetic derivatives, and naturally related isomers should not be regarded interchangeable. Endogenous itaconate is generated by IRG1/ACOD1 and is constrained by intracellular metabolic flux, transport systems, compartmentalization, and local concentration. In contrast, 4-octyl itaconate and dimethyl itaconate are more membrane permeable and electrophilic, and many of their effects may reflect derivative-specific thiol reactivity, glutathione conjugation, or incomplete conversion to free itaconate rather than faithful mimicry of the endogenous metabolite. Similarly, mesaconate and citraconate expand the itaconate-related metabolite family but differ from itaconate in abundance, origin, electrophilicity, and biological potency. Conclusions based solely on 4-OI, DMI, or related compounds should therefore be interpreted as pharmacological evidence rather than direct evidence for the physiological function of the endogenous ACOD1-itaconate axis, unless supported by endogenous itaconate measurement, ACOD1 genetic manipulation, rescue experiments, or direct target validation.The hierarchy of evidence is central to interpreting this field. The strongest evidence usually comes from Irg1/Acod1 loss- or gain-of-function models combined with quantification of endogenous itaconate and rescue at physiologically relevant concentrations. In contrast, studies relying only on exogenous derivative treatment, high-dose exposure, disease-associated ACOD1 expression, or a single model system provide useful but less definitive evidence for causality. This distinction is particularly important because ACOD1 itself may have itaconate-independent functions. Thus, a phenotype caused by ACOD1 deficiency should not automatically be attributed to loss of itaconate. Future studies should more systematically report the chemical form used, intracellular itaconate levels, dose‒response relationships, timing of exposure, dependence on ACOD1, and whether the phenotype can be rescued by itaconate supplementation or pathway-specific intervention.Differences between human and murine biology represent another unresolved and important boundary. Murine macrophages often generate robust amounts of itaconate after inflammatory stimulation, whereas human macrophages may differ in ACOD1 enzymatic activity, itaconate production, and downstream responsiveness. Species-specific differences in ACOD1 activity, promoter regulation, metabolic flux, immune cell composition, and inflammatory tone may explain some inconsistencies across studies. Similar caution applies to cell-type specificity. Macrophages, neutrophils, dendritic cells, epithelial cells, stromal cells, tumor cells, and pathogen-infected cells may differ markedly in itaconate production, uptake, target engagement, and functional outcome. Conclusions derived from mouse models or single-cell-type systems therefore require validation in human cells, tissue samples, organoids, clinical cohorts, and cross-species comparative models, especially when translational claims are made.ACOD1-dependent but itaconate-independent biology is a further controversy that deserves explicit attention. Traditionally, the biological effects of ACOD1 have been interpreted largely through its role in itaconate generation. However, emerging evidence suggests that ACOD1 may also influence cellular responses through mechanisms that are not fully explained by itaconate itself, including remodeling of mitochondrial metabolic architecture, redistribution of tricarboxylic acid cycle intermediates, modulation of protein interactions, or participation in inflammatory signaling complexes. In some infection, sepsis, or inflammatory models, the phenotypes caused by ACOD1 deficiency cannot be fully reproduced or rescued by exogenous itaconate, raising the possibility that the enzyme, its subcellular localization, or its structural effects on metabolic networks may have independent biological significance. Distinguishing ACOD1-dependent/itaconate-dependent from ACOD1-dependent/itaconate-independent effects will be essential for a more precise understanding of this pathway.At the disease level, the bidirectional behavior of itaconate should be viewed as a core feature of its biology rather than as a collection of contradictory observations. In bacterial infection, itaconate can inhibit pathogen metabolic enzymes such as isocitrate lyase while restraining host immunopathology; however, some pathogens can degrade, tolerate, or exploit itaconate-associated metabolic states to promote survival and immune evasion. In viral infection, itaconate may regulate viral replication and inflammatory injury by modulating interferon signaling, redox state, and host metabolism. In ischemia‒reperfusion and acute lung injury models, itaconate mitigates necrosis and hyperinflammation by limiting reverse electron transport, ROS accumulation, and cell death. In metabolic dysfunction-associated steatotic liver disease, atherosclerosis, and other metabolic inflammatory disorders, it can regulate fatty acid oxidation, macrophage polarization, and fibrotic remodeling. In contrast, its role in autoimmune disease and cancer is more complex: itaconate may dampen aberrant immune activation, but excessive metabolic restraint may also impair immune clearance; itaconate or its derivatives may induce metabolic collapse, oxidative stress, or cell death in tumor cells under certain conditions, whereas itaconate produced by macrophages, neutrophils, or myeloid-derived suppressor cells in the tumor microenvironment may reinforce immune suppression, impair T-cell function, stabilize PD-L1, promote resistance to ferroptosis, and reduce responsiveness to immunotherapy. Thus, itaconate should not be classified simply as anti-inflammatory, pro-inflammatory, antitumor, or protumor. Its effect must be interpreted according to the cellular source, recipient cell, disease stage, local concentration, transport route, and metabolic context.These complexities also indicate the need to move from single-pathway models toward dynamic frameworks within multicellular ecosystems. Most existing studies have focused on individual pathways regulated by itaconate, such as NRF2 activation, SDH inhibition, NLRP3 modulation, or cell death control, whereas in vivo itaconate is likely to function as an intercellular and intercompartmental metabolic signal. The mechanisms governing metabolic coupling between cell types, intracellular and extracellular transport of itaconate, its competition or interaction with related metabolites such as succinate, fumarate, and lactate, and its effects on epigenetic state and immune-cell fate remain incompletely integrated. Emerging single-cell metabolomics, spatial omics, isotope tracing, chemoproteomics, and systems immunology approaches should be leveraged to construct cross-scale metabolism-signaling-fate frameworks that capture the temporal and spatial logic of itaconate-mediated immune regulation and tissue repair.From a translational perspective, itaconate and its derivatives have demonstrated protective potential across multiple disease models, but their pharmacokinetics, tissue distribution, therapeutic window, and delivery efficiency remain key barriers to clinical application. In acute hyperinflammatory states, oxidative injury, or ischemia‒reperfusion injury, enhancing itaconate-like signaling may help limit tissue damage. In chronic infection, tumor immune suppression, or diseases requiring sustained immune clearance, excessive activation of this pathway may be harmful. Conversely, inhibition of ACOD1/itaconate production or blockade of itaconate transport may be beneficial in selected cancers or pathogen-adaptation states but could aggravate inflammatory tissue injury in other settings. Future drug development should therefore prioritize tissue-selective delivery, temporal control, therapeutic dose windows, target-biased analogs, and biomarkers capable of distinguishing protective from pathogenic itaconate states. Integrating medicinal chemistry with materials science to develop tissue-selective and stimulus-responsive prodrugs, targeted nanocarriers, hydrogels, and immune-cell-mediated controlled-release platforms may enable precise spatial and temporal regulation in both acute and chronic inflammatory settings.Interindividual variability is another major challenge for precision intervention. Evidence indicates that the itaconate response may be modulated by sex, age, redox state, immune background, metabolic status, and microbiota composition. Integrating metabolomic data with clinical cohorts and disease stratification may help define patient subgroups with distinct itaconate responsiveness and support the development of itaconate and its regulators as metabolic biomarkers for early diagnosis, disease classification, and therapeutic response prediction. This strategy could establish a metabolism-informed precision therapy paradigm in which activation, inhibition, or local modulation of the IRG1/ACOD1-itaconate axis is selected according to individual metabolic and immune features.Looking forward, itaconate research is transitioning from mechanistic elucidation to functional reprogramming. On the one hand, structural biology and medicinal chemistry can guide the design of more stable, selective, and target-biased itaconate derivatives or covalent modulators to precisely activate or inhibit key inflammatory and metabolic pathways. On the other hand, metabolic engineering may be used to enhance itaconate production in selected cellular or microbial systems, enabling metabolism-based immunotherapeutic platforms. More importantly, the field should shift from asking whether itaconate is beneficial in a given disease to asking which cells produce itaconate, when it is produced, where it travels, which targets it engages, and under what conditions it generates protective or pathogenic outcomes. With the continued convergence of multiomics technologies, systems immunology, chemical biology, structural pharmacology, and engineered delivery platforms, the IRG1/ACOD1-itaconate axis has become an important frontier in metabolic drug discovery and precision immune modulation. Overall, this pathway should not be viewed as a unidirectional anti-inflammatory mechanism but as a tunable metabolic interface linking host defense, inflammatory resolution, tissue protection, immune suppression, and disease adaptation. Defining the rules, evidence hierarchy, and controversy boundaries of this interface will be crucial for advancing itaconate-inspired therapeutics toward precision immunometabolic medicine.ReferencesWu, R. et al. ACOD1 in immunometabolism and disease. Cell Mol. Immunol. 17, 822–833 (2020).Article CAS PubMed PubMed Central Google Scholar Luan, H. H. & Medzhitov, R. Food fight: role of itaconate and other metabolites in antimicrobial defense. Cell Metab. 24, 379–387 (2016).Article CAS PubMed PubMed Central Google Scholar Chen, R. et al. Pattern recognition receptors: function, regulation and therapeutic potential. Signal Transduct. Target. Ther. 10, 216 (2025).Article PubMed PubMed Central Google Scholar Hu, T. et al. Metabolic regulation of the immune system in health and diseases: mechanisms and interventions. Signal Transduct. Target Ther. 9, 268 (2024).Article PubMed PubMed Central Google Scholar Liu, Y. et al. Pyroptosis in health and disease: mechanisms, regulation and clinical perspective. Signal Transduct. Target Ther. 9, 245 (2024).Article PubMed PubMed Central Google Scholar Nadhan, R. et al. Decoding lysophosphatidic acid signaling in physiology and disease: mapping the multimodal and multinodal signaling networks. Signal Transduct. Target Ther. 10, 337 (2025).Article CAS PubMed PubMed Central Google Scholar Zhang, F. et al. Neutrophil diversity and function in health and disease. Signal Transduct. Target Ther. 9, 343 (2024).Article PubMed PubMed Central Google Scholar Hooftman, A. & O’Neill, L. A. J. The immunomodulatory potential of the metabolite itaconate. Trends Immunol. 40, 687–698 (2019).Article CAS PubMed Google Scholar Zasłona, Z. & O’Neill, L. A. J. Cytokine-like roles for metabolites in immunity. Mol. Cell 78, 814–823 (2020).Article PubMed Google Scholar Ryan, D. G. & O’Neill, L. A. J. Krebs cycle reborn in macrophage immunometabolism. Annu. Rev. Immunol. 38, 289–313 (2020).Article CAS PubMed Google Scholar Wu, X., Song, Y., Yuan, Z. & Wu, S. Preclinical insights into the potential of itaconate and its derivatives for liver disease therapy. Metabolism 165, 156152 (2025).Article CAS PubMed Google Scholar Yang, W., Wang, Y., Tao, K. & Li, R. Metabolite itaconate in host immunoregulation and defense. Cell Mol. Biol. Lett. 28, 100 (2023).Article CAS PubMed PubMed Central Google Scholar Murphy, M. P. & O’Neill, L. A. J. Krebs cycle reimagined: the emerging roles of succinate and itaconate as signal transducers. Cell 174, 780–784 (2018).Article CAS PubMed Google Scholar McGettrick, A. F., Bourner, L. A., Dorsey, F. C. & O’Neill, L. A. J. Metabolic messengers: itaconate. Nat. Metab. 6, 1661–1667 (2024).Article CAS PubMed Google Scholar Ryan, D. G. et al. Coupling Krebs cycle metabolites to signalling in immunity and cancer. Nat. Metab. 1, 16–33 (2019).Article CAS PubMed PubMed Central Google Scholar O’Neill, L. A. J. & Artyomov, M. N. Itaconate: the poster child of metabolic reprogramming in macrophage function. Nat. Rev. Immunol. 19, 273–281 (2019).Article PubMed Google Scholar Peace, C. G. & O’Neill, L. A. The role of itaconate in host defense and inflammation. J. Clin. Investig. 132, (2022).Shi, X. et al. The signaling pathways and therapeutic potential of itaconate to alleviate inflammation and oxidative stress in inflammatory diseases. Redox Biol. 58, 102553 (2022).Article CAS PubMed PubMed Central Google Scholar Kong, X. et al. The anti-inflammatory effects of itaconate and its derivatives in neurological disorders. Cytokine Growth Factor Rev. 78, 37–49 (2024).Article CAS PubMed Google Scholar He, R. et al. The role and therapeutic potential of itaconate in lung disease. Cell Mol. Biol. Lett. 29, 129 (2024).Article PubMed Google Scholar Yuk, J. M., Park, E. J., Kim, I. S. & Jo, E. K. Itaconate family-based host-directed therapeutics for infections. Front. Immunol. 14, 1203756 (2023).Article CAS PubMed PubMed Central Google Scholar Lohia, G. K. & Riquelme, S. A. Pathogen adaptation to lung metabolites. Curr. Opin. Microbiol. 85, 102608 (2025).Article CAS PubMed PubMed Central Google Scholar Ye, D. et al. Itaconate in host inflammation and defense. Trends Endocrinol. Metab. 35, 586–606 (2024).Article CAS PubMed Google Scholar Liu, Y. et al. Itaconate: a key regulator of immune responses and potential therapeutic target for autoimmune and inflammatory diseases. Autoimmun. Rev. 24, 103885 (2025).Article CAS PubMed Google Scholar Liu, Z. & Wang, C. Dissecting S-itaconation at host-pathogen interactions with chemical proteomics tools. Curr. Opin. Microbiol 83, 102579 (2025).Article CAS PubMed Google Scholar Luo, Y. et al. Metabolic regulation of inflammation: exploring the potential benefits of itaconate in autoimmune disorders. Immunology 174, 189–202 (2025).Article CAS PubMed Google Scholar Liu, R. et al. Itaconate: A promising precursor for treatment of neuroinflammation-associated depression. Biomed. Pharmacother. 167, 115521 (2023).Article CAS PubMed Google Scholar Day, E. A. & O’Neill, L. A. J. Protein targeting by the itaconate family in immunity and inflammation. Biochem. J. 479, 2499–2510 (2022).Article CAS PubMed Google Scholar Peace, C. G., O’Carroll, S. M. & O’Neill, L. A. J. Fumarate hydratase as a metabolic regulator of immunity. Trends Cell Biol. 34, 442–450 (2024).Article CAS PubMed Google Scholar Erlich, J. R. et al. Targeting evolutionary conserved oxidative stress and immunometabolic pathways for the treatment of respiratory infectious diseases. Antioxid. Redox Signal 32, 993–1013 (2020).Article CAS PubMed PubMed Central Google Scholar Cordes, T., Michelucci, A. & Hiller, K. Itaconic acid: the surprising role of an industrial compound as a mammalian antimicrobial metabolite. Annu. Rev. Nutr. 35, 451–473 (2015).Article CAS PubMed Google Scholar Birajdar, M. S., Joo, H., Koh, W. G. & Park, H. Natural bio-based monomers for biomedical applications: a review. Biomater. Res. 25, 8 (2021).Article CAS PubMed PubMed Central Google Scholar Li, H. et al. Mechanisms and therapeutic potential of pharmacological agents targeting inflammasomes. Biomed. Pharmacother. 189, 118164 (2025).Article CAS PubMed Google Scholar Strelko, C. L. et al. Itaconic acid is a mammalian metabolite induced during macrophage activation. J. Am. Chem. Soc. 133, 16386–16389 (2011).Article CAS PubMed PubMed Central Google Scholar Tallam, A. et al. Gene regulatory network inference of Immunoresponsive Gene 1 (IRG1) identifies Interferon Regulatory Factor 1 (IRF1) as its transcriptional regulator in mammalian macrophages. PLoS One 11, e0149050 (2016).Article PubMed PubMed Central Google Scholar Li, Y. et al. The IRG1-Itaconate axis: a regulatory hub for immunity and metabolism in macrophages. Int. Rev. Immunol. 42, 364–378 (2023).Article CAS PubMed Google Scholar Gidon, A. et al. The tumor necrosis factor alpha and interleukin 6 auto-paracrine signaling loop controls mycobacterium avium infection via induction of IRF1/IRG1 in human primary macrophages. mBio 12, e0212121 (2021).Article PubMed PubMed Central Google Scholar Wang, Z. et al. Cancer cell-intrinsic biosynthesis of itaconate promotes tumor immunogenicity. EMBO J. 43, 5530–5547 (2024).Article CAS PubMed PubMed Central Google Scholar Huang, J. et al. Macrophage scavenger receptor A1 antagonizes abdominal aortic aneurysm via upregulating IRG1. Biochem. Pharm. 213, 115631 (2023).Article CAS PubMed Google Scholar Schuster, E. M. et al. TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages. Nat. Metab. 4, 856–866 (2022).Article CAS PubMed PubMed Central Google Scholar Chen, X. et al. Glutamine limits NLRP3 inflammasome activation and pyroptosis in macrophages by sustaining the IRG1/itaconate axis. FEBS J. (2025).Chen, B. et al. Itaconic acid ameliorates necrotizing enterocolitis through the TFEB-mediated autophagy-lysosomal pathway. Free Radic. Biol. Med. 226, 251–265 (2025).Article CAS PubMed Google Scholar Chen, C. et al. Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity. Dev. Cell 59, 2807–2817.e2808 (2024).Article CAS PubMed Google Scholar Wei, X. et al. Myeloid beta-arrestin 2 depletion attenuates metabolic dysfunction-associated steatohepatitis via the metabolic reprogramming of macrophages. Cell Metab. 36, 2281–2297.e2287 (2024).Article CAS PubMed PubMed Central Google Scholar Lei, I. et al. Metabolic reprogramming by immune-responsive gene 1 up-regulation improves donor heart preservation and function. Sci. Transl. Med. 15, eade3782 (2023).Article CAS PubMed PubMed Central Google Scholar Yamaguchi, A. et al. Skeletal myotube-derived extracellular vesicles enhance itaconate production and attenuate inflammatory responses of macrophages. Front. Immunol. 14, 1099799 (2023).Article CAS PubMed PubMed Central Google Scholar Wen, Y. & Liang, Z. Enhanced itaconic acid secretion from macrophages mediates the protection of mesenchymal stem cell-derived exosomes on lipopolysaccharide-induced acute lung injury mice. Biol. Direct. 19, 138 (2024).Article CAS PubMed PubMed Central Google Scholar An, L. et al. Quercetin induces itaconic acid-mediated M1/M2 alveolar macrophages polarization in respiratory syncytial virus infection. Phytomedicine 130, 155761 (2024).Article CAS PubMed Google Scholar Xiang, Y. et al. Dihydrotanshinone I attenuates diet-induced nonalcoholic fatty liver disease via up-regulation of IRG1. Phytother. Res. 39, 1531–1548 (2025).Article CAS PubMed Google Scholar Chen, S. et al. Pharmacological upregulation of macrophage-derived itaconic acid by pubescenoside C attenuated myocardial ischemia-reperfusion injury. J. Adv. Res. 74, 571–587 (2025).Article CAS PubMed Google Scholar Tie, H. et al. LXA4 protected mice from renal ischemia/reperfusion injury by promoting IRG1/Nrf2 and IRAK-M-TRAF6 signal pathways. Clin. Immunol. 261, 110167 (2024).Article CAS PubMed Google Scholar Wu, R. et al. Aconitate decarboxylase 1 is a mediator of polymicrobial sepsis. Sci. Transl. Med. 14, eabo2028 (2022).Article CAS PubMed Google Scholar Chen, F. et al. Crystal structure of cis-aconitate decarboxylase reveals the impact of naturally occurring human mutations on itaconate synthesis. Proc. Natl. Acad. Sci. USA 116, 20644–20654 (2019).Article CAS PubMed PubMed Central Google Scholar Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018).Article CAS PubMed PubMed Central Google Scholar Chen, C. et al. ABCG2 is an itaconate exporter that limits antibacterial innate immunity by alleviating TFEB-dependent lysosomal biogenesis. Cell Metab. 36, 498–510.e411 (2024).Article CAS PubMed Google Scholar He, W. et al. Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages. Nat. Metab. 4, 524–533 (2022).Article CAS PubMed Google Scholar Lang, R. & Siddique, M. Control of immune cell signaling by the immuno-metabolite itaconate. Front. Immunol. 15, 1352165 (2024).Article CAS PubMed PubMed Central Google Scholar Pålsson-McDermott, E. M. & O’Neill, L. A. J. Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation. Cell Metab. 37, 1049–1059 (2025).Article PubMed Google Scholar Chen, F. et al. Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism. Nat. Metab. 4, 534–546 (2022).Article CAS PubMed PubMed Central Google Scholar Swain, A. et al. Comparative evaluation of itaconate and its derivatives reveals divergent inflammasome and type I interferon regulation in macrophages. Nat. Metab. 2, 594–602 (2020).Article CAS PubMed PubMed Central Google Scholar Watermann, P., Kalsi, G. K., Dringen, R. & Arend, C. Differential effects of itaconate and its esters on the glutathione and glucose metabolism of cultured primary rat astrocytes. Neurochem Res 50, 24 (2024).Article PubMed PubMed Central Google Scholar Sangineto, M. et al. Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line. Mitochondrion 79, 101966 (2024).Article CAS PubMed Google Scholar Shen, H. et al. The human knockout gene CLYBL connects itaconate to vitamin B(12). Cell 171, 771–782.e711 (2017).Article CAS PubMed PubMed Central Google Scholar Sasikaran, J. et al. Bacterial itaconate degradation promotes pathogenicity. Nat. Chem. Biol. 10, 371–377 (2014).Article CAS PubMed Google Scholar Gonner, L., Cassens, E. A., König, S. & Berg, I. A. Pseudomonadal itaconate degradation gene cluster encodes enzymes for methylsuccinate utilization. Commun. Biol. 8, 1099 (2025).Article CAS PubMed PubMed Central Google Scholar Pramanik, A. & Datta, S. Structural and functional insights of itaconyl-CoA hydratase from Pseudomonas aeruginosa highlight a novel N-terminal hotdog fold. FEBS Lett. 598, 1387–1401 (2024).Article CAS PubMed Google Scholar Huang, Q. et al. Structural and functional characterization of itaconyl-CoA hydratase and citramalyl-CoA lyase involved in itaconate metabolism of Pseudomonas aeruginosa. Structure 32, 941–952.e943 (2024).Article CAS PubMed Google Scholar Zhu, X. et al. Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes. J. Leukoc. Biol. 107, 467–484 (2020).Article CAS PubMed PubMed Central Google Scholar Ku, H. C., Shen, T. C. & Cheng, C. F. The potential of using itaconate as treatment for inflammation-related heart diseases. Tzu Chi Med. J. 34, 113–118 (2022).Article PubMed Google Scholar Qin, W. et al. S-glycosylation-based cysteine profiling reveals regulation of glycolysis by itaconate. Nat. Chem. Biol. 15, 983–991 (2019).Article CAS PubMed Google Scholar Liao, S. T. et al. 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects. Nat. Commun. 10, 5091 (2019).Article PubMed PubMed Central Google Scholar Yang, W. et al. 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to promote cuproptosis in colorectal cancer. Biomed. Pharmacother. 159, 114301 (2023).Article CAS PubMed Google Scholar Liu, D. et al. Discovery of itaconate-mediated lysine acylation. J. Am. Chem. Soc. 145, 12673–12681 (2023).Article CAS PubMed Google Scholar Wu, J. et al. 4-OI Protects MIN6 cells from oxidative stress injury by reducing LDHA-mediated ROS generation. Biomolecules 12, (2022).Hayashi, K. et al. Antitumor effect of dimethyl itaconate on thymic carcinoma by targeting LDHA-mTOR axis. Life Sci. 282, 119847 (2021).Article CAS PubMed Google Scholar Meng, Y. et al. Thermal proteome profiling of itaconate interactome in macrophages. Chem. Sci. 16, 13838–13846 (2025).Article CAS PubMed PubMed Central Google Scholar Fan, Y. et al. Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1. Cell Metab. 37, 514–526.e515 (2025).Article CAS PubMed Google Scholar Lin, M. et al. Homocysitaconate controls inflammation through reshaping methionine metabolism and N-homocysteinylation. Cell Metab. 37, 1980–1997.e1988 (2025).Article CAS PubMed Google Scholar Liu, H. et al. Acod1 promotes PAD4 ubiquitination via UBR5 alkylation to modulate NETosis and exert protective effects in sepsis. Adv. Sci. 12, e11652 (2025).Article CAS Google Scholar Wang, H. C., Li, Y. C. & Hung, M. C. Itaconate targets the ERK2 signal to suppress estrogen receptor-positive breast cancer cell growth. Am. J. Cancer Res. 15, 1133–1147 (2025).Article CAS PubMed PubMed Central Google Scholar Yin, S. et al. Itaconate facilitates viral infection via alkylating GDI2 and retaining Rab GTPase on the membrane. Signal Transduct. Target Ther. 9, 371 (2024).Article CAS PubMed PubMed Central Google Scholar Wei, C. et al. Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke. Cell Death Differ. 31, 983–998 (2024).Article CAS PubMed PubMed Central Google Scholar Luo, Z. et al. Targeted macrophage phagocytosis by IRG1/itaconate axis improves the prognosis of intracerebral hemorrhagic stroke and peritonitis. EBioMedicine 101, 104993 (2024).Article CAS PubMed PubMed Central Google Scholar Gong, W. et al. 4-Octyl itaconate blocks GSDMB-mediated pyroptosis and restricts inflammation by inactivating granzyme A. Cell Prolif. 57, e13711 (2024).Article CAS PubMed PubMed Central Google Scholar Bourner, L. A. et al. Endogenously produced itaconate negatively regulates innate-driven cytokine production and drives global ubiquitination in human macrophages. Cell Rep. 43, 114570 (2024).Article CAS PubMed Google Scholar Li, W. et al. 4-octyl itaconate as a metabolite derivative inhibits inflammation via alkylation of STING. Cell Rep. 42, 112145 (2023).Article CAS PubMed Google Scholar Su, C. et al. 4-Octyl itaconate restricts STING activation by blocking its palmitoylation. Cell Rep. 42, 113040 (2023).Article CAS PubMed Google Scholar Giangregorio, N. et al. Inhibition of the mitochondrial carnitine/acylcarnitine carrier by itaconate through irreversible binding to cysteine 136: possible pathophysiological implications. Biomolecules 13, (2023).Ribó-Molina, P. et al. 4-Octyl itaconate reduces influenza A replication by targeting the nuclear export protein CRM1. J. Virol. 97, e0132523 (2023).Article PubMed PubMed Central Google Scholar Runtsch, M. C. et al. Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages. Cell Metab. 34, 487–501.e488 (2022).Article CAS PubMed Google Scholar Chen, L. L. et al. Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses. Nat. Cell Biol. 24, 353–363 (2022).Article CAS PubMed PubMed Central Google Scholar Zhang, Z. et al. Itaconate is a lysosomal inducer that promotes antibacterial innate immunity. Mol. Cell 82, 2844–2857.e2810 (2022).Article CAS PubMed Google Scholar Bambouskova, M. et al. Itaconate confers tolerance to late NLRP3 inflammasome activation. Cell Rep. 34, 108756 (2021).Article CAS PubMed PubMed Central Google Scholar Kwai, B. X. C. et al. Itaconate is a covalent inhibitor of the Mycobacterium tuberculosis isocitrate lyase. RSC Med. Chem. 12, 57–61 (2021).Article CAS PubMed Google Scholar Hooftman, A. et al. The immunomodulatory metabolite itaconate modifies NLRP3 and inhibits inflammasome activation. Cell Metab. 32, 468–478.e467 (2020).Article CAS PubMed PubMed Central Google Scholar Liu, H. et al. Four-octyl itaconate activates Keap1-Nrf2 signaling to protect neuronal cells from hydrogen peroxide. Cell Commun. Signal 16, 81 (2018).Article CAS PubMed PubMed Central Google Scholar Heinz, A. et al. Itaconate controls its own synthesis via feedback-inhibition of reverse TCA cycle activity at IDH2. Biochim. Biophys. Acta Mol. Basis Dis. 1868, 166530 (2022).Article CAS PubMed Google Scholar Cordes, T. & Metallo, C. M. Itaconate alters succinate and coenzyme A metabolism via inhibition of mitochondrial complex II and methylmalonyl-CoA mutase. Metabolites 11, (2021).Cordes, T. et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 291, 14274–14284 (2016).Article CAS PubMed PubMed Central Google Scholar Lampropoulou, V. et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 24, 158–166 (2016).Article CAS PubMed PubMed Central Google Scholar Wang, H. C. et al. IRG1/Itaconate induces metabolic reprogramming to suppress ER-positive breast cancer cell growth. Am. J. Cancer Res 13, 1067–1081 (2023).CAS PubMed PubMed Central Google Scholar Németh, B. et al. Abolition of mitochondrial substrate-level phosphorylation by itaconic acid produced by LPS-induced Irg1 expression in cells of murine macrophage lineage. FASEB J. 30, 286–300 (2016).Article PubMed Google Scholar Belosludtsev, K. N. et al. Itaconic acid impairs the mitochondrial function by the inhibition of complexes II and IV and induction of the permeability transition pore opening in rat liver mitochondria. Biochimie 176, 150–157 (2020).Article CAS PubMed Google Scholar Zhang, X. et al. Tumor-associated macrophage-derived itaconic acid contributes to nasopharyngeal carcinoma progression by promoting immune escape via TET2. Cell Commun. Signal 22, 413 (2024).Article CAS PubMed PubMed Central Google Scholar Rong, K. et al. Inflammatory macrophage-derived itaconate inhibits DNA demethylase TET2 to prevent excessive osteoclast activation in rheumatoid arthritis. Bone Res. 13, 60 (2025).Article CAS PubMed PubMed Central Google Scholar Zhang, J. X. et al. Xianglian pill alleviates ulcerative colitis by inhibiting M1 macrophage polarization via modulation of energy metabolite itaconate. Phytomedicine 135, 156179 (2024).Article CAS PubMed Google Scholar Wang, Y. Z. et al. Dissection of immunotherapeutic predictive versus prognostic transcriptional programs identifies SLC22A5-centric carnitine metabolism-driven resistance to anti-PD-(L)1 treatment in non-small cell lung cancer. Drug Resist. Updat. 84, 101313 (2025).Article PubMed Google Scholar Zhang, J. & Gu, J. Metabolic basis of fatty acid oxidation and immunotherapy resistance with clinical perspectives. Drug Resist. Updat. 84, 101317 (2025).Article PubMed Google Scholar Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis. Nature 556, 501–504 (2018).Article CAS PubMed PubMed Central Google Scholar Yang, W. et al. Immune Response Gene-1 [IRG1]/itaconate protect against multi-organ injury via inhibiting gasdermin D-mediated pyroptosis and inflammatory response. Inflammopharmacology 32, 419–432 (2024).Article CAS PubMed Google Scholar Shen, S. et al. Immune-response gene 1 deficiency aggravates inflammation-triggered cardiac dysfunction by inducing M1 macrophage polarization and aggravating Ly6C(high) monocyte recruitment. Biol. Direct. 19, 86 (2024).Article CAS PubMed PubMed Central Google Scholar Qiu, J. H. et al. Deficiency of IRG1/itaconate aggravates endotoxemia-induced acute lung injury by inhibiting autophagy in mice. Exp. Anim. 72, 164–172 (2023).Article CAS PubMed Google Scholar Xu, L. et al. 4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling. Mol. Med. 29, 58 (2023).Article CAS PubMed PubMed Central Google Scholar He, R. et al. Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury. Cell Death Discov. 8, 43 (2022).Article CAS PubMed Google Scholar Xin, Y., Zou, L. & Lang, S. 4-Octyl itaconate (4-OI) attenuates lipopolysaccharide-induced acute lung injury by suppressing PI3K/Akt/NF-κB signaling pathways in mice. Exp. Ther. Med. 21, 141 (2021).Article CAS PubMed Google Scholar Li, R. et al. 4-Octyl itaconate alleviates endothelial cell inflammation and barrier dysfunction in LPS-induced sepsis via modulating TLR4/MAPK/NF-κB signaling : 4-Octyl itaconate alleviates endothelial dysfunction. Mol. Med. 31, 240 (2025).Article CAS PubMed PubMed Central Google Scholar Darvish Khadem, M. et al. Dimethyl itaconate reprograms neurotoxic to neuroprotective primary astrocytes through the regulation of NLRP3 inflammasome and NRF2/HO-1 pathways. Mol. Cell Neurosci. 122, 103758 (2022).Article CAS PubMed Google Scholar Unni, S. et al. Structural insights into the multiple binding modes of Dimethyl Fumarate (DMF) and its analogs to the Kelch domain of Keap1. FEBS J. 288, 1599–1613 (2021).Article CAS PubMed Google Scholar Diskin, C. et al. 4-Octyl itaconate and dimethyl fumarate induce secretion of the anti-inflammatory protein annexin A1 via NRF2. J. Immunol. 211, 1032–1041 (2023).Article CAS PubMed PubMed Central Google Scholar Sun, D. S. & Chang, H. H. Emerging role of the itaconate-mediated rescue of cellular metabolic stress. Tzu Chi Med. J. 34, 134–138 (2022).Article PubMed Google Scholar Zhou, P. et al. IRG1/itaconate alleviates acute liver injury in septic mice by suppressing NLRP3 expression and its mediated macrophage pyroptosis via regulation of the Nrf2 pathway. Int. Immunopharmacol. 135, 112277 (2024).Article CAS PubMed Google Scholar Wu, X. et al. The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function. Pharm. Res. 198, 107016 (2023).Article CAS Google Scholar Wang, Y., Zhou, M., Jiang, R. Y. & Zhu, C. L. Pharmacological inhibition of STING-mediated GPX4 autophagic degradation by 4-octyl itaconate ameliorates sepsis-induced acute kidney injury. Apoptosis 30, 1410–1423 (2025).Article CAS PubMed Google Scholar Burczyk, G., Cichon, I. & Kolaczkowska, E. Itaconate Suppresses Formation of Neutrophil Extracellular Traps (NETs): involvement of hypoxia-inducible factor 1α (Hif-1α) and heme oxygenase (HO-1). Front. Immunol. 13, 864638 (2022).Article CAS PubMed PubMed Central Google Scholar Ji, J. et al. IRG1/ACOD1 promotes neutrophil reverse migration and alleviates local inflammation. J. Leukoc. Biol. 116, 854–863 (2024).Article CAS PubMed PubMed Central Google Scholar Hou, K. et al. Microbiota in health and diseases. Signal Transduct. Target Ther. 7, 135 (2022).Article PubMed PubMed Central Google Scholar Michelucci, A. et al. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc. Natl. Acad. Sci. USA 110, 7820–7825 (2013).Article CAS PubMed PubMed Central Google Scholar Nair, S. et al. Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection. J. Exp. Med. 215, 1035–1045 (2018).Article CAS PubMed PubMed Central Google Scholar Bomfim, C. C. B. et al. Mycobacterium tuberculosis Induces Irg1 in Murine Macrophages by a Pathway Involving Both TLR-2 and STING/IFNAR Signaling and Requiring Bacterial Phagocytosis. Front Cell Infect. Microbiol 12, 862582 (2022).Article CAS PubMed PubMed Central Google Scholar Krebs, A. S. et al. Human iPSC-derived alveolar macrophages reveal macrophage subtype functions of itaconate in M. tuberculosis defense. JCI Insight. 11, e198342 (2026).Ruetz, M. et al. Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair. Science 366, 589–593 (2019).Article CAS PubMed PubMed Central Google Scholar Priya, M. et al. Itaconate mechanism of action and dissimilation in Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 122, e2423114122 (2025).Article CAS PubMed PubMed Central Google Scholar Daniel, J., Oh, T. J., Lee, C. M. & Kolattukudy, P. E. AccD6, a member of the Fas II locus, is a functional carboxyltransferase subunit of the acyl-coenzyme A carboxylase in Mycobacterium tuberculosis. J. Bacteriol. 189, 911–917 (2007).Article CAS PubMed Google Scholar Wang, H. et al. An essential bifunctional enzyme in Mycobacterium tuberculosis for itaconate dissimilation and leucine catabolism. Proc. Natl. Acad. Sci. USA 116, 15907–15913 (2019).Article CAS PubMed PubMed Central Google Scholar Abhimanyu et al. TCA metabolism regulates DNA hypermethylation in LPS and Mycobacterium tuberculosis-induced immune tolerance. Proc. Natl. Acad. Sci. USA 121, e2404841121 (2024).Article CAS PubMed PubMed Central Google Scholar Breen, P., Zimbric, M. & Caverly, L. J. Itaconic acid inhibits nontuberculous mycobacterial growth in pH dependent manner while 4-octyl-itaconic acid enhances THP-1 clearance of nontuberculous mycobacteria in vitro. PLoS One 19, e0303516 (2024).Article CAS PubMed PubMed Central Google Scholar Kim, Y. J. et al. Dimethyl itaconate is effective in host-directed antimicrobial responses against mycobacterial infections through multifaceted innate immune pathways. Cell Biosci. 13, 49 (2023).Article PubMed PubMed Central Google Scholar Chen, M. et al. Itaconate is an effector of a Rab GTPase cell-autonomous host defense pathway against Salmonella. Science 369, 450–455 (2020).Article CAS PubMed PubMed Central Google Scholar Liu, Z., Liu, D. & Wang, C. In situ chemoproteomic profiling reveals itaconate inhibits de novo purine biosynthesis in pathogens. Cell Rep. 43, 114737 (2024).Article CAS PubMed Google Scholar Zhu, X. et al. Itaconic acid exerts anti-inflammatory and antibacterial effects via promoting pentose phosphate pathway to produce ROS. Sci. Rep. 11, 18173 (2021).Article CAS PubMed PubMed Central Google Scholar Hersch, S. J. & Navarre, W. W. The Salmonella LysR family regulator RipR activates the SPI-13-encoded itaconate degradation cluster. Infect. Immun. 88, (2020).Ki, N. et al. Isocitrate binds to the itaconic acid-responsive LysR-type transcriptional regulator RipR in Salmonella pathogenesis. J. Biol. Chem. 298, 102562 (2022).Article CAS PubMed PubMed Central Google Scholar Hammerer, F. et al. Small Molecule restores itaconate sensitivity in Salmonella enterica: a potential new approach to treating bacterial infections. Chembiochem 17, 1513–1517 (2016).Article CAS PubMed Google Scholar Naujoks, J. et al. IFNs modify the proteome of legionella-containing vacuoles and restrict infection Via IRG1-derived itaconic acid. PLoS Pathog. 12, e1005408 (2016).Article PubMed PubMed Central Google Scholar Price, J. V. et al. IRG1 and inducible nitric oxide synthase act redundantly with other interferon-gamma-induced factors to restrict intracellular replication of Legionella pneumophila. mBio. 10, (2019).Kohl, L. et al. Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever. EMBO Mol. Med. 15, e15931 (2023).Article CAS PubMed Google Scholar Siddique, M. et al. Divergent effects of itaconate isomers on Coxiella burnetii growth in macrophages and in axenic culture. Front. Immunol. 15, 1427457 (2024).Article CAS PubMed PubMed Central Google Scholar Demars, A. et al. Aconitate decarboxylase 1 participates in the control of pulmonary Brucella infection in mice. PLoS Pathog. 17, e1009887 (2021).Article CAS PubMed PubMed Central Google Scholar Lacey, C. A. et al. MyD88-dependent glucose restriction and itaconate production control Brucella infection. Infect. Immun. 89, e0015621 (2021).Article PubMed PubMed Central Google Scholar Jessop, F. et al. Interferon gamma reprograms host mitochondrial metabolism through inhibition of complex II To control intracellular bacterial replication. Infect. Immun. 88, (2020).Roberts, L. M. et al. Itaconate indirectly influences expansion of effector T cells following vaccination with Francisella tularensis live vaccine strain. Cell Immunol. 373, 104485 (2022).Article CAS PubMed Google Scholar Tomlinson, K. L. et al. Staphylococcus aureus induces an itaconate-dominated immunometabolic response that drives biofilm formation. Nat. Commun. 12, 1399 (2021).Article CAS PubMed PubMed Central Google Scholar Loi, V. V. et al. Staphylococcus aureus adapts to the immunometabolite itaconic acid by inducing acid and oxidative stress responses, including S-bacillithiolations and S-itaconations. Free Radic. Biol. Med. 208, 859–876 (2023).Article CAS PubMed Google Scholar Ferreira, A. V. et al. Dimethyl itaconate induces long-term innate immune responses and confers protection against infection. Cell Rep. 42, 112658 (2023).Article CAS PubMed Google Scholar Zhao, R. et al. Itaconate induces tolerance of Staphylococcus aureus to aminoglycoside antibiotics. Front. Microbiol 15, 1450085 (2024).Article CAS PubMed PubMed Central Google Scholar Chen, Y. T. et al. Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia. Nat. Commun. 16, 7050 (2025).Article CAS PubMed PubMed Central Google Scholar Tomlinson, K. L. et al. Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst. Cell Rep. 42, 112064 (2023).Article CAS PubMed PubMed Central Google Scholar Forde, A. J. et al. Metabolic rewiring tunes dermal macrophages in staphylococcal skin infection. Sci. Immunol. 8, eadg3517 (2023).Article CAS PubMed Google Scholar Singh, S. et al. Integrative metabolomics and transcriptomics identifies itaconate as an adjunct therapy to treat ocular bacterial infection. Cell Rep. Med. 2, 100277 (2021).Article PubMed PubMed Central Google Scholar Zeng, Y. R. et al. The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response. J. Clin. Investig. 133, (2023).McBride, M. A. et al. Immunoresponsive gene 1 facilitates TLR4 agonist-induced augmentation of innate antimicrobial immunity. J. Leukoc. Biol. 117, (2025).Ho, D. K. et al. Itaconic acid increases the efficacy of tobramycin against Pseudomonas aeruginosa Biofilms. Pharmaceutics. 12, (2020).Gao, N. et al. Hyperglycemia-suppressed Acod1 expression contributes to innate immune deficiency in Pseudomonas aeruginosa Keratitis. Invest Ophthalmol. Vis. Sci. 66, 51 (2025).Article CAS PubMed PubMed Central Google Scholar Riquelme, S. A. et al. CFTR-PTEN-dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection. Sci. Transl. Med. 11, (2019).Runtsch, M. C. & O’Neill, L. A. J. Pseudomonas persists by feeding off itaconate. Cell Metab. 31, 1045–1047 (2020).Article CAS PubMed Google Scholar Riquelme, S. A. et al. Pseudomonas aeruginosa utilizes host-derived itaconate to redirect its metabolism to promote biofilm formation. Cell Metab. 31, 1091–1106.e1096 (2020).Article CAS PubMed PubMed Central Google Scholar Tomlinson, K. L. et al. Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection. Cell Metab. 35, 1767–1781.e1766 (2023).Article CAS PubMed PubMed Central Google Scholar Chen, Y. T. et al. A host-pathogen metabolic synchrony that facilitates disease tolerance. Nat. Commun. 16, 3729 (2025).Article CAS PubMed PubMed Central Google Scholar Li, S. et al. Acetylation of CspC controls the las quorum-sensing system through translational regulation of rsaL in Pseudomonas aeruginosa. mBio 13, e0054722 (2022).Article PubMed PubMed Central Google Scholar O’Callaghan, A. A. et al. Intestinal metabolites influence macrophage phagocytosis and clearance of bacterial infection. Front Cell Infect. Microbiol 11, 622491 (2021).Article PubMed PubMed Central Google Scholar He, Y. et al. Dimethyl itaconate alleviates escherichia coli-induced endometritis through the guanosine-CXCL14 axis via increasing the abundance of norank_f_Muribaculaceae. Adv. Sci 12, e2414792 (2025).Article Google Scholar Han, P. et al. Metabolomics reveals immunomodulation as a possible mechanism for the antibiotic effect of Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross. Metabolomics 14, 91 (2018).Article PubMed PubMed Central Google Scholar Zhang, T., Hasegawa, Y. & Waldor, M. K. Enteric bacterial infection stimulates remodelling of bile metabolites to promote intestinal homeostasis. Nat. Microbiol. 9, 3376–3390 (2024).Article CAS PubMed PubMed Central Google Scholar Nguyen, T. V. et al. Itaconic acid inhibits growth of a pathogenic marine Vibrio strain: a metabolomics approach. Sci. Rep. 9, 5937 (2019).Article PubMed PubMed Central Google Scholar Zhan, Z. et al. Overabundance of Veillonella parvula promotes intestinal inflammation by activating macrophages via LPS-TLR4 pathway. Cell Death Discov. 8, 251 (2022).Article CAS PubMed PubMed Central Google Scholar Li, Y. et al. Itaconate inhibits SYK through alkylation and suppresses inflammation against hvKP-induced intestinal dysbiosis. Cell Mol. Life Sci. 80, 337 (2023).Article CAS PubMed PubMed Central Google Scholar Sohail, A. et al. Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection. PLoS Pathog. 18, e1010219 (2022).Article CAS PubMed PubMed Central Google Scholar Sethy, B. et al. Design, synthesis, and biological evaluation of itaconic acid derivatives as potential anti-influenza agents. J. Med. Chem. 62, 2390–2403 (2019).Article CAS PubMed Google Scholar Ryan, T. A. J. et al. Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon. Nat. Commun. 14, 3513 (2023).Article CAS PubMed PubMed Central Google Scholar Liu, Y. et al. A urinary proteomic landscape of COVID-19 progression identifies signaling pathways and therapeutic options. Sci. China Life Sci. 65, 1866–1880 (2022).Article CAS PubMed PubMed Central Google Scholar Cui, S. et al. Integration of metabolomics methodologies for the development of predictive models for mortality risk in elderly patients with severe COVID-19. BMC Infect. Dis. 25, 10 (2025).Article CAS PubMed PubMed Central Google Scholar Daniels, B. P. et al. The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons. Immunity 50, 64–76.e64 (2019).Article CAS PubMed PubMed Central Google Scholar Cui, B. C. et al. Suppression of HIV-TAT and cocaine-induced neurotoxicity and inflammation by cell penetrable itaconate esters. J. Neurovirol. 30, 337–352 (2024).Article CAS PubMed PubMed Central Google Scholar Ren, K. et al. Suppression of IRG-1 reduces inflammatory cell infiltration and lung injury in respiratory syncytial virus infection by reducing production of reactive oxygen species. J. Virol. 90, 7313–7322 (2016).Article CAS PubMed PubMed Central Google Scholar Liu, Y. et al. N (6)-methyladenosine RNA modification-mediated cellular metabolism rewiring inhibits viral replication. Science 365, 1171–1176 (2019).Article CAS PubMed Google Scholar Yue, Y. X. et al. 4-Octyl itaconate inhibits poly(I:C)-induced interferon-β secretion in mouse bone marrow-derived macrophages partially by activating Nrf2. Heliyon 9, e23001 (2023).Article CAS PubMed PubMed Central Google Scholar Gu, L. et al. Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO-1 signaling pathway. Immunol. Cell Biol. 98, 229–241 (2020).Article CAS PubMed PubMed Central Google Scholar Márquez, S. et al. Tricarboxylic acid cycle activity and remodeling of glycerophosphocholine lipids support cytokine induction in response to fungal patterns. Cell Rep. 27, 525–536.e524 (2019).Article PubMed Google Scholar Wu, Y. et al. Dimethyl itaconate ameliorates the deficits of goal-directed behavior in Toxoplasma gondii-infected mice. PLoS Negl. Trop. Dis. 17, e0011350 (2023).Article CAS PubMed PubMed Central Google Scholar He, Y. et al. A metabolite attenuates neuroinflammation, synaptic loss and cognitive deficits induced by chronic infection of Toxoplasma gondii. Front. Immunol. 13, 1043572 (2022).Article CAS PubMed Google Scholar Prenen, F. et al. Itaconate has limited protective effects in experimental malaria models. Eur. J. Immunol. 55, e202451595 (2025).Article CAS PubMed Google Scholar Ramalho, T. et al. Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells. Cell Metab. 36, 484–497.e486 (2024).Article CAS PubMed PubMed Central Google Scholar Kihel, A. et al. Itaconate: a nexus metabolite fueling leishmania survival through lipid metabolism modulation. Microorganisms 13, (2025).Wang, C. et al. Suppressing neutrophil itaconate production attenuates Mycoplasma pneumoniae pneumonia. PLoS Pathog. 20, e1012614 (2024).Article CAS PubMed PubMed Central Google Scholar Frieler, R. A. et al. Aconitate decarboxylase 1 regulates glucose homeostasis and obesity in mice. Obesity 30, 1818–1830 (2022).Article CAS PubMed PubMed Central Google Scholar Muñoz, V. R. et al. Portal vein-enriched metabolites as intermediate regulators of the gut microbiome in insulin resistance. Cell Metab. 37, 2048–2065.e2046 (2025).Article PubMed PubMed Central Google Scholar Yu, Z. et al. Itaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis. Cell Rep. 43, 114142 (2024).Article CAS PubMed Google Scholar Sakai, A., Kusumoto, A., Kiso, Y. & Furuya, E. Itaconate reduces visceral fat by inhibiting fructose 2,6-bisphosphate synthesis in rat liver. Nutrition 20, 997–1002 (2004).Article CAS PubMed Google Scholar Park, S. Y. et al. Dimethyl itaconate attenuates palmitate-induced insulin resistance in skeletal muscle cells through the AMPK/FGF21/PPARδ-mediated suppression of inflammation. Life Sci. 287, 120129 (2021).Article CAS PubMed Google Scholar Zhu, L. et al. Acod1/itaconate activates Nrf2 in pulmonary microvascular endothelial cells to protect against the obesity-induced pulmonary microvascular endotheliopathy. Respir. Res. 25, 205 (2024).Article CAS PubMed PubMed Central Google Scholar Drougard, A. et al. An acute microglial metabolic response controls metabolism and improves memory. Elife. 12, (2024).Pan, W. et al. Dimethyl itaconate ameliorates cognitive impairment induced by a high-fat diet via the gut-brain axis in mice. Microbiome 11, 30 (2023).Article PubMed PubMed Central Google Scholar Eberhart, T. et al. ACOD1 deficiency offers protection in a mouse model of diet-induced obesity by maintaining a healthy gut microbiota. Cell Death Dis. 15, 105 (2024).Article CAS PubMed PubMed Central Google Scholar He, S. et al. 4-Octyl itaconate attenuates glycemic deterioration by regulating macrophage polarization in mouse models of type 1 diabetes. Mol. Med. 29, 31 (2023).Article CAS PubMed Google Scholar Shao, M. et al. 4-Octyl itaconate attenuates renal tubular injury in db/db mice by activating Nrf2 and promoting PGC-1α-mediated mitochondrial biogenesis. Ren. Fail 46, 2403653 (2024).Article PubMed PubMed Central Google Scholar Zou, X. et al. 4-octyl itaconate inhibits high glucose induced renal tubular epithelial cell fibrosis through TGF-β-ROS pathway. J. Recept Signal Transduct. Res. 44, 27–34 (2024).Article CAS PubMed Google Scholar Tang, C. et al. Activation of Keap1-Nrf2 signaling by 4-octyl itaconate protects human umbilical vein endothelial cells from high glucose. Biochem Biophys. Res. Commun. 508, 921–927 (2019).Article CAS PubMed Google Scholar El-Derany, M. O. et al. Itaconate potentiates hepatic gluconeogenesis through NRF2 induction. PLoS One 20, e0322946 (2025).Article CAS PubMed PubMed Central Google Scholar Zhang, X. et al. Immune response gene 1 deficiency aggravates high-fat diet-induced nonalcoholic fatty liver disease via promotion of redox-sensitive AKT suppression. Biochim. Biophys. Acta Mol. Basis Dis. 1869, 166656 (2023).Article CAS PubMed Google Scholar Weiss, J. M. et al. Itaconic acid underpins hepatocyte lipid metabolism in non-alcoholic fatty liver disease in male mice. Nat. Metab. 5, 981–995 (2023).Article CAS PubMed PubMed Central Google Scholar Cyr, Y. et al. The IRG1-itaconate axis protects from cholesterol-induced inflammation and atherosclerosis. Proc. Natl. Acad. Sci. USA 121, e2400675121 (2024).Article CAS PubMed PubMed Central Google Scholar Song, J. et al. Itaconate suppresses atherosclerosis by activating a Nrf2-dependent antiinflammatory response in macrophages in mice. J. Clin. Invest. 134, (2023).Haase, L. et al. Modulation of the ACOD1/itaconate pathway differentially affects atherosclerosis severity across genetic models and sexes. J. Clin. Invest. 135, (2025).Harber, K. J. et al. Targeting the ACOD1-itaconate axis stabilizes atherosclerotic plaques. Redox Biol. 70, 103054 (2024).Article CAS PubMed PubMed Central Google Scholar Song, H. et al. Itaconate prevents abdominal aortic aneurysm formation through inhibiting inflammation via activation of Nrf2. EBioMedicine 57, 102832 (2020).Article PubMed PubMed Central Google Scholar Li, X. et al. Anti-inflammatory cytokines IL-35 and IL-10 block atherogenic lysophosphatidylcholine-induced, mitochondrial ROS-mediated innate immune activation, but spare innate immune memory signature in endothelial cells. Redox Biol. 28, 101373 (2020).Article CAS PubMed Google Scholar Dong, Q. et al. 4-Octyl itaconate inhibits vascular calcification partially via modulation of HMOX-1 signaling. Eur. J. Pharm. 985, 177122 (2024).Article CAS Google Scholar Marcero, J. R. et al. The immunometabolite itaconate inhibits heme synthesis and remodels cellular metabolism in erythroid precursors. Blood Adv. 5, 4831–4841 (2021).Article CAS PubMed PubMed Central Google Scholar Burch, J. S. et al. Glutamine via α-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis. Blood 132, 987–998 (2018).Article CAS PubMed PubMed Central Google Scholar Liang, J. Y. et al. Itaconate inhibits corticosterone-induced necroptosis and neuroinflammation via up-regulating menin in HT22 cells. J. Physiol. Biochem. 80, 393–405 (2024).Article CAS PubMed Google Scholar Liu, N. et al. Itaconate restrains acute proinflammatory activation of microglia after traumatic brain injury in mice. Sci. Transl. Med. 17, eadn2635 (2025).Article CAS PubMed Google Scholar Ni, L. et al. Immune-responsive gene 1/itaconate activates nuclear factor erythroid 2-related factor 2 in microglia to protect against spinal cord injury in mice. Cell Death Dis. 13, 140 (2022).Article CAS PubMed PubMed Central Google Scholar Qian, Z. et al. ACOD1, rather than itaconate, facilitates p62-mediated activation of Nrf2 in microglia post spinal cord contusion. Clin. Transl. Med. 14, e1661 (2024).Article CAS PubMed PubMed Central Google Scholar Deng, J. et al. Immune-responsive gene 1/itaconate pathway inhibits microglia activation to alleviate traumatic optic neuropathy in mice. Int. Immunopharmacol. 149, 114199 (2025).Article CAS PubMed Google Scholar Ghotbeddin, Z. et al. Neonatal febrile seizures: Dimethyl itaconate’s role in behavioral recovery and glutathione enzyme modulation in adult rats. PLoS One 20, e0318430 (2025).Article CAS PubMed PubMed Central Google Scholar Zhang, L. et al. 4-octyl itaconate alleviates cisplatin-induced ferroptosis possibly via activating the NRF2/HO-1 signalling pathway. J. Cell Mol. Med. 28, e18207 (2024).Article CAS PubMed PubMed Central Google Scholar Abbaszadeh, M., Ghotbeddin, Z., Tabandeh, M. R. & Rahimi, K. The impact of dimethyl itaconate on c-Fos expression in the spinal cord in experimental pain models. Neurosci. Lett. 828, 137741 (2024).Article CAS PubMed Google Scholar Lin, J. et al. Dimethyl itaconate attenuates CFA-induced inflammatory pain via the NLRP3/ IL-1β signaling pathway. Front. Pharm. 13, 938979 (2022).Article CAS Google Scholar Sun, Q. et al. IRG1/itaconate increases IL-10 release to alleviate mechanical and thermal hypersensitivity in mice after nerve injury. Front. Immunol. 13, 1012442 (2022).Article CAS PubMed PubMed Central Google Scholar Ren, J. et al. Dimethyl itaconate inhibits neuroinflammation to alleviate chronic pain in mice. Neurochem. Int. 154, 105296 (2022).Article CAS PubMed Google Scholar Rahimi, K., Abbaszadeh, M., Bakhtazad, S. & Ghotbeddin, Z. Effects of dimethyl itaconate on expressions of NGFI-A and NGFI-B and inflammatory cytokines in the spinal cord in the formalin test. Brain Commun. 6, fcae397 (2024).Article CAS PubMed PubMed Central Google Scholar Azari, N., Rezaee, M., Dayer, D. & Tabandeh, M. R. Dimethyl itaconate modulates neuroprotective effect on primary rat astrocytes under inflammatory condition by regulating the expression of neurotrophic factors and TrkA/B-P75 receptors. Neurol. Res. 46, 1137–1148 (2024).Article CAS PubMed Google Scholar Ohm, M. et al. The potential therapeutic role of itaconate and mesaconate on the detrimental effects of LPS-induced neuroinflammation in the brain. J. Neuroinflamm. 21, 207 (2024).Article CAS Google Scholar Wang, X., Kong, W., Yang, R. & Yang, C. 4-octyl itaconate ameliorates ventilator-induced lung injury. Arch. Biochem. Biophys. 752, 109853 (2024).Article CAS PubMed Google Scholar Liu, C. et al. Itaconic acid regulation of TFEB-mediated autophagy flux alleviates hyperoxia-induced bronchopulmonary dysplasia. Redox Biol. 72, 103115 (2024).Article CAS PubMed PubMed Central Google Scholar Titz, B. et al. Multi-omics systems toxicology study of mouse lung assessing the effects of aerosols from two heat-not-burn tobacco products and cigarette smoke. Comput. Struct. Biotechnol. J. 18, 1056–1073 (2020).Article CAS PubMed PubMed Central Google Scholar Hu, Z. et al. OTUB1-SLC7A11 axis mediates 4-octyl itaconate protection against acetaminophen-induced ferroptotic liver injury. Antioxidants. 14, (2025).Hu, Z. et al. 4-octyl itaconate protects against oxidative stress-induced liver injury by activating the Nrf2/Sirt3 pathway through AKT and ERK1/2 phosphorylation. Biochem. Pharm. 220, 115992 (2024).Article CAS PubMed Google Scholar Li, R. et al. 4-OI attenuates carbon tetrachloride-induced hepatic injury via regulating oxidative stress and the inflammatory response. Front. Pharm. 12, 651444 (2021).Article CAS Google Scholar Ni, S. T. et al. Anti-necroptotic effects of itaconate and its derivatives. Inflammation 47, 285–306 (2024).Article CAS PubMed Google Scholar Lu, S. et al. 4-octyl itaconate attenuates acute pancreatitis and associated lung injury by suppressing ferroptosis in mice. Inflammation (2025).Wu, L. et al. Itaconic acid alleviates perfluorooctanoic acid-induced oxidative stress and intestinal damage by regulating the Keap1/Nrf2/Ho-1 pathway and reshaping the gut microbiota. Int. J. Mol. Sci. 25, (2024).Wang, F. et al. Analysis of serum metabolism in premature infants before and after feeding using GC-MS and the relationship with necrotizing enterocolitis. Biomed. Chromatogr. 37, e5505 (2023).Article CAS PubMed Google Scholar Huangfu, S. et al. Itaconate suppresses neonatal intestinal inflammation via metabolic reprogramming of M1 macrophage. Clin. Transl. Med. 15, e70419 (2025).Article CAS PubMed PubMed Central Google Scholar Zheng, Y. et al. Four-octyl itaconate activates Nrf2 cascade to protect osteoblasts from hydrogen peroxide-induced oxidative injury. Cell Death Dis. 11, 772 (2020).Article CAS PubMed PubMed Central Google Scholar Du, Y. et al. 4-Octyl itaconate promotes alveolar ridge preservation following tooth extraction. Odontology 112, 1069–1079 (2024).Article CAS PubMed Google Scholar Crossley, J. L. et al. Itaconate-producing neutrophils regulate local and systemic inflammation following trauma. JCI Insight. 8, (2023).Maassen, S. et al. Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages. Redox Biol. 59, 102591 (2023).Article CAS PubMed Google Scholar Lina, I. A. et al. Identifying phenotypically distinct fibroblast subsets in type 2 diabetes-associated iatrogenic laryngotracheal stenosis. Otolaryngol. Head. Neck Surg. 166, 712–719 (2022).Article PubMed Google Scholar Chausse, B., Lewen, A., Poschet, G. & Kann, O. Selective inhibition of mitochondrial respiratory complexes controls the transition of microglia into a neurotoxic phenotype in situ. Brain Behav. Immun. 88, 802–814 (2020).Article CAS PubMed Google Scholar Wang, G. et al. Itaconate promotes mitophagy to inhibit neuronal ferroptosis after subarachnoid hemorrhage. Apoptosis 30, 991–1004 (2025).Article CAS PubMed Google Scholar Kuo, P. C. et al. Immunoresponsive gene 1 modulates the severity of brain injury in cerebral ischaemia. Brain Commun. 3, fcab187 (2021).Article PubMed PubMed Central Google Scholar Cordes, T. et al. Itaconate modulates tricarboxylic acid and redox metabolism to mitigate reperfusion injury. Mol. Metab. 32, 122–135 (2020).Article CAS PubMed Google Scholar Zhang, D. et al. A likely protective effect of dimethyl itaconate on cerebral ischemia/reperfusion injury. Int Immunopharmacol. 77, 105924 (2019).Article CAS PubMed Google Scholar Yang, Y. et al. Protecting effects of 4-octyl itaconate on neonatal hypoxic-ischemic encephalopathy via Nrf2 pathway in astrocytes. J. Neuroinflamm. 21, 132 (2024).Article CAS Google Scholar Nazarizadeh, S., Ghotbeddin, Z., Ghafouri, S. & Sarkaki, A. The protective effect of DMI on hippocampus EEG, behavioral and biochemical parameters in hypoxia-induced seizure on neonatal period. PLoS One 19, e0309240 (2024).Article CAS PubMed PubMed Central Google Scholar Duan, X. et al. IRG1 prevents excessive inflammatory responses and cardiac dysfunction after myocardial injury. Biochem. Pharm. 213, 115614 (2023).Article CAS PubMed Google Scholar Gong, S. et al. TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53. Cell Death Differ. 31, 239–253 (2024).Article CAS PubMed PubMed Central Google Scholar Yang, J. et al. 4-Octyl itaconate alleviates myocardial ischemia-reperfusion injury through promoting angiogenesis via ERK signaling activation. Adv. Sci. 12, e2411554 (2025).Article Google Scholar Yi, Z. et al. Immune-responsive gene 1/Itaconate activates nuclear factor erythroid 2-related factor 2 in hepatocytes to protect against liver ischemia-reperfusion injury. Hepatology 72, 1394–1411 (2020).Article CAS PubMed PubMed Central Google Scholar Zhang, H. et al. Pre-operative exercise therapy triggers anti-inflammatory trained immunity of Kupffer cells through metabolic reprogramming. Nat. Metab. 3, 843–858 (2021).Article CAS PubMed PubMed Central Google Scholar Zhang, T. et al. Itaconate facilitates methane-induced Nrf2 pathway activation for mitigating liver ischemia and reperfusion injury. Iliver 4, 100144 (2025).Article CAS PubMed PubMed Central Google Scholar Fan, K. et al. Negative regulation of pro-apoptotic AMPK/JNK pathway by itaconate in mice with fulminant liver injury. Cell Death Dis. 14, 486 (2023).Article CAS PubMed PubMed Central Google Scholar Zhu, D. et al. Irg1-itaconate axis protects against acute kidney injury via activation of Nrf2. Am. J. Transl. Res. 13, 1155–1169 (2021).CAS PubMed PubMed Central Google Scholar Li, X. K. et al. 4-Octyl itaconate alleviates renal ischemia reperfusion injury by ameliorating endoplasmic reticulum stress via Nrf2 pathway. Exp. Biol. Med. 248, 2408–2420 (2023).CAS Google Scholar Shan, M. et al. Itaconate promotes inflammatory responses in tissue-resident alveolar macrophages and exacerbates acute lung injury. Cell Metab. 37, 1750–1765.e1757 (2025).Article CAS PubMed Google Scholar Gao, X. et al. Activation of Nrf2 pathway by 4-Octyl itaconate enhances donor lung function in cold preservation settings. Respir. Res. 26, 69 (2025).Article CAS PubMed PubMed Central Google Scholar Wu, Y. T. et al. 4-octyl itaconate ameliorates alveolar macrophage pyroptosis against ARDS via rescuing mitochondrial dysfunction and suppressing the cGAS/STING pathway. Int. Immunopharmacol. 118, 110104 (2023).Article CAS PubMed Google Scholar Ganta, V. C. et al. A MicroRNA93-interferon regulatory factor-9-immunoresponsive gene-1-itaconic acid pathway modulates M2-like macrophage polarization to revascularize ischemic muscle. Circulation 135, 2403–2425 (2017).Article CAS PubMed PubMed Central Google Scholar Luo, G. et al. Itaconic acid induces angiogenesis and suppresses apoptosis via Nrf2/autophagy to prolong the survival of multi-territory perforator flaps. Heliyon 9, e17909 (2023).Article CAS PubMed PubMed Central Google Scholar Liu, S. et al. Dimethyl itaconate: An effective antioxidant for promoting angiogenesis under oxidative stress. Talanta 293, 128024 (2025).Article CAS PubMed Google Scholar Kong, X. et al. Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis. J. Neuroinflamm. 21, 104 (2024).Article CAS Google Scholar Liu, Y. et al. Inhibition of Alzheimer’s disease by 4-octyl itaconate revealed by RNA-seq transcriptome analysis. Eur. J. Pharm. 968, 176432 (2024).Article CAS Google Scholar Xiong, J. et al. Dimethyl itaconate reduces cognitive impairment and neuroinflammation in APPswe/PS1ΔE9 transgenic mouse model of Alzheimer’s disease. Neuromol. Med. 25, 179–192 (2023).Article CAS Google Scholar Zhou, G. J. et al. Itaconate alleviates β(2)-microglobulin-induced cognitive impairment by enhancing the hippocampal amino-β-carboxymuconate-semialdehyde-decarboxylase/picolinic acid pathway. Biochem. Pharm. 202, 115137 (2022).Article CAS PubMed Google Scholar Xia, N. et al. Microglia-dependent neuroprotective effects of 4-octyl itaconate against rotenone-and MPP+-induced neurotoxicity in Parkinson’s disease. Sci. Rep. 13, 15539 (2023).Article CAS PubMed PubMed Central Google Scholar Sun, G. et al. Itaconate attenuates neuroinflammation and exerts dopamine neuroprotection in Parkinson’s disease through inhibiting NLRP3 inflammasome. Brain Sci. 12, (2022).Ni, L. et al. Itaconate attenuates osteoarthritis by inhibiting STING/NF-κB axis in chondrocytes and promoting M2 polarization in macrophages. Biochem. Pharm. 198, 114935 (2022).Article CAS PubMed Google Scholar Pan, X. et al. Four-octyl itaconate improves osteoarthritis by enhancing autophagy in chondrocytes via PI3K/AKT/mTOR signalling pathway inhibition. Commun. Biol. 5, 641 (2022).Article CAS PubMed PubMed Central Google Scholar Pan, X. et al. 4-Octyl itaconate protects chondrocytes against IL-1β-induced oxidative stress and ferroptosis by inhibiting GPX4 methylation in osteoarthritis. Int. Immunopharmacol. 137, 112531 (2024).Article CAS PubMed Google Scholar Zhang, Q. et al. 4-octyl Itaconate inhibits lipopolysaccharide (LPS)-induced osteoarthritis via activating Nrf2 signalling pathway. J. Cell Mol. Med. 26, 1515–1529 (2022).Article CAS PubMed PubMed Central Google Scholar Cai, L. et al. Deficiency of immune-responsive gene 1 exacerbates interleukin-1beta-elicited the inflammatory response of chondrocytes via enhancing the activation of NLRP3 inflammasome. Int. Immunopharmacol. 114, 109456 (2023).Article CAS PubMed Google Scholar Tang, Y. Z. et al. 4-Octyl itaconate inhibits synovitis in the mouse model of post-traumatic osteoarthritis and alleviates pain. Chin. J. Traumatol. 28, 50–61 (2025).Article CAS PubMed Google Scholar Huang, B. et al. Activation of Nrf2 signaling by 4-octyl itaconate attenuates the cartilaginous endplate degeneration by inhibiting E3 ubiquitin ligase ZNF598. Osteoarthr. Cartil. 31, 213–227 (2023).Article CAS Google Scholar Kieler, M. et al. Itaconate is a metabolic regulator of bone formation in homeostasis and arthritis. Ann. Rheum. Dis. 83, 1465–1479 (2024).Article CAS PubMed PubMed Central Google Scholar Li, Y. et al. 4-Octyl Itaconate attenuates postmenopausal osteoporosis by inhibiting ferroptosis and enhancing osteogenesis via the Nrf2 pathway. Inflammation (2025).Wang, F. et al. The absence of IRG1 exacerbates bone loss in a mouse model of ovariectomy-induced osteoporosis by increasing osteoclastogenesis through the potentiation of NLRP3 inflammasome activation. Int. Immunopharmacol. 148, 114099 (2025).Article CAS PubMed Google Scholar Wang, Y. et al. Aging relevant metabolite itaconate inhibits inflammatory bone loss. Front Endocrinol. 13, 885879 (2022).Article Google Scholar An, Y. et al. Hydrogen activates ACOD1-itaconate pathway to ameliorate steroid-associated osteonecrosis. Biomaterials 323, 123428 (2025).Article CAS PubMed Google Scholar Sun, X. et al. Octyl itaconate inhibits osteoclastogenesis by suppressing Hrd1 and activating Nrf2 signaling. FASEB J. 33, 12929–12940 (2019).Article CAS PubMed PubMed Central Google Scholar Peng, X. et al. 4-Octyl itaconate suppresses the osteogenic response in aortic valvular interstitial cells via the Nrf2 pathway and alleviates aortic stenosis in mice with direct wire injury. Free Radic. Biol. Med. 188, 404–418 (2022).Article CAS PubMed Google Scholar Yang, C. et al. The experimental study on the effect of the NRF2 activator dimethyl itaconate on hypoxia-induced scleral fibroblasts. Zhonghua Yan Ke Za Zhi 61, 609–617 (2025).CAS PubMed Google Scholar Marchese, P. et al. A novel high-throughput screening platform identifies itaconate derivatives from marine penicillium antarcticum as inhibitors of mesenchymal stem cell differentiation. Mar. Drugs 18, (2020).Wu, Y. X. et al. 4-OI ameliorates bleomycin-induced pulmonary fibrosis by activating Nrf2 and suppressing macrophage-mediated epithelial-mesenchymal transition. Inflamm. Res. 72, 1133–1145 (2023).Article CAS PubMed Google Scholar Han, Y. Y. et al. Protective effect of dimethyl itaconate against fibroblast-myofibroblast differentiation during pulmonary fibrosis by inhibiting TXNIP. J. Cell Physiol. 236, 7734–7744 (2021).Article CAS PubMed Google Scholar Ogger, P. P. et al. Itaconate controls the severity of pulmonary fibrosis. Sci. Immunol. 5, (2020).Fan, K. et al. Immune response gene 1 deficiency impairs Nrf2 activation and aggravates liver fibrosis in mice. Biochem. Biophys. Res. Commun. 607, 103–109 (2022).Article CAS PubMed Google Scholar Zhou, P. et al. IRG1/Itaconate inhibits hepatic stellate cells ferroptosis and attenuates TAA-induced liver fibrosis by regulating SLC39A14 expression. Int. Immunopharmacol. 146, 113945 (2025).Article CAS PubMed Google Scholar Tian, F. et al. 4-Octyl itaconate protects against renal fibrosis via inhibiting TGF-β/Smad pathway, autophagy and reducing generation of reactive oxygen species. Eur. J. Pharm. 873, 172989 (2020).Article CAS Google Scholar Ke, Q. et al. SGLT2 inhibitor counteracts NLRP3 inflammasome via tubular metabolite itaconate in fibrosis kidney. FASEB J. 36, e22078 (2022).Article CAS PubMed Google Scholar Chen, Y. et al. 4-octyl itaconate improves the viability of D66H cells by regulating the KEAP1-NRF2-GCLC/HO-1 pathway. J. Cell Mol. Med. 27, 962–975 (2023).Article CAS PubMed PubMed Central Google Scholar Yu, B. Y., Ngo, H. H., Choi, W. J. & Keum, Y. S. Dimethyl itaconate inhibits melanogenesis in B16F10 cells. Antioxidants. 12, (2023).Jang, S., Chi, W. J. & Kim, S. Y. Dimethyl itaconate reduces α-MSH-induced pigmentation via modulation of AKT and p38 MAPK signaling pathways in B16F10 mouse melanoma cells. Molecules. 27, (2022).You, M. et al. 4-Octyl itaconate inhibits inflammation to attenuate psoriasis as an agonist of oxeiptosis. Int. Immunopharmacol. 124, 110915 (2023).Article CAS PubMed Google Scholar Hosseinkhani, F., Hosseinifar, S. & Tabandeh, M. R. Dimethyl itaconate mitigates histological distortions, inflammation, and oxidative stress in the rat model of polycystic ovary syndrome. J. Steroid Biochem. Mol. Biol. 243, 106546 (2024).Article CAS PubMed Google Scholar Yang, L. et al. Rescuing fertility: Itaconic acid prevents ovarian damage through NRF2-mediated pyroptosis pathways in diminished ovarian reserve models. Cell Signal 131, 111766 (2025).Article CAS PubMed Google Scholar Xin, L. et al. Four-Octyl itaconate ameliorates periodontal destruction via Nrf2-dependent antioxidant system. Int. J. Oral. Sci. 14, 27 (2022).Article CAS PubMed PubMed Central Google Scholar Wang, Y. et al. Dimethyl itaconate inhibits antigen-specific Th17 cell responses and autoimmune inflammation via modulating NRF2/STAT3 signaling. FASEB J. 38, e23607 (2024).Article CAS PubMed Google Scholar Jiang, Q. et al. Itaconate ameliorates experimental autoimmune uveitis by modulating Teff/Treg Cell imbalance via the DNAJA1/CDC45 Axis. Investig. Ophthalmol. Vis. Sci. 65, 23 (2024).Article CAS Google Scholar Aso, K. et al. Itaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming. Nat. Commun. 14, 984 (2023).Article CAS PubMed PubMed Central Google Scholar Li, F. et al. Itaconate and its derivatives ameliorate autoimmunity by suppressing Th17 cells via regulating mitophagy. Cell Commun. Signal 24, 117 (2026).Article CAS PubMed PubMed Central Google Scholar Wang, Q. et al. 4-Octyl itaconate inhibits proinflammatory cytokine production in Behcet’s uveitis and experimental autoimmune uveitis. Inflammation 47, 909–920 (2024).Article CAS PubMed Google Scholar Kuo, P. C. et al. Dimethyl itaconate, an itaconate derivative, exhibits immunomodulatory effects on neuroinflammation in experimental autoimmune encephalomyelitis. J. Neuroinflamm. 17, 138 (2020).Article CAS Google Scholar Zhao, N. et al. 4-Octyl itaconate attenuates neuroinflammation in experimental autoimmune encephalomyelitis via regulating microglia. Inflammation 48, 151–164 (2025).Article CAS PubMed Google Scholar Li, T. et al. 4-Octyl itaconate inhibits inflammation via the NLRP3 pathway in neuromyelitis optica spectrum disorders. Ann. Clin. Transl. Neurol. 11, 1732–1749 (2024).Article CAS PubMed PubMed Central Google Scholar Zhang, Q. et al. Itaconate attenuates autoimmune hepatitis via PI3K/AKT/mTOR pathway-mediated inhibition of dendritic cell maturation and autophagy. Heliyon 9, e17551 (2023).Article CAS PubMed PubMed Central Google Scholar Yang, W. et al. Hepatoprotective role of 4-octyl itaconate in concanavalin A-induced autoimmune hepatitis. Mediat. Inflamm. 2022, 5766434 (2022).Article Google Scholar Yang, W. et al. Immune-responsive gene 1 protects against liver injury caused by concanavalin A via the activation Nrf2/HO-1 pathway and inhibition of ROS activation pathways. Free Radic. Biol. Med. 182, 108–118 (2022).Article CAS PubMed Google Scholar Zhang, T. et al. Tripterygium wilfordii protects against an animal model of autoimmune hepatitis. J. Ethnopharmacol. 309, 116365 (2023).Article CAS PubMed Google Scholar Zeng, L. et al. IRG1/itaconate enhances efferocytosis by activating Nrf2-TIM4 signaling pathway to alleviate con A induced autoimmune liver injury. Cell Commun. Signal 23, 63 (2025).Article CAS PubMed PubMed Central Google Scholar Zhou, P. et al. IRG1/Itaconate inhibits proliferation and promotes apoptosis of CD69(+)CD103(+)CD8(+) tissue-resident memory T cells in autoimmune hepatitis by regulating the JAK3/STAT3/P53 signalling pathway. Apoptosis 29, 1738–1756 (2024).Article CAS PubMed Google Scholar Li, Y. et al. Itaconate inhibits CD103 + T RM cells and alleviates hepatobiliary injury in mouse models of primary sclerosing cholangitis. Hepatology 79, 25–38 (2024).Article PubMed Google Scholar Kim, H. W. et al. Aconitate decarboxylase 1 deficiency exacerbates mouse colitis induced by dextran sodium sulfate. Int. J. Mol. Sci. 23 (2022).Wang, Y. et al. 4-Octyl itaconate alleviates dextran sulfate sodium-induced ulcerative colitis in mice via activating the KEAP1-NRF2 pathway. Inflammopharmacology 32, 2555–2574 (2024).Article CAS PubMed Google Scholar Yang, W. et al. Protective effects of IRG1/itaconate on acute colitis through the inhibition of gasdermins-mediated pyroptosis and inflammation response. Genes Dis. 10, 1552–1563 (2023).Article CAS PubMed Google Scholar Li, W. et al. Alleviating pyroptosis of intestinal epithelial cells to restore mucosal integrity in ulcerative colitis by targeting delivery of 4-octyl-itaconate. ACS Nano 18, 16658–16673 (2024).Article CAS PubMed Google Scholar Zhang, Y. et al. M-CSF protects against ulcerative colitis via aconitate: mendelian randomization and experimental evidence. J. Inflamm. Res 18, 10313–10329 (2025).Article CAS PubMed PubMed Central Google Scholar Tada, M. et al. Itaconate reduces proliferation and migration of fibroblast-like synoviocytes and ameliorates arthritis models. Clin. Immunol. 264, 110255 (2024).Article CAS PubMed Google Scholar Kachler, K. et al. Acod1-mediated inhibition of aerobic glycolysis suppresses osteoclast differentiation and attenuates bone erosion in arthritis. Ann. Rheum. Dis. 83, 1691–1706 (2024).Article CAS PubMed PubMed Central Google Scholar Daly, R. et al. Changes in plasma itaconate elevation in early rheumatoid arthritis patients elucidates disease activity associated macrophage activation. Metabolites. 10, (2020).Michopoulos, F. et al. Targeted metabolic profiling of the Tg197 mouse model reveals itaconic acid as a marker of rheumatoid arthritis. J. Proteome Res 15, 4579–4590 (2016).Article CAS PubMed Google Scholar Henry, ÓC. & O’Neill, L. A. J. Metabolic reprogramming in stromal and immune cells in rheumatoid arthritis and osteoarthritis: therapeutic possibilities. Eur. J. Immunol. 55, e202451381 (2025).Article CAS PubMed PubMed Central Google Scholar Papathanassiu, A. E. et al. BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases. Nat. Commun. 8, 16040 (2017).Article CAS PubMed PubMed Central Google Scholar Rajendiran, A. et al. NRF2/itaconate axis regulates metabolism and inflammatory properties of T cells in children with JIA. Antioxidants. 11, (2022).Blanco, L. P. et al. Modulation of the itaconate pathway attenuates murine lupus. Arthritis Rheumatol. 74, 1971–1983 (2022).Article CAS PubMed PubMed Central Google Scholar Tang, C. et al. 4-Octyl itaconate activates Nrf2 signaling to inhibit pro-inflammatory cytokine production in peripheral blood mononuclear cells of systemic Lupus erythematosus patients. Cell Physiol. Biochem. 51, 979–990 (2018).Article CAS PubMed Google Scholar Li, Y., Liang, L., Deng, X. & Zhong, L. Lipidomic and metabolomic profiling reveals novel candidate biomarkers in active systemic lupus erythematosus. Int. J. Clin. Exp. Pathol. 12, 857–866 (2019).CAS PubMed PubMed Central Google Scholar Patiño-Martinez, E. et al. The aconitate decarboxylase 1/itaconate pathway modulates immune dysregulation and associates with cardiovascular disease markers and disease activity in systemic lupus erythematosus. J. Immunol. 213, 419–434 (2024).Article PubMed PubMed Central Google Scholar Auger, J. P. et al. Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids. Nature 629, 184–192 (2024).Article CAS PubMed Google Scholar Henderson, J. et al. The cell-permeable derivative of the immunoregulatory metabolite itaconate, 4-octyl itaconate, is anti-fibrotic in systemic sclerosis. Cells 10, (2021).Henderson, J. et al. Metabolic reprogramming of glycolysis and glutamine metabolism are key events in myofibroblast transition in systemic sclerosis pathogenesis. J. Cell Mol. Med. 24, 14026–14038 (2020).Article CAS PubMed PubMed Central Google Scholar Liu, Q. et al. Itaconate derivative 4-OI inhibits M1 macrophage polarization and restores its impaired function in immune thrombocytopenia through metabolic reprogramming. Chin. Med. J. 138, 2006–2015 (2025).Article CAS PubMed PubMed Central Google Scholar Pereira, M. et al. Acute iron deprivation reprograms human macrophage metabolism and reduces inflammation in vivo. Cell Rep. 28, 498–511.e495 (2019).Article CAS PubMed PubMed Central Google Scholar Beier, U. H. et al. Tissue metabolic profiling shows that saccharopine accumulates during renal ischemic-reperfusion injury, while kynurenine and itaconate accumulate in renal allograft rejection. Metabolomics 16, 65 (2020).Article CAS PubMed PubMed Central Google Scholar Li, Y. et al. Itaconate suppresses house dust mite-induced allergic airways disease and Th2 cell differentiation. Mucosal Immunol. 17, 1174–1183 (2024).Article CAS PubMed PubMed Central Google Scholar Xie, Q. M. et al. Itaconate suppresses the activation of mitochondrial NLRP3 inflammasome and oxidative stress in allergic airway inflammation. Antioxidants 12, (2023).Yin, M. et al. 4-Octyl itaconate alleviates airway eosinophilic inflammation by suppressing chemokines and Eosinophil development. J. Immunol. 212, 13–23 (2024).Article CAS PubMed PubMed Central Google Scholar Zhao, X. et al. 4-Octyl itaconate alleviates experimental autoimmune prostatitis by inhibiting the NLRP3 inflammasome-induced pyroptosis through activating Nrf2/HO-1 pathway. Prostate 84, 329–341 (2024).Article CAS PubMed Google Scholar Molina-Lopez, C., Hurtado-Navarro, L., O’Neill, L. A. J. & Pelegrin, P. 4-octyl itaconate reduces human NLRP3 inflammasome constitutive activation with the cryopyrin-associated periodic syndrome p.R262W, p.D305N and p.T350M variants. Cell Mol. Life Sci. 82, 209 (2025).Article CAS PubMed PubMed Central Google Scholar Olagnier, D. et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 9, 3506 (2018).Article PubMed PubMed Central Google Scholar Waqas, S. F. et al. ISG15 deficiency features a complex cellular phenotype that responds to treatment with itaconate and derivatives. Clin. Transl. Med. 12, e931 (2022).Article CAS PubMed PubMed Central Google Scholar Gu, J. et al. The role of histone H1.2 in pancreatic cancer metastasis and chemoresistance. Drug Resist. Updat. 73, 101027 (2024).Article CAS PubMed Google Scholar Chai, Q. Q. et al. Engineering nanoplatforms of bacterial outer membrane vesicles to overcome cancer therapy resistance. Drug Resist. Updat. 83, 101277 (2025).Article CAS PubMed Google Scholar Ding, W. et al. Metabolic reprogramming of tumor-associated macrophages via adenosine-A(2A)R signaling drives cross-resistance in non-small cell lung cancer. Drug Resist. Updat. 82, 101272 (2025).Article CAS PubMed Google Scholar Zhang, X. et al. The multifaceted contributions of cancer-associated fibroblasts to drug resistance in primary and metastatic tumors. Drug Resist. Updat. 82, 101273 (2025).Article CAS PubMed Google Scholar Zhang, Z. et al. Polyphenol nanocomplex modulates lactate metabolic reprogramming and elicits immune responses to enhance cancer therapeutic effect. Drug Resist. Updat. 73, 101060 (2024).Article CAS PubMed Google Scholar Liu, K. et al. Induction of autophagy-dependent ferroptosis to eliminate drug-tolerant human retinoblastoma cells. Cell Death Dis. 13, 521 (2022).Article PubMed PubMed Central Google Scholar Qu, C. et al. Itaconic acid induces ferroptosis by activating ferritinophagy. Biochem. Biophys. Res. Commun. 583, 56–62 (2021).Article CAS PubMed Google Scholar Hayashi, Y. et al. 4-Octyl Itaconate attenuates cell proliferation by cellular senescence via glutathione metabolism disorders and mitochondrial dysfunction in melanoma. Antioxid. Redox Signal 42, 547–565 (2025).Article CAS PubMed Google Scholar Gautam, A. K. et al. Preclinical evaluation of dimethyl itaconate against hepatocellular carcinoma via activation of the e/iNOS-mediated NF-κB-dependent apoptotic pathway. Front Pharm. 12, 823285 (2021).Article CAS Google Scholar Sana, I. et al. Dimethyl itaconate selectively targets inflammatory and metabolic pathways in chronic lymphocytic leukemia. Eur. J. Immunol. 53, e2350418 (2023).Article PubMed Google Scholar Zhan, Z. et al. OI inhibits development of ovarian cancer by blocking crosstalk between cancer cells and macrophages via HIF-1α pathway. Biochem Biophys. Res. Commun. 606, 142–148 (2022).Article CAS PubMed Google Scholar Liu, Y. et al. STING-IRG1 inhibits liver metastasis of colorectal cancer by regulating the polarization of tumor-associated macrophages. iScience 26, 107376 (2023).Article CAS PubMed PubMed Central Google Scholar Zhou, M. et al. IRG1 restrains M2 macrophage polarization and suppresses intrahepatic cholangiocarcinoma progression via the CCL18/STAT3 pathway. Cancer Sci. 115, 777–790 (2024).Article CAS PubMed PubMed Central Google Scholar Beielstein, A. C. et al. Macrophages are activated toward phagocytic lymphoma cell clearance by pentose phosphate pathway inhibition. Cell Rep. Med. 5, 101830 (2024).Article CAS PubMed PubMed Central Google Scholar Weiss, J. M. et al. Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors. J. Clin. Investig. 128, 3794–3805 (2018).Article PubMed PubMed Central Google Scholar Scheurlen, K. M. et al. Itaconate and obesity-related hormones promote tumor progression - new insights on metabolic dysfunction in early-onset colon cancer. Front. Immunol. 16, 1572985 (2025).Article CAS PubMed PubMed Central Google Scholar Gu, X. et al. Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8(+) T-cell exhaustion. Nat. Commun. 14, 8154 (2023).Article CAS PubMed PubMed Central Google Scholar Chen, Y. J. et al. Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy. Sci. Adv. 9, eadg0654 (2023).Article CAS PubMed PubMed Central Google Scholar Yang, X. et al. Macrophage-derived itaconate suppresses dendritic cell function to promote acquired resistance to anti-PD-1 immunotherapy. Cancer Res. 85, 1842–1856 (2025).Article CAS PubMed Google Scholar Zhao, Y. et al. Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab. 35, 1688–1703.e1610 (2023).Article CAS PubMed PubMed Central Google Scholar Zhao, H. et al. Myeloid-derived itaconate suppresses cytotoxic CD8(+) T cells and promotes tumour growth. Nat. Metab. 4, 1660–1673 (2022).Article CAS PubMed PubMed Central Google Scholar Lin, H. et al. Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance. Cancer Cell 42, 2032–2044.e2036 (2024).Article CAS PubMed PubMed Central Google Scholar Waqas, F. H., Chen, C. & Pessler, F. Aconitate decarboxylase (ACOD1) has found a disease. Trends Endocrinol. Metab. 35, 561–562 (2024).Article CAS PubMed Google Scholar Huang, Y. et al. Nrf2 inhibition increases sensitivity to chemotherapy of colorectal cancer by promoting ferroptosis and pyroptosis. Sci. Rep. 13, 14359 (2023).Article CAS PubMed PubMed Central Google Scholar Wang, X. et al. Metabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors. Nat. Commun. 14, 5778 (2023).Article CAS PubMed PubMed Central Google Scholar Zhang, J. et al. The role of the aging process and related factor EMP1 in promoting progression of resectable pancreatic cancer. Genes Dis. 12, 101490 (2025).Article CAS PubMed Google Scholar Gu, J. et al. Artificial intelligence in tumor drug resistance: mechanisms and treatment prospects. Intell. Oncol. 1, 73–88 (2025).Article Google Scholar Gu, J. et al. Hsa-miR-3178/RhoB/PI3K/Akt, a novel signaling pathway regulates ABC transporters to reverse gemcitabine resistance in pancreatic cancer. Mol. Cancer 21, 112 (2022).Article CAS PubMed PubMed Central Google Scholar Diaz-Diaz, S. et al. Heterogeneity of SOS response expression in clinical isolates of Escherichia coli influences adaptation to antimicrobial stress. Drug Resist. Updat. 75, 101087 (2024).Article CAS PubMed Google Scholar Dong, S. et al. Resistance to immunotherapy in non-small cell lung cancer: unraveling causes, developing effective strategies, and exploring potential breakthroughs. Drug Resist. Updat. 81, 101215 (2025).Article CAS PubMed Google Scholar Du, Z. et al. Molecular mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer. Drug Resist. Updat. 82, 101266 (2025).Article CAS PubMed Google Scholar Jiang, M. et al. EMT and cancer stem cells: drivers of therapy resistance and promising therapeutic targets. Drug Resist. Updat. 83, 101276 (2025).Article CAS PubMed Google Scholar Li, T. et al. BCL7A inhibits the progression and drug-resistance in acute myeloid leukemia. Drug Resist. Updat. 76, 101120 (2024).Article CAS PubMed Google Scholar Niu, X. et al. Cancer plasticity in therapy resistance: Mechanisms and novel strategies. Drug Resist. Updat. 76, 101114 (2024).Article CAS PubMed Google Scholar Wei, J. R. et al. Overcoming cancer therapy resistance: From drug innovation to therapeutics. Drug Resist. Updat. 81, 101229 (2025).Article CAS PubMed Google Scholar Wu, G. Y. et al. Drug resistance in breast cancer: Mechanisms and strategies for management. Drug Resist. Updat. 83, 101288 (2025).Article CAS PubMed Google Scholar Liu, S. et al. Drug-induced tolerant persisters in tumor: mechanism, vulnerability and perspective implication for clinical treatment. Mol. Cancer 24, 150 (2025).Article CAS PubMed PubMed Central Google Scholar Liu, Z. et al. Biological and pharmacological roles of m(6)A modifications in cancer drug resistance. Mol. Cancer 21, 220 (2022).Article CAS PubMed PubMed Central Google Scholar Li, S. et al. Overcoming multi-drug resistance in SCLC: a synergistic approach with venetoclax and hydroxychloroquine targeting the lncRNA LYPLAL1-DT/BCL2/BECN1 pathway. Mol. Cancer 23, 243 (2024).Article CAS PubMed PubMed Central Google Scholar Lin, Z. et al. Metabolic reprogramming promotes apoptosis resistance in acute lymphoblastic leukemia through CASP3 lactylation. Mol. Cancer 24, 204 (2025).Article CAS PubMed PubMed Central Google Scholar Ling, L. et al. M6A-Methylated circRAPGEF5 drives lung adenocarcinoma progression and metastasis via IGF2BP2/NUP160-mediated autophagy suppression. Mol. Cancer 24, 192 (2025).Article CAS PubMed PubMed Central Google Scholar Wang, X. et al. Targeting PERP promotes anti-tumor immunity in HNSCC by regulating tumor immune microenvironment and metabolic homeostasis. Mol. Cancer 24, 168 (2025).Article CAS PubMed PubMed Central Google Scholar Zhao, F. Y. et al. Decoding the ubiquitin network: molecular mechanisms and therapeutic vulnerabilities for precision radio-sensitization in cancer. Mol. Cancer 24, 233 (2025).Article CAS PubMed PubMed Central Google Scholar Liu, P., Zhou, Y., Zeng, S. & Chen, X. Comprehensive bioinformatic analysis reveals an autophagy-related gene signature for predicting outcome, immune status, and drug sensitivity in hepatocellular carcinoma. Recent Pat. Anticancer Drug Discov. 20, 397–414 (2024).Yang, J. et al. Identification of immune infiltration-related molecular features in ovarian cancer patients and experimental validation of immune response molecular mechanisms through integrated WGCNA, Machine Learning, and Single-cell sequencing analysis. Recent Pat. Anticancer Drug Discov. 20, 710–726 (2024).Zhang, Y., Sun, X., Guan, Y. & Sun, Y. Exosome-derived cargos in immune microenvironment in esophageal carcinoma: a mini-review. Recent Pat. Anticancer Drug Discov. 20, 137–144 (2025).Article CAS PubMed Google Scholar Zheng, C., Guo, H., Mo, Y. & Liu, G. Integrating bioinformatics and drug sensitivity analyses to identify molecular characteristics associated with targeting necroptosis in breast cancer and their clinical prognostic significance. Recent Pat. Anticancer Drug Discov. 19, 681–694 (2024).Article CAS PubMed Google Scholar Tsanov, K. M. et al. SMAD4 induces opposite effects on metastatic growth from pancreatic tumors depending on the organ of residence. Nat. Cancer 6, 1839–1856 (2025).Becher, B., Derfuss, T. & Liblau, R. Targeting cytokine networks in neuroinflammatory diseases. Nat. Rev. Drug Discov. 23, 862–879 (2024).Article CAS PubMed Google Scholar Glorieux, C., Liu, S., Trachootham, D. & Huang, P. Targeting ROS in cancer: rationale and strategies. Nat. Rev. Drug Discov. 23, 583–606 (2024).Article CAS PubMed Google Scholar Trefny, M. P., Kroemer, G., Zitvogel, L. & Kobold, S. Metabolites as agents and targets for cancer immunotherapy. Nat. Rev. Drug Discov. 24, 764–784 (2025).Article CAS PubMed Google Scholar Yuan, X. et al. Targeting hypoxia-inducible factors: therapeutic opportunities and challenges. Nat. Rev. Drug Discov. 23, 175–200 (2024).Article CAS PubMed Google Scholar Zhang, D. D. Thirty years of NRF2: advances and therapeutic challenges. Nat. Rev. Drug Discov. 24, 421–444 (2025).Article CAS PubMed Google Scholar Barreira-Silva, P., Lian, Y., Kaufmann, S. H. E. & Moura-Alves, P. The role of the AHR in host-pathogen interactions. Nat. Rev. Immunol. 25, 178–194 (2025).Article CAS PubMed Google Scholar Canè, S., Geiger, R. & Bronte, V. The roles of arginases and arginine in immunity. Nat. Rev. Immunol. 25, 266–284 (2025).Article PubMed Google Scholar De Martino, M., Rathmell, J. C., Galluzzi, L. & Vanpouille-Box, C. Cancer cell metabolism and antitumour immunity. Nat. Rev. Immunol. 24, 654–669 (2024).Article PubMed PubMed Central Google Scholar Mann, E. R., Lam, Y. K. & Uhlig, H. H. Short-chain fatty acids: linking diet, the microbiome and immunity. Nat. Rev. Immunol. 24, 577–595 (2024).Article CAS PubMed Google Scholar Mirchandani, A. S., Sanchez-Garcia, M. A. & Walmsley, S. R. How oxygenation shapes immune responses: emerging roles for physioxia and pathological hypoxia. Nat. Rev. Immunol. 25, 161–177 (2025).Article CAS PubMed Google Scholar Zhang, Z. & Zhang, C. Regulation of cGAS-STING signalling and its diversity of cellular outcomes. Nat. Rev. Immunol. 25, 425–444 (2025).Article CAS PubMed Google Scholar Lee, C. B. et al. Discovery of orally available prodrugs of itaconate and derivatives. J. Med. Chem. 68, 3433–3444 (2025).Article CAS PubMed PubMed Central Google Scholar Camelo, S. Repurposing dimethyl fumarate targeting Nrf2 to slow down the growth of areas of geographic atrophy. Int. J. Mol. Sci. 26, 6112 (2025).Tsai, J. et al. Topical SCD-153, a 4-methyl itaconate prodrug, for the treatment of alopecia areata. PNAS Nexus 2, pgac297 (2023).Article PubMed Google Scholar Abruzzo, A. et al. Surfactants from itaconic acid: toxicity to HaCaT keratinocytes in vitro, micellar solubilization, and skin permeation enhancement of hydrocortisone. Int. J. Pharm. 524, 9–15 (2017).Article CAS PubMed Google Scholar Krause, B. M. et al. ItaCORMs: conjugation with a CO-releasing unit greatly enhances the anti-inflammatory activity of itaconates. RSC Med. Chem. 12, 2053–2059 (2021).Article CAS PubMed PubMed Central Google Scholar Paprocka, R. et al. Antibacterial and central nervous system activity of (4,5-DIARYL-4H-1,2,4-TRIAZOL-3-YL)methacrylic acid derivatives. Acta Pol. Pharm. 74, 289–292 (2017).CAS PubMed Google Scholar Perković, I. et al. Itaconic acid hybrids as potential anticancer agents. Mol. Divers. 26, 1–14 (2022).Article PubMed Google Scholar Ma, L. et al. Development of molecularly imprinted polymers to block quorum sensing and inhibit bacterial biofilm formation. ACS Appl. Mater. Interfaces 10, 18450–18457 (2018).Article CAS PubMed Google Scholar Cavaleiro, E. et al. Novel linear polymers able to inhibit bacterial quorum sensing. Macromol. Biosci. 15, 647–656 (2015).Article CAS PubMed Google Scholar Chen, X. et al. Mitochondria-targeted supramolecular coordination container encapsulated with exogenous itaconate for synergistic therapy of joint inflammation. Theranostics 12, 3251–3272 (2022).Article CAS PubMed PubMed Central Google Scholar Yuan, Y. S. et al. Reprogramming mitochondrial metabolism to enhance macrophages polarization by ROS-responsive nanoparticles for osteoarthritis. Biomaterials 322, 123395 (2025).Article CAS PubMed Google Scholar Zheng, T. et al. Injured myocardium-targeted theranostic nanoplatform for multi-dimensional immune-inflammation regulation in acute myocardial infarction. Adv. Sci. 12, e2414740 (2025).Article Google Scholar Nakkala, J. R. et al. Dimethyl itaconate-loaded nanofibers rewrite macrophage polarization, reduce inflammation, and enhance repair of myocardic infarction. Small 17, e2006992 (2021).Article PubMed Google Scholar Liao, X. et al. Acid-triggered cascaded responsive supramolecular peptide alleviates myocardial ischemia‒reperfusion injury by restoring redox homeostasis and protecting mitochondrial function. Adv. Health. Mater. 14, e2404319 (2025).Article Google Scholar Hong, N. E. et al. Nanoparticle-based itaconate treatment recapitulates low-cholesterol/low-fat diet-induced atherosclerotic plaque resolution. Cell Rep. 43, 114911 (2024).Article CAS PubMed PubMed Central Google Scholar Hong, N. E. et al. Itaconate alleviates cholesterol burden via ABCA1 stabilization and cholesterol efflux. Atherosclerosis 408, 120445 (2025).Article CAS PubMed PubMed Central Google Scholar Liu, Y. et al. Nanoparticles with reprogramming of mitochondrial respiratory chain complex and epigenetic modifications functions for osteoporosis treatment. Biomaterials 324, 123468 (2026).Article CAS PubMed Google Scholar Peng, C. et al. Charge-reversal nanoassembly for rheumatoid arthritis therapy via cell-free DNA scavenging and microenvironment reprogramming. Biomaterials 325, 123591 (2026).Article CAS PubMed Google Scholar Ghanbarzadeh, S., Arami, S., Pourmoazzen, Z. & Khorrami, A. Improvement of the antiproliferative effect of rapamycin on tumor cell lines by poly (monomethylitaconate)-based pH-sensitive, plasma stable liposomes. Colloids Surf. B Biointerfaces 115, 323–330 (2014).Article CAS PubMed Google Scholar Huang, L. et al. Direct surface grafting of mesoporous silica nanoparticles with phospholipid choline-containing copolymers through chain transfer free radical polymerization and their controlled drug delivery. J. Colloid Interface Sci. 508, 396–404 (2017).Article CAS PubMed Google Scholar Sun, Y. et al. Synthesis and characterization of pH-sensitive poly(itaconic acid)-poly(ethylene glycol)-folate-poly(l-histidine) micelles for enhancing tumor therapy and tunable drug release. J. Colloid Interface Sci. 458, 119–129 (2015).Article CAS PubMed Google Scholar Dong, K. et al. Amplification of oxidative stress in MCF-7 cells by a novel pH-responsive amphiphilic micellar system enhances anticancer therapy. Mol. Pharm. 16, 689–700 (2019).Article CAS PubMed Google Scholar Poorgholy, N. et al. Intelligent anticancer drug delivery performances of two poly(N-isopropylacrylamide)-based magnetite nanohydrogels. Drug Dev. Ind. Pharm. 44, 1254–1261 (2018).Article CAS PubMed Google Scholar Kumari, S. et al. Synthesis and characterization of temperature- and pH-responsive PIA-b-PNIPAM@Fe(3)O(4) nanocomposites. Nanomaterials 15, 1041 (2025).Mahmoodzadeh, F., Jannat, B. & Ghorbani, M. Chitosan-based nanomicelle as a novel platform for targeted delivery of methotrexate. Int. J. Biol. Macromol. 126, 517–524 (2019).Article CAS PubMed Google Scholar Dellali, K. Z. et al. Assessment of physicochemical and in vivo biological properties of polymeric nanocapsules based on chitosan and poly(N-vinyl pyrrolidone-alt-itaconic anhydride). Polymers 14, 1811 (2022).Chen, Z. et al. Reprogramming tumor-associated macrophages and blocking PD-L1 via engineered outer membrane vesicles to enhance T cell infiltration and cytotoxic functions. J. Nanobiotechnol. 23, 514 (2025).Article CAS Google Scholar Nekipelov, K. et al. A novel series of synthetic heparin-mimetics-itaconic acid-containing copolymers for targeting tumor cell coagulability and metastasis. Macromol. Biosci. 25, e2400633 (2025).Article PubMed PubMed Central Google Scholar Qiu, C. et al. Reprogramming glucose metabolism of macrophage for acute liver failure therapy with itaconate lipo-nanodrug. Adv. Health. Mater. 14, e2500019 (2025).Article Google Scholar Zhuang, J. et al. A self-assembled metabolic regulator reprograms macrophages to combat cytokine storm and boost sepsis immunotherapy. Reserach 8, 0663 (2025).CAS Google Scholar Vuong, M. D. L. et al. Degradation of polymer-drug conjugate nanoparticles based on lactic and itaconic acid. Int. J. Mol. Sci. 23, 14461 (2022).Omar, S. M., Maziad, N. A. & El-Tantawy, N. M. Design of isoniazid smart nanogel by gamma radiation-induced template polymerization for biomedical application. Pharm. Res. 34, 1872–1885 (2017).Article CAS PubMed Google Scholar Omar, S. M., Maziad, N. A. & El-Tantawy, N. M. Pulmonary delivery of isoniazid in nanogel-loaded chitosan hybrid microparticles for inhalation. J. Aerosol Med. Pulm. Drug Deliv. 32, 78–87 (2019).Article CAS PubMed Google Scholar Moussa, A. K., Abd El-Rahman, H. A., Mohamed, R. R. & Hanna, D. H. Hyaluronic acid-based pH-sensitive nanogel: synthesis, characterization, and assessment for acyclovir delivery in vitro and in vivo. Biomacromolecules 26, 341–362 (2025).Article CAS PubMed Google Scholar Liu, Y. et al. Nanotherapeutics-mediated tolerogenic induction for enabling adeno-associated virus vector gene therapy re-administration by overcoming anti-drug antibodies. Mater. Horiz. 12, 6751–6764 (2025).Article CAS PubMed Google Scholar Woodworth, K. E. et al. Development of itaconate polymers microparticles for intracellular regulation of pro-inflammatory macrophage activation. Adv. Health. Mater. 14, e2405257 (2025).Article Google Scholar Cicuéndez, M. et al. Macrophage inflammatory and metabolic responses to graphene-based nanomaterials differing in size and functionalization. Colloids Surf. B Biointerfaces 186, 110709 (2020).Article PubMed Google Scholar Milašinović, N. et al. Stimuli-sensitive hydrogel based on N-isopropylacrylamide and itaconic acid for entrapment and controlled release of Candida rugosa lipase under mild conditions. Biomed. Res. Int. 2014, 364930 (2014).Article PubMed PubMed Central Google Scholar Chaudhary, H. K. et al. Microcrystalline cellulose and itaconic acid pH sensitive semi-interpenetrating network hydrogel for oral insulin delivery. Int. J. Biol. Macromol. 282, 136804 (2024).Article CAS PubMed Google Scholar Mudassir, J., Darwis, Y., Muhamad, S. & Khan, A. A. Self-assembled insulin and nanogels polyelectrolyte complex (Ins/NGs-PEC) for oral insulin delivery: characterization, lyophilization and in-vivo evaluation. Int. J. Nanomed. 14, 4895–4909 (2019).Article CAS Google Scholar Koetting, M. C. et al. pH-responsive and enzymatically-responsive hydrogel microparticles for the oral delivery of therapeutic proteins: Effects of protein size, crosslinking density, and hydrogel degradation on protein delivery. J. Control Release 221, 18–25 (2016).Article CAS PubMed Google Scholar Demirdirek, B. & Uhrich, K. E. Novel salicylic acid-based chemically crosslinked pH-sensitive hydrogels as potential drug delivery systems. Int. J. Pharm. 528, 406–415 (2017).Article CAS PubMed Google Scholar Rashid, Z. et al. Preparation and evaluation of ph responsive poly(2-hydroxyethyl methacrylate-co-itaconic acid) microgels for controlled drug delivery. Acta Pol. Pharm. 73, 1045–1055 (2016).CAS PubMed Google Scholar Shahzad, M. K. et al. Relative bioavailability of risedronate sodium administered in superabsorbent copolymer particles versus oral solution to normal healthy rabbits. Acta Pol. Pharm. 73, 1267–1274 (2016).CAS PubMed Google Scholar Fallon, M. et al. Synthesis and characterisation of novel temperature and pH sensitive physically cross-linked poly (N-vinylcaprolactam-co-itaconic acid) hydrogels for drug delivery. Gels 5, (2019).Hu, X. et al. Redox/pH dual stimuli-responsive degradable Salecan-g-SS-poly(IA-co-HEMA) hydrogel for release of doxorubicin. Carbohydr. Polym. 155, 242–251 (2017).Article CAS PubMed Google Scholar Fathi, M. et al. Dual thermo-and pH-sensitive injectable hydrogels of chitosan/(poly(N-isopropylacrylamide-co-itaconic acid)) for doxorubicin delivery in breast cancer. Int. J. Biol. Macromol. 128, 957–964 (2019).Article CAS PubMed Google Scholar Chiriac, A. P. et al. Hybrid gels by conjugation of hyaluronic acid with poly(itaconic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5)undecane) copolymers. Int. J. Biol. Macromol. 98, 407–418 (2017).Article CAS PubMed Google Scholar Nita, L. E. et al. Multifunctional nanogels with dual temperature and pH responsiveness. Int J. Pharm. 515, 165–175 (2016).Article CAS PubMed Google Scholar Nita, L. E. et al. Multifunctional hybrid 3D network based on hyaluronic acid and a copolymer containing pendant spiroacetal moieties. Int. J. Biol. Macromol. 125, 191–202 (2019).Article CAS PubMed Google Scholar Ma, J., Li, T., Luo, M. & Lei, B. Single-component self-healing antibacterial anti-inflammatory intracellular-antioxidative poly(itaconic acid-pluronic) hydrogel for rapid repair of MRSA-impaired wound. ACS Appl. Mater. Interfaces 15, 33413–33424 (2023).Article CAS PubMed Google Scholar Ding, Q. et al. Multifunctional hydrogel loaded with 4-octyl itaconate exerts antibacterial, antioxidant and angiogenic properties for diabetic wound repair. Biomater. Adv. 139, 212979 (2022).Article CAS PubMed Google Scholar Ding, Q. et al. Bioinspired multifunctional black phosphorus hydrogel with antibacterial and antioxidant properties: a stepwise countermeasure for diabetic skin wound healing. Adv. Health. Mater. 11, e2102791 (2022).Article Google Scholar He, J. et al. Anti-inflammatory and anti-oxidative electrospun nanofiber membrane promotes diabetic wound healing via macrophage modulation. J. Nanobiotechnol. 22, 116 (2024).Article CAS Google Scholar Wan, Y. et al. Multifunctional hydrogel loaded with 4-octyl itaconate and exosomes to induce bone regeneration for diabetic infected bone defect via Keap1-Nrf2 pathway. Mater. Today Bio 31, 101588 (2025).Article CAS PubMed PubMed Central Google Scholar Moussa, A. K., Abd El-Rahman, H. A., Mohamed, R. R. & Hanna, D. H. Multifunctional plasticized hyaluronic-acid-based nanogel dressing for accelerating diabetic and nondiabetic wounds. Biomacromolecules 26, 3495–3513 (2025).Article CAS PubMed Google Scholar Liu, H. et al. Bioinspired 3D-printed NIR-responsive MXene-based multifunctional eutectogel microneedles for personalized infected wound healing. Adv. Health. Mater. 14, e2501344 (2025).Article Google Scholar Bao, R. et al. Fabrication of injectable alginate hydrogels with sustained release of 4-octyl itaconate for articular anti-inflammatory. Biomed. Mater. Eng. 35, 475–485 (2024).CAS PubMed Google Scholar Xiao, H. et al. Injectable hydrogel loaded with 4-octyl itaconate enhances cartilage regeneration by regulating macrophage polarization. Biomater. Sci. 11, 2445–2460 (2023).Article CAS PubMed Google Scholar Yu, H. et al. Intracellular delivery of itaconate by metal-organic framework-anchored hydrogel microspheres for osteoarthritis therapy. Pharmaceutics. 15, 724 (2023).Zha, K. et al. Regulation of metabolic microenvironment with a nanocomposite hydrogel for improved bone fracture healing. Bioact. Mater. 37, 424–438 (2024).CAS PubMed PubMed Central Google Scholar Zhou, S. et al. Injectable hydrogel of chitosan-octyl itaconate conjugate modulates inflammatory response. ACS Biomater. Sci. Eng. 10, 4823–4838 (2024).Article CAS PubMed Google Scholar Muduli, S. et al. Proliferation and osteogenic differentiation of amniotic fluid-derived stem cells. J. Mater. Chem. B 5, 5345–5354 (2017).Article CAS PubMed Google Scholar Calles, J. A. et al. Preliminary characterization of dexamethasone-loaded cross-linked hyaluronic acid films for topical ocular therapy. Int. J. Pharm. 509, 237–243 (2016).Article CAS PubMed Google Scholar Gupta, V. K. et al. Antioxidant activity and controlled drug delivery potential of tragacanth gum-cl- poly (lactic acid-co-itaconic acid) hydrogel. Int. J. Biol. Macromol. 107, 2534–2543 (2018).Article CAS PubMed Google Scholar Sood, S. et al. Controlled release of antibiotic amoxicillin drug using carboxymethyl cellulose-cl-poly(lactic acid-co-itaconic acid) hydrogel. Int. J. Biol. Macromol. 101, 612–620 (2017).Article CAS PubMed Google Scholar Pathania, D. et al. Novel nanohydrogel based on itaconic acid grafted tragacanth gum for controlled release of ampicillin. Carbohydr. Polym. 196, 262–271 (2018).Article CAS PubMed Google Scholar Calles, J. A. et al. Hyaluronan-itaconic acid-glutaraldehyde films for biomedical applications: preliminary studies. Sci. Pharm. 84, 61–72 (2016).Article CAS PubMed Google Scholar Sun, K. et al. Fabrication of dual-sensitive keratin-based polymer hydrogels and their controllable release behaviors. J. Biomater. Sci. Polym. Ed. 27, 1926–1940 (2016).Article CAS PubMed Google Scholar Wang, K. et al. Preliminary assessment of the safety evaluation of novel pH-sensitive hydrogel. Eur. J. Pharm. Biopharm. 82, 332–339 (2012).Article CAS PubMed Google Scholar Schneider-Chaabane, A. et al. Stimulus-responsive polyzwitterionic surfaces made from itaconic acid: self-triggered antimicrobial activity, protein repellency, and cell compatibility. ACS Appl. Mater. Interfaces 12, 21242–21253 (2020).Article CAS PubMed Google Scholar Qian, H. L. et al. Spongy skin as a robust strategy to deliver 4-octyl itaconate for conducting dual-regulation against in-stent restenosis. Biomaterials 296, 122069 (2023).Article CAS PubMed Google Scholar Gao, Y. et al. Anti-inflammatory itaconate-loaded, cell-adhesive peptide-conjugated artificial small diameter vascular grafts for blood vessel regeneration. Acta Biomater. (2025).Davenport Huyer, L. et al. One-pot synthesis of unsaturated polyester bioelastomer with controllable material curing for microscale designs. Adv. Health. Mater. 8, e1900245 (2019).Article Google Scholar Bannerman, D. et al. Itaconate and citrate releasing polymer attenuates foreign body response in biofabricated cardiac patches. Mater. Today Bio 24, 100917 (2024).Article CAS PubMed Google Scholar Qian, H. et al. Pressure-driven microinjection (PMI) of porous-coated balloon for ultrafast endoluminal drug delivery across biological barriers. Sci. Adv. 11, eadv1182 (2025).Article CAS PubMed PubMed Central Google Scholar Pedram, P. et al. Synthesis and characterization of a dental cement based on bioactive glass/zinc oxide modified with organic resin as a novel pulp capping agent. Biomed. Mater. 18, (2023).Amiryaghoubi, N., Noroozi Pesyan, N., Fathi, M. & Omidi, Y. Injectable thermosensitive hybrid hydrogel containing graphene oxide and chitosan as dental pulp stem cells scaffold for bone tissue engineering. Int. J. Biol. Macromol. 162, 1338–1357 (2020).Article CAS PubMed Google Scholar Huyer, L. D. et al. Macrophage immunomodulation through new polymers that recapitulate functional effects of itaconate as a power house of innate immunity. Adv. Funct. Mater. 31, 2003341 (2021).Download referencesAcknowledgementsThis work was sponsored by the National Natural Science Foundation of China (No. 82203165) and the Graduate Research and Innovation Foundation of Chongqing, China (No. CYB25071) for J.G.; Chongqing Technology Innovation and Application Development Special Key Project (No. CSTB2022TIAD-KPX0170) and the Chongqing Science and Health Joint Medical Research Major Project (No. 2024DBXM003) for H.W.; Guangdong Medical Science and Technology Research Fund (No. A2025241) and Plan on enhancing scientific research in GMU for W.Z.; National Natural Science Foundation of China (No. 82502416) and Postdoctoral Fellowship Program and China Postdoctoral Science Foundation (No. BX20250243) for S.Z.; National Natural Science Foundation of China (No. 82573500) for L.C.; Natural Science Foundation of Chongqing, China (No. CSTB2024NSCQ-MSX1113) for R.X. The authors would like to thank Xianxing Wang and Jiali Yang for their helpful discussions and support during the preparation of this manuscript.Author informationAuthor notesThese authors contributed equally: Jianyou Gu, Wenying Zhang, Junfeng ZhangAuthors and AffiliationsInstitute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, School of Medicine, Chongqing University, Chongqing, ChinaJianyou Gu, Junfeng Zhang, Renpei Xia, Lei Cai, Shixiang Guo & Huaizhi WangDepartment of Nephrology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaWenying ZhangUniversity of Chinese Academy of Sciences (UCAS) Chongqing School, Chongqing Medical University, Chongqing, ChinaJunfeng Zhang & Huaizhi WangDepartment of Hepatobiliary Surgery Ⅰ, Zhujiang Hospital, Southern Medical University, Guangzhou, ChinaSilue ZengDepartment of Pancreas Center, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, ChinaXiaosheng ZhongChongqing Key Laboratory of Intelligent Medicine Engineering for Hepatopancreatobiliary Diseases, Chongqing, ChinaShixiang Guo & Huaizhi WangDepartment of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, USAZhe-Sheng ChenAuthorsJianyou GuView author publicationsSearch author on:PubMed Google ScholarWenying ZhangView author publicationsSearch author on:PubMed Google ScholarJunfeng ZhangView author publicationsSearch author on:PubMed Google ScholarSilue ZengView author publicationsSearch author on:PubMed Google ScholarRenpei XiaView author publicationsSearch author on:PubMed Google ScholarLei CaiView author publicationsSearch author on:PubMed Google ScholarXiaosheng ZhongView author publicationsSearch author on:PubMed Google ScholarShixiang GuoView author publicationsSearch author on:PubMed Google ScholarHuaizhi WangView author publicationsSearch author on:PubMed Google ScholarZhe-Sheng ChenView author publicationsSearch author on:PubMed Google ScholarContributionsJianyou Gu conceived the overall structure of the review, collected and organized the literature, drafted and revised the manuscript, and prepared all figures. Wenying Zhang and Junfeng Zhang contributed to the literature collection, drafted and revised the manuscript, and provided critical discussion. Silue Zeng, Renpei Xia, Lei Cai, and Xiaosheng Zhong assisted with literature organization, reference checking, and table preparation. Shixiang Guo, Huaizhi Wang, and Zhe-Sheng Chen provided conceptual guidance, supervision, critical revision, and final approval of the manuscript. All authors have read and approved the article.Corresponding authorsCorrespondence to Shixiang Guo, Huaizhi Wang or Zhe-Sheng Chen.Ethics declarationsCompeting interestsThe authors declare no competing interests.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationRights and permissionsOpen Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.Reprints and permissionsAbout this article