IntroductionMetabolic intermediates fulfill their traditional metabolic roles and also serve as signaling molecules to execute non-metabolic functions. PTMs induced by metabolites substantially influence cellular function. Lactylation, a novel PTM driven by the metabolic byproduct lactate, operates as a dynamic regulatory mechanism that links cellular metabolism with epigenetic processes.1,2 This discovery unveils an additional dimension of lactate beyond being merely a metabolic byproduct and signaling regulatory molecule by positioning it as a precursor for lactylation.3 Lactylation was identified on histones, playing an essential role in modulating chromatin accessibility and transcriptional activation.4,5 Subsequent studies have also detected that lactylation occurs on non-histone proteins, and is classified into enzymatic L-lactylation and non-enzymatic D-lactylation based on the major sources of the lactyl moiety and enzyme involvement, thereby establishing its extensive regulatory potential.6,7,8,9 Canonical enzymatic L-lactylation uses lactyl-coenzyme A (lactyl-CoA) as a precursor of the L-lactyl moiety, followed by covalent attachment of the lactyl group to lysine residues via lactyltransferases. While glyoxalase II substrate S-D-lactoylglutathione (SLG) acts as a precursor of the D-lactyl moiety for non-enzymatic D-lactylation, highlighting the multifaceted characteristics of lactylation as a biological regulatory system consisting of substrate specificity, lactate source, and enzyme dependence.10,11 Non-histone protein lactylation plays a pivotal role in transcriptional activation, protein function, and cellular processes.Functionally, lactylation orchestrates a multifaceted regulatory network spanning, including transcriptional activation, protein stability, enzyme activity, protein‒protein interactions, protein subcellular translocation, and crosstalk with other PTMs.12,13 Moreover, its emerging significance in modulating RNA modification, epigenetic instability, and phase separation underscores its ability to integrate metabolic signals with nuclear and cytoplasmic regulatory mechanisms.14,15,16 Physiologically, lactylation governs critical developmental processes, such as embryonic development, somatic cell reprogramming, neural development, and cochlear development.17,18,19,20 Dysregulated lactylation contributes to the onset and progression of various cancers through metabolic adaptation, immune evasion, programmed cell death modulation, epigenetic rewiring, stemness maintenance, invasion, and metastasis.21,22,23,24 Lactylation also dictates the pathological process of neurological, cardiovascular, and ophthalmic diseases, as well as immunoinflammatory and metabolic dysfunction.25,26,27,28,29 With the continuous deepening of research on lactylation, it is expected to serve as a biomarker for the early diagnosis and prognosis of diseases, and targeted lactylation is expected to become a potential strategy for disease diagnosis and treatment.The research on lactylation is increasingly expanding, necessitating a comprehensive review and summarization. This review elucidates the modification process and molecular biological significance of lactylation, as well as its involvement in various physiologies and multiple diseases, describes the potential of lactylation as a biomarker for diagnosis and prognosis, and emphasizes the promise of lactylation-targeted therapies. Moreover, future research directions are proposed to offer insights into the clinical applications of lactylation.Lactate: from metabolic waste to signal transducerLactate has long been mischaracterized as a metabolic waste product under hypoxic conditions, traditionally associated with detrimental effects and hypoxia.30 As a canonical byproduct of glucose metabolism, it is primarily generated through glycolysis, where glucose is converted to pyruvate and then to lactate by lactate dehydrogenase (LDH).31,32 Notably, lactate accumulation leads to lactic acidosis, posing more risks than other fuel molecules.33 Alternatively, mitochondrial pyruvate can be irreversibly decarboxylated to acetyl-CoA by pyruvate dehydrogenase (PDH), entering the TCA cycle for oxidative metabolism.34,35 Lactate can also be converted back to glucose via gluconeogenesis to meet energy needs.36,37 Thus, the systemic equilibrium among glycolytic flux, TCA cycle activity, and gluconeogenic capacity constitutes a critical determinant of lactate homeostasis. In cancer cells, however, lactate can also originate from glutaminolysis.38,39 Glutamine traverses the plasma membrane via amino acid transporter type 2 (ASCT2) and sodium-coupled neutral amino acid transporter 5 (SN2), where cytosolic glutaminase converts it to glutamate and then to α-ketoglutarate (α-KG), which enters the TCA cycle.40 Within this cycle, glutamine-derived carbon is converted to oxaloacetate and then to malate, which exits the mitochondria and is decarboxylated to NADPH and pyruvate by cytosolic malic enzyme (ME1), ultimately yielding lactate.41,42Lactate transport is mediated by proton-coupled monocarboxylate transporters (MCTs), encoded by the SLC16A gene family and comprising 14 transmembrane protein isoforms, among which MCT1 and MCT4 are functionally predominant.43 MCT1 is ubiquitously expressed in oxidative tissues such as cardiac muscle and slow-twitch muscle fibers, aiding lactate uptake. In contrast, MCT4 localizes predominantly to glycolytically active tissues such as fast-twitch fibers and tumor cells, enabling rapid lactate efflux under high lactate concentrations.44,45 The coordinated activity of MCTs establishes lactate transport between glycolytic and oxidative cells, serving as a critical determinant of lactate homeostasis across tissues. The proposal of “lactate shuttle” elucidates both systemic and intracellular lactate trafficking, redefining lactate not merely as an anaerobic metabolic byproduct but also as a primary energy substrate and a signaling molecule.46 Complementarily, G protein-coupled receptors (GPCRs) on cell membranes, especially GPR81, orchestrate lactate signaling by serving as critical regulators of lactate shuttling.47Emerging evidence has unveiled lactate as a pleiotropic molecule functioning beyond mere metabolic waste, serving as an energy substrate, redox buffer, fatty acid metabolism modulator, immunometabolic regulator, and intercellular signaling mediator.30,48,49,50,51 Notably, the discovery of lactylation underscores the pivotal role of lactate in driving epigenetic reprogramming, thereby establishing a mechanistic bridge between cellular metabolism and epigenetic regulation.Lactylation: a novel epimetabolic codeLactylation has garnered significant scientific interest and achieved rapid progress, including the sequential discovery of both histone and non-histone protein lactylation substrates, comprehensive mapping of modification sites, and systematic characterization of regulatory enzymes, which have collectively contributed to our expanding understanding of this PTM (Fig. 1).Fig. 1Full size imageMolecular mechanisms, historical development, and detection flow of protein lactylation. a The modification process of lysine lactylation and the corresponding regulatory enzymes. Endogenous L-lactate and L-lactate produced by exogenous transport or glycolysis are converted into L-lactyl-CoA, which directly contributes as an L-lactyl moiety (La) in the enzymatic transfer of L-lactate to lysine residues of proteins. This reversible enzymatic modification process is orchestrated by the catalysis of writers, recognition by readers, and removal of the lactyl group by erasers. b Timeline of landmark events in lactylation research, including the initial discovery of enzymatic histone L-lactylation, the identification of non-enzymatic D-lactylation, non-histone lactylation, and successive discoveries of erasers, readers, and lactyl-CoA synthetase. c The workflow for the identification of lysine lactylation using LC‒MS/MS based on proteomics technology. Proteins isolated from biological samples, such as cultured cells or tissues, are digested into peptide fragments using trypsin. The peptides are then enriched through the application of specific antibodies, followed by fractionation. Subsequently, the peptides are identified using LC‒MS/MS. Finally, quantitative analysis and visualization are conducted utilizing bioinformatics tools. The figure was generated with FigDraw (https://www.figdraw.com). MCT monocarboxylate transporter, LDH lactate dehydrogenase, GLUT glucose transporter, LGSH lactylglutathione, Lactyl-CoA lactyl-coenzyme A, Kla lysine lactylation, CBP CREB-binding protein, GCN5 general control non-depressible 5, KAT lysine acetyltransferase, TIP60 tat-interactive protein 60, HBO1 histone acetyltransferase binding to ORC1, NAA10 N-α-acetyltransferase 10, AARS1~2 alanyl-tRNA synthetase 1~2, Brg1 brahma-related gene 1, DPF2 double PHD finger 2, HDAC histone deacetylases, Sirt sirtuin, HMGB1 high mobility group-box 1, ACSS2 acyl-CoA synthetase short chain family member 2, GTPSCS glutathione transferase pseudocatalytic superfamily, LC‒MS/MS liquid chromatography‒mass spectrometry/mass spectrometryDefinition and molecular mechanism of lactylationLactylation was first identified on histone lysine by Zhang et al. in 2019.1 The researchers elucidated that this occurs through the covalent attachment of lactyl-CoA, which is derived from lactate, to lysine residues. Notably, the level of histone Kla is typically in parallel with lactate production. Lactylation and acetylation exhibit overlapping characteristics and functions.52 Their similarity is rooted in the fact that both lactyl-CoA and acetyl-CoA are primarily generated from pyruvate, an intermediate product of glycolysis, and have similar molecular structures.53,54 Like acetylation, it preferentially targets lysine residues for epigenetic modulation. However, histone lactylation follows a distinct temporal pattern compared to acetylation.1 Additionally, subsequent studies have indicated that lactylation displays slower kinetics at lysine than acetylation, and intracellular concentrations of lactyl-CoA are lower than those of acetyl-CoA.37,52 By utilizing isotope labeling and mass spectrometry, 28 Kla sites were identified on core histones in both human and mouse cells. Subsequent investigations have demonstrated that histone Kla can directly enhance the transcription and expression of stable genes by modulating chromatin accessibility.1,28 Histone Kla intricately links metabolic processes, particularly glycolysis, with epigenetic regulation of gene expression.53 These pioneering findings have garnered significant interest among researchers in the field of lactylation.Afterwards, subsequent discoveries have identified increased lactylation in histone and non-histone proteins, particularly with the development of YnLac, an alkynyl-functionalized chemical reporter. YnLac has enabled the detection and identification of protein lactylation, revealing numerous new modification sites in non-histone proteins. This powerful tool has significantly advanced the understanding of protein lactylation and its functions.55 Moreover, Wan et al. subsequently proposed a cyclic immonium ion of lactyllysine in tandem mass spectrometry, confirming its sensitivity and specificity through detailed analysis of lactylproteomes and spectral libraries. This work expands the understanding of lactylation beyond histones, revealing its presence in both enriched and unenriched human proteomes.56 The discovery of lactylation opens up a brand-new perspective for expanding the role of lactate in physiology and pathology.Lactylation primarily pertains to enzymatic lysine L-lactylation induced by L-lactate. Recent research, however, has identified non-enzymatic lysine D-lactylation. Methylglyoxal (MGO), a glycolysis byproduct, interacts with glutathione (GSH) via glyoxalase 1 (GLO1) to generate lactoylglutathione (LGSH). GLO2 then hydrolyzes LGSH, regenerating GSH and producing D-lactate, which transfers lactyl groups to lysine residues.11 Notably, the nearby cysteine residue also aids this non-enzymatic lactylation, further supplementing the regulatory mechanism of D-lactylation.10Overall, current research predominantly concentrates on L-lactylation, with limited revelation of non-enzymatic lysine D-lactylation, whose mechanism remains ambiguous and needs further investigation. Notably, a recent study identified L-lactylation as the primary form induced by hypoxia in tumors, linking it to hypoxia markers and tumor malignancy.57 Future research is anticipated to progressively elucidate the mechanisms underlying non-enzymatic D-lactylation, as well as the specific conditions and states that facilitate its occurrence.Regulatory enzymes of lactylationThe lactylation modification process involves specific regulatory enzymes, including writers, readers, and erasers, that are responsible for the addition, recognition, or removal of the lactyl moiety, respectively. These enzymes possess unique roles and functions and ensure the seamless and reversible progression of lactylation. Therefore, it is imperative to obtain a comprehensive understanding of the characteristics and regulatory mechanisms of these enzymes to facilitate in-depth exploration of lactylation (Fig. 1 and Table 1).Table 1 Regulatory enzymes of lactylation identified in mammalsFull size tableWritersHistone acetyltransferase (HAT) familyp300/CBP is the first identified writer of lactylation, which was previously recognized as an important member of HAT.58 Essentially, as the co-activator of cAMP-responsive element binding protein (CREB), p300/CBP is recruited by CREB to form a transcriptional complex and participates in gene transcription.59 Zhao et al. found that p300 overexpression induced a modest increase in histone Kla levels, while p300 deletion decreased histone Kla levels, indicating that lactate-derived Kla is p300-dependent.1 In addition, combined with in vitro enzymatic experiments, they found that p300 is a potential writer for histone Kla. Subsequently, p300 has been widely reported as a writer of lactylation of both histones and non-histones within diverse cellular processes.6,17,19,60,61,62,63,64Lysine acetyltransferase (KAT) is another appellation of HAT and is named for catalyzing the acetylation of lysine in proteins, especially histones.65 Several members of the KAT family serve as writers of Kla. Lysine acetyltransferase 2A (KAT2A), also known as general control non-depressible 5 (GCN5) and belonging to the GCN5-related N-acetyltransferase (GNAT) subfamily of HAT, functions as the lactyltransferase responsible for H3K18la, implying the role of GCN5 as a writer for histone Kla.66 Additionally, KAT2A acts as a lactyltransferase by interacting with lactyl-CoA synthetase acetyl-CoA synthetase 2 (ACSS2), which converts lactate to lactyl-CoA, to synergistically lactylate histone H3, especially H3K18la and H3K14la.67 Moreover, KAT2B has also been identified to directly catalyze early growth response 1 (EGR1) lactylation at lysine 364, serving as a writer of lactylation.68The MYST family is another subfamily of HAT and is named for its members, including monocytic leukemia zinc-finger protein (MOZ), yeast bromodomain factor 2 (Ybf2), SAGA-associated factor 2 (Sas2), and tat-interactive protein of 60 kDa (Tip60).69 Interestingly, several members of the MYST family have also been reported as writers of Kla. Specifically, Tip60, also known as KAT5, has been identified as a lysine lactyltransferase by utilizing lactylation modification-specific proteomics and mass spectrometry analysis. It directly interacts with Nijmegen breakage syndrome protein 1 (NBS1) at K388 to promote DNA repair.15 Meanwhile, Tip60 also functions as a lactyltransferase for vacuolar protein sorting 34 (Vps34) lactylation at K356 and K781.70 Furthermore, HAT binding to ORC1 (HBO1), another member of the MYST family also referred to as KAT7, acts as a writer to facilitate H3K9la.71 In addition, KAT8 has been recognized as a writer for catalyzing the lactylation of several proteins, such as elongation factor 1-α 2 (eEF1A2).72N-α-acetyltransferase (NAT) familyN-α-acetyltransferase 10 (NAA10), as a catalytic subunit of N-acetyltransferase A (NatA), has been documented to acetylate lysine residues of several protein substrates, including hypoxia-inducible factor 1 alpha (HIF-1α), Runt-related transcription factor 2 (Runx2), β-catenin, and myosin light-chain kinase.73,74 Intriguingly, NAA10 has been recently identified to catalyze the lactylation of K508 on NOP2/Sun RNA methyltransferase 2 (NSUN2), which further enhances its catalyzing activity as an RNA methyltransferase to facilitate the m5C of glutamate-cysteine ligase catalytic subunit (GCLC) mRNA.75Aminoacyl-tRNA synthetase (AARS) familyThe intracellular concentration of lactyl-CoA is much lower than that of acetyl-CoA, potentially limiting lactyltransferase activity.52 Consequently, a novel regulation mode of lactylation using lactate as a direct donor without necessitating the formation of lactyl-CoA is proposed, expanding the substrate range of lactylation. Currently, the lysine lactosyltransferases that directly transfer lactate for lactylation are mainly members of the aminoacyl-tRNA synthetase (AARS) family, whose usual function is to catalyze the ligation of l-alanine to tRNA.76For instance, AARS1 functions as an intracellular lactate sensor, directly binding lactate to form lactate-AMP, and mediates lactylation of K120/139 on p53 within its DNA-binding domain (DBD), which prevents the binding of p53 to DNA containing p53 response elements (p53RE-DNA) and subsequent p53 liquid‒liquid phase separation (LLPS).22 In addition, AARS1 senses intracellular lactate and serves as a bona fide lactyltransferase that directly uses lactate and ATP to catalyze the lactylation of Yes-associated protein (YAP) at K90 and the transcriptional enhanced associate domain (TEAD) at K108. Meanwhile, AARS1 itself has been identified as a target gene of Hippo signaling, forming a positive feedback loop with activated YAP-TEAD signaling.13Moreover, AARS2 is capable of directly catalyzing L-lactate for ATP-dependent lactylation. It interacts with cyclic GMP-AMP synthase (cGAS) and acts as a lactyltransferase to mediate cGAS lactylation.77 Additionally, AARS2 also mediates the lactylation of pyruvate dehydrogenase E1 component subunit alpha (PDHA1) at K336 and carnitine palmitoyltransferase 2 (CPT2) at K457/8, leading to the inactivation of both of these enzymes.78 These findings indicate that AARS1/2 does not function as a Pan Kla writer and that distinct enzymes are responsible for mediating lactylation and acetylation processes.ReadersThe readers of lactylation are defined as proteins or domains that can specifically recognize and interact with lactylation groups. Currently, research on lactylation readers is limited, with only Brahma-related gene 1 (Brg1) and double plant homeodomain fingers 2 (DPF2) identified thus far. Brg1, a member of the switching defective/sucrose non-fermenting (SWI/SNF) family, acts as an ATPase subunit that repositions nucleosomes to affect DNA accessibility.79 A recent study showed that Brg1 could bind to H3K18la, highlighting its role in recognizing histone lactylation and paving the way for researchers to comprehend the mechanisms of lactylation recognition.80 Subsequently, DPF2, an epigenetic regulator with a plant homeodomain, has been identified to bind to H3K14la and colocalize at oncogenic gene promoters, indicating its function in reading histone lactylation to drive transcription.81ErasersAlmost all histone deacetylases (HDACs), mainly including class Ⅰ HDACs and class Ⅲ HDACs, have been identified as delactylases (erasers) of lactylation. A systematic identification of the entire HDAC family revealed that class I HDACs, including HDAC1 ~ 3, and class III HDACs, including Sirt1 ~ 3, all serve as delactylases. HDAC1 ~ 3 exhibit the most potent capacity for removing histone Kla.82 Accumulating evidence has demonstrated that HDAC1 ~ 3 acts as an eraser in mediating lactylation of both histones21,83,84,85,86 and non-histones81,87,88,89 in various biological processes.With the continuous deepening and increasing advancement of lactylation research, increasing evidence has confirmed the role of Sirt1 ~ 3 as the erasers of lactylation. Slightly different from class I HDACs, Sirt1 ~ 3 have been reported to facilitate a greater degree of delactylation in non-histone proteins compared to histone proteins, which may be attributed to the subcellular localization of Sirt1 and Sirt2 being predominantly in the cytoplasm and mitochondrial matrix, respectively.90,91,92,93,94,95Lactyl-CoA synthetaseLactyl-CoA serves as the direct donor for lactylation and is a critical prerequisite, but exists in much lower concentrations than other acyl-CoAs in cells. Consequently, it is imperative to explore the enzyme that mediates its endogenous generation, namely, lactyl-CoA synthase. This enzyme converts lactate into lactyl-CoA, thereby providing the necessary donor for lactylation. Notably, a recent study identified ACSS2, previously known for acetyl-CoA synthetase, as a bona fide lactyl-CoA synthetase. It converts lactate to lactyl-CoA and couples KAT2A to mediate H3K18/14la.67 Almost concurrently, another study found that guanosine triphosphate (GTP)-specific SCS (GTPSCS), initially known as a mitochondrial succinyl-CoA synthetase, also acts as a lactyl-CoA synthase. GTPSCS translocates into the nucleus depending on a nuclear localization signal in the GTPSCS G1 subunit and acetylation at residue K73 of the G2 subunit and interacts with p300 to synergistically regulate H3K18la.96In summary, the identification of regulatory enzymes significantly enhances the understanding of lactylation modification patterns and regulatory mechanisms. Nevertheless, it is important to note that there is a lack of studies examining the priority and specificity of these enzymes in regulating lactylation, which complicates the determination of the optimal conditions for catalyzing this modification. Consequently, further research is necessary to elucidate the conditions under which these enzymes preferentially facilitate lactylation over other acylation processes.Molecular biological significance of lactylationLactylation plays a pivotal role in orchestrating diverse molecular biological processes, involving DNA, RNA, and proteins. It predominantly affects gene transcription, protein stability, enzyme activity, protein‒protein interactions, protein translocation, and crosstalk with other PTMs. Additionally, lactylation influences RNA post-transcriptional modification, genomic instability, and phase separation. These molecular regulatory functions provide a fundamental biological framework that is crucial for maintaining physiological activity and mediating pathology (Fig. 2).Fig. 2Full size imageMultifaceted molecular biological functions of lactylation. a Lactylation of histones and transcription factors facilitates transcriptional activation of the downstream genes. b Lactylation usually increases protein stability and is mainly achieved by inhibiting protein ubiquitination and degradation. c Lactylation of some enzymes governs their own enzyme activity, including enhancing or decreasing enzyme activity. d Lactylation promotes or suppresses protein‒protein interactions. e Lactylation manages protein subcellular localization, such as facilitating nuclear translocation, cytoplasmic translocation, and subsequent extracellular secretion via exosomes. It also restrains the mitochondrial localization of proteins by inhibiting interactions with proteins on mitochondria. f Lactylation exerts crosstalk with other PTMs, such as protein methylation, acetylation, phosphorylation, and ubiquitination. g Lactylation regulates RNA post-transcriptional modification, including RNA alternative splicing and RNA methylation. h Lactylation improves genomic instability by promoting DNA repair and regulating the cell cycle. i Lactylation of certain non-histone proteins abolishes LLPS and DNA sensing, while the lactylation of some non-histone proteins triggers their own LLPS. The figure was generated with FigDraw (https://www.figdraw.com). HIF-1α hypoxia-inducible factor 1α, YY1 yin yang-1, Ikzf1 lkaros family zinc-finger protein 1, DCBLD1 discoidin, cub and lccl domain-containing 1, NUSAP1 nucleolar and spindle-associated protein 1, LCP1 lymphocyte cytosolic protein 1, ALDOA aldolase A, c-Myc v-myc avian myelocytomatosis viral oncogene homolog, NLRP3 nod-like receptor thermal protein domain associated protein 3, TFEB transcription factor EB, NMNAT1 nicotinamide nucleotide adenylyltransferase 1, METTL3 methyltransferase-like 3, DDX17 dead-box deconjugate enzyme 17, TWIST1 twist family bHLH transcription factor 1, Tufm Tu translation elongation factor, mitochondrial, TGFβ transforming growth factor beta, EndoMT endothelial-to-mesenchymal transition, Tomm40 translocase of outer mitochondrial membrane 40, TTK threonine tyrosine kinase, BUB1B mitotic checkpoint serine/threonine kinase B, RUNX1 runt-related transcription factor 1, Fis1 mitochondrial fission protein 1, NADD nicotinamide adenine dinucleotide, NCL nucleolin, MYB myb proto-oncogene protein, SRSF10 serine/arginine-rich splicing factor 10, FTO fat mass and obesity-associated protein, IGF2BP3 insulin-like growth factor 2 mRNA binding protein 3, m6A N6-methyladenosine, m5C 5-methylcytosine, NRF2 nuclear factor erythroid 2-related factor 2, HK1 hexokinase 1, RAD50 RAD50 recombination repair and DNA nucleosome binding protein, DSBs double-strand breaks, HR homologous recombination, CCNB1 cyclin B1, LLPS liquid-liquid phase separation, PUMA p53 upregulated modulator of apoptosis, SORBS3 sorbin and SH3-domain-containing 3, FBXO2 F-box protein 2, FLOT1 flotillin 1Gene transcriptionThe primary molecular function of lactylation, especially histone Kla, is to regulate gene transcription. Accumulating evidence has indicated that lactylation of both histones and transcription factors modulates transcriptional regulation (Fig. 2a).Histone lactylationHistone Kla is believed to regulate gene transcription through epigenetic mechanisms, especially H3K18la-induced gene transcription regulation, involving specific gene sets. H3K18la improves genome stability and triggers the expression of pluripotency genes.17 Additionally, H3K18la promotes the transcription of various types of genes, such as oncogenes, immune factors, energy metabolism genes, and epigenetic gene sets in different cellular processes.27,64,66,84,97,98,99 Moreover, increasing histone Kla with multiple sites has been identified to regulate gene transcriptional activation, such as H3K9la,21,100 H3K14la,67,81 H3K56la,101,102,103 H4K5la,104 H4K8la,105 H4K12la,86,106,107,108 and H4K16la.109 Conversely, histone Kla also regulates transcriptional inhibition. For example, H3K9la in ECs and oxygen-induced retinopathy (OIR) mouse retinas inhibits HDAC2 expression, forming a feedback loop of H3K9la/HDAC2 to regulate angiogenesis.85 Likewise, H4K8la in astrocytes suppresses the expression of IL-6, IL-1β, and TNF-α, ultimately reducing neuronal death.99Lactylation of transcription factorsThe activation of transcription factors represents a fundamental mechanism for the regulation of gene transcription. Accumulating evidence has provided substantial insights into the lactylation of transcription factors, including HIF-1α, Yin Yang-1 (YY1), IKAROS family zinc-finger 1 (Ikzf1), YAP, and p53. Lactylation of HIF-1α enhances the transcriptional activation of KIAA1199 and subsequent angiogenesis.24 Similarly, the lactylation of YY1 at lysine 183 (K183la) in microglia augments the transcription of fibroblast growth factor 2 (FGF2).110 Intriguingly, YY1-K183la also promotes the transcriptional activation of F-box only protein 33 (FBXO33) in gallbladder cancer (GBC) cells.111 Furthermore, the hyperlactylation of IKAROS family zinc-finger 1 (Ikzf1) at lysine 164 downregulates the expression of interleukin-2 (IL-2) and interleukin-4 (IL-4) while simultaneously enhancing the expression of Toll-like receptor 4 (Tlr4) and Runt-related transcription factor 1 (Runx1).112 Moreover, YAP, a crucial transcriptional co-activator, also undergoes lactylation and enhances its nuclear localization and subsequent interaction with TEAD, thereby collectively promoting the expression of Hippo pathway target genes.13 Additionally, specific lactylation plays a role in transcriptional inhibition. For instance, AARS1-mediated lactylation of p53 at lysines 120 and 139 suppresses the transcription of p21, and p53 upregulates modulator of apoptosis (PUMA) by disrupting p53 LLPS and its DNA-binding capability.22 Similarly, the lactylation of methylated CpG-binding protein 2 (MeCP2), a nuclear protein selectively recognizing and binding to DNA, inhibits epiregulin (Ereg) transcription and the subsequent Egfr/MAPK pathway.89Interaction with non-coding RNAs (ncRNAs)ncRNAs and lactylation have been recently reported to mutually regulate each other in transcriptional processes. For instance, CircXRN2, a circular ncRNA, suppresses H3K18la, accompanied by the downregulation of LCN2.113 Conversely, lactylation in turn influences ncRNA transcriptional activation. Specifically, H4K8la is enriched at the promoter of LINC00152, a long non-coding RNA, upregulating its expression in colorectal cancer (CRC) tissues and promoting cell invasion and migration.105Protein stabilityRecent studies have increasingly demonstrated that protein lactylation significantly influences protein stability, primarily by inhibiting protein degradation (Fig. 2b). For example, lactylation of apolipoprotein C-II (APOC2) at lysine 70 prevents its degradation and stabilizes the protein, leading to free fatty acid (FFA) release and accumulation in regulatory T cells.88 Similarly, the lactylation of nucleolar and spindle-associated protein 1 (NUSAP1) at lysine 34 (K34) enhances NUSAP1 expression by inhibiting its degradation. Specifically, NUSAP1-K34la facilitates its interaction with c-Myc and HIF-1α, thereby forming a transcriptional regulatory complex that localizes to the lactate dehydrogenase A (LDHA) promoter and upregulates its expression.83 Furthermore, hypoxia-induced lactylation of β-catenin in CRC cells enhances the protein stability and expression of β-catenin, which is associated with the inhibition of protein degradation.114 Inhibition of glycolysis reduces the lactylation of lymphocyte cytosolic protein 1 (LCP1) and leads to its degradation.115 Conversely, lactylation also promotes protein degradation. For instance, lactylation of cGAS at K21 contributes to its proteasomal degradation.116 Additionally, lactylation of domain-containing type I (DCBLD1) stabilizes its expression to activate the downstream pentose phosphate pathway (PPP) in cervical cancer cells.117 Similarly, lactylation of c-myc in hepatocellular carcinoma (HCC) cells is positively correlated with its protein stability and expression.118 Hypoxia/reoxygenation-induced lactylation of NLR family pyrin domain-containing 3 (NLRP3) in H9c2 cells increases its protein stability.119 Another recent study has also demonstrated that the lactylation of aldolase A (ALDOA) at K147 augments its protein stability, thereby contributing to the reshaping of ALDOA functionality.120Enzyme activityLactylation has been increasingly proven to play a regulatory role in enzyme activity, particularly in metabolism-related enzymes, including enhancing and inhibiting enzyme activity (Fig. 2c). The lactylation of K62 on pyruvate kinase M2 (PKM2), a crucial enzyme in glycolysis, inhibits its transition from tetramer to dimer and enhances its pyruvate kinase activity, thereby suppressing inflammatory metabolic adaptation in pro-inflammatory macrophages.121 Conversely, lactylation of ALDOA, an essential enzyme in glycolysis and gluconeogenesis, abolishes its enzymatic activity, ultimately affecting its biological function in living cells.120 Similarly, lactylation also alters the activity of enzymes related to OXPHOS. Concretely, lactylation of PDHA1 at K336 and CPT2 at K457/8 results in the inactivation of both enzymes and the inhibition of OXPHOS by restricting acetyl-CoA influx from pyruvate and fatty acid oxidation, respectively.78 Moreover, glucose-6-phosphate dehydrogenase (G6PD), a pivotal enzyme in the PPP, also serves as a significant substrate for lactylation. G6PD-K45 lactylation in cervical cancer cells inhibits its enzymatic activity.122 Additionally, under glucose deprivation conditions, lactylation of nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) in pancreatic adenocarcinoma cells maintains its enzymatic activity, accompanied by supporting the nuclear NAD+ salvage pathway.92 Furthermore, Kla also alters the kinase activity of enzymes related to lipid metabolism. For instance, mitochondrial pyruvate carrier 1 (MPC1) knockout promotes the accumulation of lactate and the subsequent lactylation of fatty acid synthase (FASN) at K673, which further inhibits FASN activity and reduces lipid accumulation.123 Vps34 lactylation at K356 and K781 enhances its interaction with Beclin1, Atg14L, and UVRAG and then increases Vps34 lipid kinase activity, thereby promoting autophagic flux and endolysosomal trafficking.70 Additionally, lactylation at K91 of transcription factor EB (TFEB) impedes it from interacting with E3 ubiquitin ligase WW domain-containing E3 ubiquitin protein ligase 2 (WWP2), thereby inhibiting TFEB ubiquitination and proteasome degradation and eventually augmenting TFEB activity.12 Intriguingly, the enzyme activity of cGAS is also modulated by lactylation. Specifically, AARS2-mediated cGAS Kla leads to the inactivation of cGAS, which abolishes cGAS LLPS and DNA sensing.77Protein‒protein interactionLactylation has been demonstrated to modify the conformation and stability of proteins, thereby influencing protein‒protein interactions (Fig. 2d). Notably, lactylation enhances protein‒protein interactions in certain proteins while inhibiting such interactions in others. For instance, Vps34-K356/781la enhances the interaction of Vps34 with Beclin1, Atg14L, and UVRAG, which promote autophagic flux and endolysosomal trafficking in skeletal muscle and cancer cells.70 Moreover, lactylation of X-ray cross-complementing protein 1 (XRCC1) facilitates its interaction with importin-α and subsequently promotes its nuclear translocation and the consequent augmentation of DNA repair.124 Furthermore, lactylation of membrane-organizing extension spike protein (MOESIN) enhances its interaction with transforming growth factor beta (TGF-β) receptor I, thereby activating downstream SMAD3 signaling in HCC.7 Similarly, the lactylated NUSAP1 at K34 increases its binding to c-Myc and HIF-1α, forming a transcription regulatory complex localized to the promoter region of LDHA, consequently establishing an NUSAP1-LDHA-glycolysis-lactate feedforward loop to promote the Warburg effect.83 A recent study intriguingly identified that the lactylation of K124 on regulator of chromosome condensation 2 (RCC2), a chromosome condensation regulation-related protein, assists in the recruitment of free SERBP1, which further stabilizes MAD2L1 mRNA and promotes the proliferation of breast cancer cells.125 In addition, lactylation of α-myosin heavy chain (α-MHC) at K1897 maintains sarcomeric structure and alleviates heart failure by facilitating its interaction with Titin.26 Similarly, the lactylation of MeCP2 at K271 facilitates the interaction between MeCP2 and H3K36me3, leading to increased chromatin accessibility and transcriptional repression of RUNX1.89 Additionally, the binding affinity between protein disulfide-isomerase (P4HB) and prostaglandin G/H synthase 2 (PTGS2) is enhanced by lactylation of P4HB at K311, subsequently leading to SH3-domain-containing GRB2-like protein B1 (SH3GLB1)-mediated mtROS accumulation and coiled-coil domain-containing protein 2 (NDP52)-induced mitophagy.126 The lactylation of EGR1 at K364 facilitates its interaction with importin-α, in turn promoting its nuclear localization.68In contrast, lactylation of some other proteins weakens protein‒protein interactions. For example, the lactylation of K230 and K322 on ALDOA abolishes its interaction with dead-box deconjugate enzyme 17 (DDX17), thereby enhancing the regulatory function of DDX17.101 Additionally, hyperlactylation of polypyrimidine tract binding protein 1 (PTBP1) in GSCs inhibits its interaction with tripartite motif-containing 21 (TRIM21), enhances its RNA-binding affinity, and facilitates the mRNA stabilization of PFKFB4.127 Similarly, the lactylation of K286 on Tufm, a critical factor in mitophagy, impedes the interaction between Tufm and Tomm40 on mitochondria, thereby suppressing mitophagy and exacerbating mitochondrial dysfunction.128 Likewise, in macrophages, lactylation of K33 on NEDD4, a crucial E3 ubiquitin ligase, reduces the ubiquitination of Caspase-11 by diminishing their binding affinity, leading to Caspase-11-dependent non-canonical pyroptosis.91 In addition, lactylation at K91 of TFEB inhibits its interaction with the E3 ubiquitin ligase WWP2, leading to reduced ubiquitination and proteasomal degradation of TFEB, thereby resulting in enhanced TFEB activity.12Protein subcellular localizationThe subcellular localization of proteins is intricately associated with lactylation, which affects their distribution and biological functions. Lactylation predominantly directs proteins to the nucleus but also targets them to mitochondria, lysosomes, the cytoplasm, and subsequent extracellular secretion (Fig. 2e).Nuclear localizationLactylation influences protein nuclear translocation. For instance, lactylation of XRCC1 enhances its binding affinity with importin-α, promoting increased nuclear translocation of XRCC1 in ALDH1A3-overexpressing glioblastoma.124 Similarly, lactylated EGR1 at K364 also promotes its nuclear localization by facilitating its interaction with importin-α.68 Furthermore, Kla of certain proteins facilitates the transcriptional activation of downstream genes by promoting nuclear translocation of the corresponding substrate proteins. Specifically, the highly expressed K430la of ATP-binding cassette subfamily F member 1 (ABCF1) in HCC tissues enhances its nuclear localization, accompanied by its binding to the lysine demethylase 3A (KDM3A) promoter, leading to KDM3A upregulation and subsequent activation of the KDM3A-H3K9me2-HIF1A axis.87 However, Twist1-K150la augments its nuclear translocation and facilitates TGFβ1 transcription in ECs following hypoxia.129 Similarly, Snail1 lactylation enhances its nuclear translocation, triggering the expression of N-cadherin and Vimentin in pancreatic cancer cells.130 Additionally, ALDOA-K147la, YAP-K90la, and NMNAT1-K128la all facilitate the nuclear translocation of their respective substrate proteins.13,92,120Cytoplasm translocation and extracellular secretionLactylation promotes the transfer of proteins from the nucleus to the cytoplasm and their subsequent release via exosomal secretion. Concretely, p300-dependent lactylation of HMGB1 facilitates its translocation into lysosomes in the cytoplasm of macrophages and release via exosome secretion, disrupting endothelium barrier function by decreasing VE-cadherin and claudin 5 expression and increasing ICAM1 expression in human umbilical cord endothelial cells (HUVECs).6 Likewise, sepsis-induced lactylation of cold-inducible RNA-binding protein (CIRP) promotes its transfer from the nucleus to the cytoplasm and exosomal release from macrophages, leading to ZBP1-dependent PANoptosis.131Mitochondrial and lysosomal distributionLactylation affects protein distribution on mitochondria and lysosomes. Specifically, lactylation of Tufm at K286 impedes its interaction with Tomm40 on mitochondria, thereby inhibiting the mitochondrial localization of Tufm and Tufm-mediated mitophagy in injured neurons.128 Notably, inhibiting lactylation at K215 and K224 on canopy FGF signaling regulator 3 (CNPY3), a key regulator of protein folding in the endoplasmic reticulum, compromises the formation of the CNPY3 complex with auxiliary molecular chaperones for protein folding and lysosomal transport, thereby affecting its cellular localization and promoting lysosome rupture and pyroptosis in prostate cancer cells.90Crosstalk with other PTMsThere is a complex crosstalk relationship between lactylation and other PTMs, such as methylation, acetylation, ubiquitination, and phosphorylation, which plays an important role in cell signal transduction, gene expression regulation, and protein function maintenance (Fig. 2f).MethylationThe interaction between lactylation and methylation plays an essential role in the progression and remission of diseases. Specifically, ABCF1-K430la in HCC tissues enhances the dimethylation of H3K9 (H3K9me2) through binding with the KDM3A promoter and upregulating its expression, subsequently regulating HIF1A and the accompanying lactate production. This lactate-ABCF1 (K430la)-HIF1A-lactate loop is mediated by lactylation and histone methylation.87 Conversely, during the process of exercise preventing against atherosclerosis, the interaction between MeCP2-K271la and H3K36me3 is required to synergistically increase chromatin accessibility and transcriptional repression of RUNX1, thereby promoting M2 macrophage polarization.89AcetylationLactylation interacts synergistically or through competitive inhibition with acetylation. For instance, p300/CBP-mediated lactylation of HMGB1 concurrently inhibits deacetylase Sirt1 activity and enhances HMGB1 acetylation. Consequently, HMGB1 is released via exosomes through both lactylation and acetylation.6 Coincidentally, downregulated Sirtuin 3 (Sirt3)-mediated hyperacetylation of PDHA1 promotes the lactylation of mitochondrial fission 1 protein (Fis1) at K20 by increasing lactate overproduction in renal tubular epithelial cells, resulting in excessive mitochondrial injury.132 In addition, H3K18 lacylation competes with its acetylation for activating hepatic stellate cells.84 Another study has shown that lactylation and acetylation can occur on the same residues in the self-modified domain of PARP1. Lactylation might competitively inhibit acetylation, restoring the ADP-ribosylation activity of PARP1 and promoting DNA repair and synergistically regulating multifunctional gene expression.55 Hence, lactylation and acetylation can compete for the same protein sites, affecting protein function. They interact molecularly within cellular networks, playing synergistic or antagonistic roles in biological processes. These modifications may occur at different times or states, adding complexity to regulation.PhosphorylationLactylation and phosphorylation can be mutually regulated, which may be for the same protein or for different proteins. For example, Twist1-K150la simultaneously promotes its phosphorylation and nuclear translocation, consequently inducing the transcriptional activation of TGFβ1 in ECs.129 Moreover, H3K18la promotes the phosphorylation of LDHA at tyrosine 239 and the production of lactate. This synergistic effect of lactylation and phosphorylation forms a positive feedback pathway of metabolism and epigenetics in PDAC cells.97 In turn, the phosphorylation of LDHA at serine 196 induces the lactylation of Vps34 at K356/781, enhancing the interaction of Vps34 with Beclin1, ATG14, and UVRAG, eventually promoting macroautophagy/autophagy and facilitating the endolysosomal degradation pathway under nutrient-deprivation conditions.133UbiquitinationOn the one hand, lactylation of proteins competitively inhibits their ubiquitination. For instance, APOC2-K70la results in FFA release and resistance to immunotherapy in non-small cell lung cancer (NSCLC) cells by promoting its deubiquitination, which subsequently prevents its degradation and enhances protein stability.88 On the other hand, ubiquitin ligases themselves undergo Kla. Specifically, NEDD4, a crucial E3 ubiquitin ligase, reduces its binding affinity with Caspase-11 and subsequent Caspase-11 ubiquitination in bone marrow-derived macrophages (BMDMs) through lactylation at K33.91 In addition, lactylation can regulate ubiquitination by interacting with ubiquitin ligases. For example, TFEB-K91la impedes the ubiquitination and degradation of TFEB by weakening its interaction with the E3 ubiquitin ligase WWP2, ultimately leading to increased TFEB activity and autophagy flux in pancreatic cancer cells.12 Besides, lactylation also indirectly establishes a connection with ubiquitination through a signaling axis. For example, YY1-K183la promotes the polyubiquitination of p53 at K291/292 by facilitating the transcription of FBXO33 in GBC.111 Moreover, lactylation of aldehyde dehydrogenase 2 (ALDH2) at K52 inhibits protein‒protein interaction with prohibitin 2 (PHB2) and aggravates mitochondrial dysfunction in HK2 cells by facilitating PHB2 ubiquitination and degradation.95RNA post-transcriptional modificationPost-transcriptional modification of RNA refers to the process of chemical modification and processing of RNA molecules after transcription to ensure proper biological function.134 These modifications, including RNA splicing and RNA methylation, affect RNA stability, transport, translation efficiency, and gene expression regulation.135 Recent studies have revealed that RNA modifications such as splicing and methylation interact with lactylation to regulate gene expression and cellular function. Generally, lactylation affects the activity of RNA modification-related enzymes by enhancing transcription activation via histone Kla or directly lactylating these enzymes, eventually regulating RNA modification (Fig. 2g).RNA splicingLactylation modulates RNA splicing by influencing the expression of splicing factors. For instance, serine- and arginine-rich splicing factor 10 (SRSF10) upregulates key glycolysis-related enzymes, including glucose transporter 1 (GLUT1), hexokinase 1 (HK1), and lactate dehydrogenase A (LDHA), by stabilizing MYB RNA, resulting in lactate accumulation in hepatoma cells. In turn, lactate-induced H3K18la upregulates SRSF10 expression in macrophages, eventually forming the SRSF10/glycolysis/H3K18la positive feedback loop with tumor cells and promoting M2 macrophage polarization in the tumor microenvironment (TME).136 Similarly, circMETTL3-156aa, a novel peptide encoded by circMETTL3 derived from METTL3 in secondary hemophagocytic lymphohistiocytosis (sHLH) patient plasma exosomes, promotes M1 macrophage polarization by binding with LDHA and enhancing macrophage glycolysis. The glycolysis metabolite lactate upregulates SRSF10 expression via H3K18la and eventually forms a circMETTL3/METTL3-156aa/LDHA/lactate/SRSF10 positive feedback loop in THP-1 cells.137 Moreover, non-histone lactylation plays an essential role in regulating RNA splicing. Concretely, lactylation of K477 on nucleolin (NCL), an RNA-binding protein in the nucleus, upregulates MAP kinase-activating death domain protein (MADD) through binding to its primary transcript and avoiding alternative splicing that generates premature termination in iCCA cells.138 Notably, RNA splicing in turn regulates lactylation. Specifically, 14th exon skipping of ATP citrate lyase (Acly) pre-mRNA creates two isoforms: Acly Long (Acly L) and Acly Short (Acly S). Acly L undergoes lactylation at K918/995, affecting metabolic activity and boosting immunoregulatory functions in pro-inflammatory macrophages from RBM25-deficient mice.139RNA methylationRNA methylation, such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), and 5-methylcytosine (m5C), has been revealed to be regulated by lactylation, involving histone Kla-induced expression of methylation-related enzymes and the direct lactylation of these proteins (Fig. 2g).Histone Kla regulates the expression of RNA methylation-related enzymes, including writers, readers, and erasers. For example, H3K18la increases the expression of METTL3, a canonical m6A modification writer, inducing m6A modification of Jak1 mRNA and subsequent activation of the JAK1/STAT3 signaling pathway in tumor-infiltrating myeloid cells (TIMs). Notably, the zinc-finger domain of METTL3 itself undergoes lactylation, enhancing its ability to capture m6A-modified RNA.63 Moreover, H3K18la upregulates the expression of fat mass and obesity-associated protein (FTO), a classic demethylase (eraser) of m6A, which subsequently stabilizes CDK2 mRNA in ECs.140 In addition, H3K18la facilitates the expression of YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2), a typical m6A reader, leading to the recognition of m6A-modified PER1 and TP53 mRNAs in ocular melanoma cells.62 Coincidentally, α-ketoglutarate-dependent dioxygenase homolog 3 (ALKBH3), an eraser of m1A, is also upregulated by H3K18la, which in turn mediates m1A modification of SP100A mRNA in ocular melanoma cells.141Furthermore, RNA methylation-related enzymes are subject to lactylation. For instance, the reader of m6A, insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), undergoes lactylation at K76, promoting the m6A modification of phosphoenolpyruvate carboxykinase 2 (PCK2) and nuclear factor erythroid 2-related factor 2 (NRF2) mRNAs, which reprogram serine metabolism in HCC cells.14 Similarly, lactylation of METTL16 at K229 mediates m6A modification on FDX1 mRNA, consequently promoting cuproptosis in gastric cancer cells.142 NSUN2, a typical RNA m5C methyltransferase, undergoes lactylation at several different lysine sites, including K508, targeting GCLC mRNA to facilitate GCLC m5C formation and mRNA stabilization in gastric cancer cells.75 However, lactylation of K356 on NSUN2, an RNA m5C methyltransferase, facilitates its ability to capture target RNAs, such as enolase 1 (ENO1) mRNA in CRC cells. Notably, this process is interconnected with the upregulation of NSUN2 mediated by H3K18la.143 Intriguingly, lactylation of HDAC indirectly regulates RNA methylation by modulating the expression of RNA methylation-related enzymes. Inhibiting HDAC1 lactylation at K412 facilitates the significant activation of FTO and ALKBH5, which reduces ferroptosis suppressor protein (FSP1) mRNA m6A methylation in CRC cells.144Genomic instabilityThe DNA damage response (DDR) is a highly conserved defense network activated by cells in response to DNA damage, such as double-strand breaks (DSBs) or DNA replication stress. Its core function is to detect and transmit damage signals and coordinate repair while determining cell fate to maintain genomic stability.145,146,147,148,149 Remarkably, recent studies have indicated that lactylation plays a role in DDR and genome maintenance (Fig. 2h).DNA damage is frequently observed across various pathological conditions, with DSBs representing the most deleterious form of DNA damage.150 These breaks pose significant threats to genomic stability and are implicated in the pathology of cancer, neurological disorders, growth retardation, and immune deficiencies.151 Homologous recombination (HR) is an error-free pathway responsible for the repair of DSBs, with one of the critical initial steps being the end resection of damaged DNA, initiated by the MRE11-RAD50-NBS1 (MRN) complex.152,153,154 Recent studies have demonstrated that both MRE11 and NBS1 undergo lactylation. Upon DNA damage, MRE11 is lactylated at K673, subsequently promoting its binding to DNA and facilitating DNA end resection and HR in cancer cells. Inhibiting p300/CBP or LDH, as well as blocking MRE11 lactylation using a cell-penetrating peptide, suppresses HR.155 Additionally, the lactylation of K388 on NBS1, another crucial HR protein, promotes DNA repair by affecting the formation of MRN complexes.15 Moreover, lactylation of K247 on XRCC1, a pivotal protein in DNA damage repair, enhances its interaction with importin α and nuclear translocation, ultimately augmenting DNA repair activity in GSCs.124Additionally, abnormal regulation of the cell cycle is one of the core causes and key mechanisms that trigger and exacerbate genomic instability. Dysregulation of the cell cycle leads to DNA replication and eventually results in genomic instability.156 Interestingly, Warburg metabolism-mediated H4K12la activates cyclin B1 (CCNB1) transcription, accelerating DNA replication and the cell cycle in lung cancer brain metastatic subpopulation cells (PC9-BrM3).107Phase separationLLPS denotes the formation of phase-separated droplets characterized by distinct components and properties arising from the interactions among specific biomolecules, such as proteins and RNA, within cellular environments.157 LLPS is prevalent within the nucleus, cytoplasm, and organelles, serving as a distinctive substructure integral to numerous cellular processes.158,159 As a significant biophysical phenomenon, LLPS is pivotal in signal transduction and the pathogenesis of various diseases.160 Remarkably, lactylation has been identified as an essential regulator in LLPS (Fig. 2i). For example, the lactylation of p53 at K120/139 impairs p53 LLPS, DNA binding, and transcriptional activation, contributing to tumorigenesis.22 Similarly, AARS2-mediated cGAS lactylation abrogates cGAS LLPS with DNA and barely loses the ability to read self-DNA, consequently facilitating innate immune evasion and intensifying viral replication in mouse PBMCs and BMDMs.77 Intriguingly, a recent study found that lactylation of SH3-domain-containing 3 (SORBS3) in skeletal muscle cells triggered its LLPS, enhancing interaction with flotillin 1 and sorting of F-box protein 2 (FBXO2) into small extracellular vesicles.16In summary, lactylation governs multifaceted molecular regulatory functions, involving the regulation of properties and functions of DNA, RNA, and proteins. These insights enhance our comprehension of the molecular regulatory mechanisms of lactylation, providing insights into identifying predictive biomarkers and developing innovative therapeutic strategies targeting lactylation.Involvement of lactylation in physiologyLactate is an essential substance for various cellular physiological functions, playing a crucial regulatory role in energy metabolism, signal transduction, and maintaining microenvironment homeostasis.161 Recently, increasing evidence has suggested that lactate-derived lactylation occurs naturally and coordinates various physiological processes, such as somatic cell reprogramming, embryonic development, neural development, and cochlear development (Fig. 3 and Table 2).Fig. 3Full size imageThe involvement of lactylation in physiology. Lactylation is implicated in the regulation of various physiological processes. a Histone Kla, especially H3K18la, induces pluripotency during MET in iPSC reprogramming by enhancing the transcriptional activation of pluripotent genes. b During embryonic development, histone Kla plays a crucial role in several pre-implantation stages, including the germinal vesicle stage, fertilization, and zygotic genome activation, as well as during the implantation phase and post-implantation, by facilitating gene transcription. c Histone Kla, including H3K18la and H4K12la, facilitate neurogenesis by promoting the neuronal differentiation and cell proliferation, as well as regulating the cell cycle, respectively. d H3K9la promotes the expression of Sox family transcription factors to facilitate hair cell regeneration in cochlear development. The figure was generated with FigDraw (https://www.figdraw.com). ZGA zygotic genome activation, Ccnt1 cyclin T1, Dppa2 developmental pluripotency associated 2, Zscan4 zinc-finger and scan domain-containing 4, Zfp352 zinc-finger protein 352, Dux double homeobox protein, Sox sex-determining region Y-box, Cdh1 Cadherin 1, Oct4 octamer-binding transcription factor 4, sall4 sal-like protein 4, iPSC induced pluripotent stem cell, MET mesenchymal-epithelial transition, MDM2 murine double minute 2Table 2 Protein lactylation identified in various human physiology and diseasesFull size tableSomatic cell reprogrammingLactylation is also involved in somatic cell reprogramming, a physiological process related to the induction of pluripotency162 (Fig. 3a). For instance, Glis1-upregulated glycolysis increases lactate production and triggers histone Kla, especially H3K18la.17 Consequently, the elevated histone Kla upregulates pluripotent genes such as Oct4, Sall4, and Mycn and promotes somatic cell reprogramming and pluripotency, revealing a glycolysis-driven signaling cascade linking the epigenome and metabolome in cell-fate determination.Furthermore, a recent study highlighted the critical role of H3K18la in the mesenchymal-epithelial transition (MET) during the initial stages of iPSC reprogramming.163 Specifically, Dux, known for enhancing pluripotency during the transition from embryonic stem cells to 2-cell-like ESCs, induces H3K18la through a metabolic switch and p300 recruitment, boosting gene activation for pluripotency and epithelial cells and ultimately accelerating reprogramming efficiency.80 The involvement of lactylation in somatic cell reprogramming implies the significant role of the epigenome-metabolome-epigenome signaling in cell fate. Nonetheless, further comprehensive studies are required to elucidate the potentially complex mechanisms through which lactylation regulates cell reprogramming.Embryonic developmentLactate is significantly increased and indispensable for embryonic development.164 Notably, lactate-derived lactylation influences embryonic development, including the germinal vesicle stage, post-fertilization, and implantation (Fig. 3b). Abundant nuclear accumulation of H3K23la, H3K18la, and pan histone Kla is detected in mouse oocytes and pre-implantation embryos, with H3K23la and pan histone Kla present on MII oocyte chromosomes. Although these markers are faint in zygotes after fertilization, both parental pronuclei are homogeneously stained. Hypoxic in vitro culture decreases histone Kla levels, compromising mouse pre-implantation embryonic development.18During the maternal-to-zygotic transition, histone Kla, especially H3K18la, regulates the expression of zygotic genome activation (ZGA) genes such as Ccnt1 and Dppa2, promoting embryonic development at the late G2 phase of the 2-cell stage in mouse embryos.165 Coincidentally, in embryonic stem cells, lactate enhances H3K18la to facilitate transcriptional elongation of germline and ZGA genes, influencing pre-implantation development.166Lactylation is also implicated in the implantation stage of embryonic development. A comprehensive proteomic analysis of the ligand‒receptor pathway at the maternal-fetal interface has uncovered a new function of enhanced conceptus glycolysis in reshaping uterine receptivity by inducing endometrial histone lactylation.167 High levels of H3K18la are found in both the caruncular and intercaruncular endometrial areas in pregnant sheep, but these levels drop significantly in the endometrium undergoing pregnancy failure contrarily, indicating the essential role of histone Kla in establishing endometrial receptivity.Neural crest cells (NCCs) are vital in vertebrate embryonic development, and their behavior is linked to nervous system defects. A recent study elucidated the role of lactylation in modulating the epigenetic landscape, facilitating gene expression essential for NCC development. Specifically, lactylation is deposited on the activity enhancers in the NCC gene regulatory network, promoting chromatin accessibility and influencing NCC behavior like migration.60 These findings elucidate the significant implication of histone Kla in almost every stage of embryonic development, with particular emphasis on nervous system development associated with NCCs.Neural developmentLactate is essential for neocortex development and angiogenesis, serving as an important energy source for neural development.168,169 Lactate-derived lactylation, found throughout the brain, influences chromatin state and gene expression (Fig. 3c). Notably, H3K18la is extensively involved in transcriptome remodeling to promote neuronal differentiation and cell proliferation, thereby facilitating cell-fate transitions in telencephalon development.19 Moreover, lactate homeostasis is vital for adult hippocampal neurogenesis and cognition. Intriguingly, a recent study has unveiled the involvement of lactate-derived histone Kla in dominating hippocampal neurogenesis. Lactate shuttling links histone Kla, particularly H4K12la, to neural stem cells (NSCs) proliferation through murine double minute 2 (MDM2)-p53 signaling pathway and eventually regulates cell cycle and endows NSCs neurogenic potential in the adult hippocampus.170 These discoveries preliminarily offer momentous insights for sequential studies on lactylation in neural development.Cochlear developmentHair cells in the cochlea possess limited regenerative potential, serving as a promising hearing restoration strategy.171,172 Metabolism modulation is a promising target for driving hair cell regeneration. Intriguingly, a recent study highlighted the crucial role of glycolysis-induced lactylation in cochlear development and hair cell regeneration (Fig. 3d). Concretely, upregulated PKM2 lactylates histone H3, especially H3K9la, facilitating the expression of Sox family transcription factors through epigenetic modification. This process reprograms metabolism and supports cochlear development.20Altogether, lactate-driven lactylation is vital for regulating gene expression, signal transduction, and various physiological functions, influencing cell proliferation, differentiation, and fate.Role of lactylation in diverse diseasesEmerging evidence highlights the pivotal regulatory role of lactylation in the development and progression of various disorders, such as cancers, neurological and cardiovascular diseases, eye disorders, immune-inflammatory conditions, and metabolic issues. Notably, lactylation of certain proteins aids in disease recovery and improvement (Figs. 4–10 and Table 2).Fig. 4Full size imageThe role of lactylation in the occurrence and progression of cancers involving multifaceted cellular processes. Lactylation regulates the tumor immune microenvironment by modulating gene transcription and protein stability, facilitating immune remodeling and immune evasion. Moreover, histone Kla and lactylation of metabolism-related enzymes govern multiple metabolic pathways, such as glycolysis, OXPHOS, lipolysis, PPP, and serine metabolism, thereby leading to metabolic reprogramming in cancers. RNA methylation in cancer is also regulated by lactylation of histone or epigenetic-related enzymes, including writers, readers, and erasers, which alters RNA stability and ultimately leads to epigenetic rewiring. Lactylation is implicated in the management of PCDs, such as promoting autophagy and inhibiting ferroptosis to result in tumorigenesis, as well as exerting antitumor effects through facilitating pyroptosis and cuproptosis. In addition, lactylation induces the invasion and metastasis of cancer by affecting EMT and angiogenesis. Lactylation promotes cancer stem cell maintenance and self-renewal by modulating stemness-related genes and pathways. The figure was generated with FigDraw (https://www.figdraw.com). PPP pentose phosphate pathway, G6PD glucose-6-phosphate dehydrogenase, OXPHOS oxidative phosphorylation, FFA free fatty acid, SAM s-adenosylmethionine, PD-L1 programmed death-ligand 1, ALKBH3 alkylated DNA repair enzyme ALK b homolog 3, YTHDF2 YTH N6-methyladenosine RNA-binding protein 2, SHMT2 serine hydroxymethyltransferase 2, EMT epithelial‒mesenchymal transition, AKT protein kinase B, mTOR mammalian target of rapamycin, VCAM1 vascular cell adhesion protein 1, PI3K phosphatidylinositol 3-kinase, VEGFA vascular endothelial growth factor A, Sema3A semaphorin 3A, UVRAG UV radiation resistance-associated gene, RUBCNL Rubicon-like autophagy regulator, FDX1 ferredoxin 1, GCLC glutamate-cysteine ligase catalytic subunitFig. 5Full size imageThe role of lactylation in neurological diseases. Elevated lactylation of histone and tau in microglia and neurons, respectively, contributes to AD pathology via various cellular processes. However, lactylation of APP ameliorates AD pathology. Moreover, abnormal lactylation is implicated in the pathogenesis of cerebrovascular diseases, such as cerebral ischemia and SAH, as well as traumatic conditions, such as TBI. Histone Kla contributes to locomotor function recovery in SCI. Lactylation plays an indispensable role in contributing to GBM via multiple molecular mechanisms. Furthermore, histone Kla is positively influenced by neural excitation resulting from social defeat stress. However, physical exercise-induced lactylation suppresses anxiolysis. The figure was generated with FigDraw (https://www.figdraw.com). AD Alzheimer’s disease, GBM glioblastoma, SCI spinal cord injury, TBI traumatic brain injury, APP amyloid precursor protein, IDH3β isocitrate dehydrogenase 3β, TCA tricarboxylic acid, PAX6 paired-box 6, SASP senescence-associated secretory phenotype, NCOA4 nuclear receptor co-activator 4, FTH1 ferritin heavy chain 1, NEK never in mitosis gene a related kinase, ARF1 ATP-ribosylation factor 1, BRD4 bromodomain-containing protein 4, LRP1 low-density lipoprotein receptor-related protein 1, PSMD14 proteasome 26S subunit, non-ATPase 14, I/R ischemia/reperfusion, SAH subarachnoid hemorrhage, SNAP91 synaptosome-associated protein 91, ERK extracellular signal-regulated kinase, EGF epidermal growth factor, GDF15 growth differentiation factor 15, TNFSF9 tumor necrosis factor ligand superfamily member 9, PFKFB4 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4, PTBP1 polypyrimidine tract binding protein 1, XRCC1 X-ray repair cross-complementing 1Fig. 6Full size imageThe role of lactylation in CVDs. Lactylation in multiple cells is frequently involved in the pathogenesis of myocardial infarction and post-myocardial infarction by impacting immune homeostasis, EndMT, and various forms of PCD. Moreover, lactylation plays a critical role in exacerbating atherosclerosis by promoting EndMT in ECs, inducing senescence in VSMCs, and facilitating macrophage phenotypic transformation. Conversely, lactylation mitigates atherosclerosis by reducing cell adhesion and inflammation. In addition, lactylation contributes to the pathology of other CVDs, including vascular calcification, aortic aneurysm and dissection, neointimal hyperplasia, pulmonary hypertension, and RIHD, by regulating diverse cellular biological processes while exerting inhibitory effects on heart failure. The figure was generated with FigDraw (https://www.figdraw.com). CVDs cardiovascular disease, MDH2 malate dehydrogenase 2, ACSL4 acyl-CoA synthetase long-chain family member 4, GPX4 glutathione peroxidase 4, EndMT endothelial-mesenchymal transition, Lrg1 leucine-rich α-2-glycoprotein 1, ASF1A anti-silencing function 1A histone chaperone, Arg1 arginase 1, P4HB prolyl 4-hydroxylase subunit beta, PTGS2 prostaglandin-endoperoxide synthase 2, SH3GLB1 sh3-domain grb2-like protein 1, NDP52 neighbor of brca1 gene 2, STAT3 signal transducer and activator of transcription 3, CHI3L1 chitinase 3-like 1, Phospho1 phosphatase orphan 1Fig. 7Full size imageThe role of lactylation in ophthalmic disorders. Histone Kla, especially H3K18la, is instrumental in the tumorigenesis of ocular melanoma by establishing crosstalk with mRNA methylation. Additionally, H3K18la is implicated in the pathogenesis of myopia by promoting Notch1-mediated FMT. Lactylation also plays an essential role in neovascularization by governing angiogenesis. Moreover, lactylation is a potential positive regulatory cascade in autoimmune uveitis by promoting Th17 cell differentiation. The figure was generated with FigDraw (https://www.figdraw.com). FMT fibroblast-to-myofibroblast transdifferentiation, CDK2 cyclin-dependent kinase 2, FGF2 fibroblast growth factor 2, Ikzf1 lkaros family zinc-finger protein 1, Tlr4 toll-like receptor 4, Th17 helper 17Fig. 8Full size imageThe role of lactylation in immunoinflammatory disorders and metabolic dysfunction. Lactylation is widely present in multiple immunoinflammatory diseases, such as sepsis and its associated lung and kidney injuries, IBDs, asthma, and arthritis. Lactylation plays an indispensable role in metabolic disorders, such as diet-induced obesity, fatty liver diseases, and osteoporosis. The figure was generated with FigDraw (https://www.figdraw.com). HPSE heparanase, EGR1 early growth response 1, ZBP1 z-DNA-binding protein 1, CIRP cold-inducible RNA-binding protein, UGDH udp-glucuronate decarboxylase, STAT1 signal transducer and activator of transcription 1, MAPK mitogen-activated protein kinase, COL1A2 collagen type I alpha 2, COMP cartilage oligomeric matrix protein, ENPP1 ectonucleotide pyrophosphatase/phosphodiesterase 1, TCF7L2 transcription factor 7-Like 2, α-MSH α-melanocyte-stimulating hormoneFig. 9Full size imageThe role of lactylation in other diseases. Lactylation is implicated in various pathological processes, such as liver, lung, and kidney diseases, as well as skin injuries and intervertebral disc degeneration. The figure was generated with FigDraw (https://www.figdraw.com). NFALD non-alcoholic fatty liver disease, HSC hematopoietic stem cell, AMPKα amp-activated protein kinase alpha, SLUG snail family transcriptional repressor 2, PTEN phosphatase and tensin homolog, TGF-β1 transforming growth factor beta 1, Twist1 twist family bHLH transcription factor 1, AKI acute kidney injury, CKD chronic kidney disease, ECM extracellular matrixFig. 10Full size imageAltered lactylation identified in the human body. Lactylation is frequently present in various human diseases. Aberrant lactylation usually contributes to the initiation and progression of diseases, while some specific lactylation exerts inhibitory effects on diseases, even within the same disease. AAD aortic aneurysm/dissection, BC breast cancer, BCa bladder cancer, AS atherosclerosis, CD Crohn’s disease, CI cerebral ischemia, EC endometrial carcinoma, HF heart failure, MI myocardial infarction, MM multiple myeloma, NAFLD non-alcoholic fatty liver disease, NIH neointimal hyperplasia, OA osteoarthritis, PH pulmonary hypertension, RA rheumatoid arthritis, S-AKI sepsis-induced acute kidney injury, S-ALI sepsis-associated acute lung injury, UC ulcerative colitis, VC vascular calcificationLactylation in cancers involving various biological processesAnaerobic glycolysis, a cancer hallmark, rapidly produces energy for tumor growth by generating lactate.173 Lactate influences the tumor microenvironment (TME) by promoting proliferation and metastasis, altering metabolism, and hindering immune defenses.174,175,176,177 The identification of lactylation has further elucidated the multifaceted role of lactate in oncogenesis. Typically, lactylation plays an indispensable role in propelling cancer progression. However, lactylation of certain specific proteins can also suppress cancer, even within the same cancer. For instance, DCBLD1 lactylation promotes cervical cancer progression by activating PPP.117 However, G6PD lactylation rewires the PPP, thereby inhibiting cervical cancer cell proliferation.122 Increasing evidence indicates that lactylation affects cancer occurrence, progression, and treatment by affecting processes such as immune remodeling, inflammation regulation, metabolic reprogramming, programmed cell death, epigenetic reprogramming, stemness maintenance, invasion, and metastasis (Fig. 4).Evidence links, by affecting processes like immune response and inflammation.Immunological remodelingThe immune system typically identifies and destroys cancer cells, while cancer can evade immune detection through immunosuppression.178 Lactate plays a crucial role in immunological remodeling by altering the metabolism and signaling of immune and tumor cells, affecting their functions.179,180,181 Accumulating evidence shows the involvement of lactylation in tumor immunity. Understanding and targeting lactylation-induced changes could enhance the effectiveness of immunotherapy.Tumor-infiltrating myeloid cells (TIMs), immune cells from bone marrow, infiltrate into tumor tissue and aid tumor immune evasion.182 Interestingly, a recent study highlighted the involvement of lactylation in the immunosuppressive activities of TIMs in CRC. Concretely, lactate accumulated in the TME induces H3K18la in TIMs, enhancing the expression of methyltransferase-like 3 (METTL3), a well-known RNA methyltransferase. This upregulation leads to Jak1 mRNA m6A modification, promoting its translation and subsequent signal transducer and activator of transcription 3 (STAT3) phosphorylation. Notably, METTL3 undergoes lactylation, which is essential for capturing target RNA, ultimately reinforcing the immunosuppressive functions of TIMs in CRC via the H3K18la-METTL3/m6A/JAK1/STAT3 signaling pathway.63Macrophages are a major component of TIMs within TME and are crucial for the immune response, existing as pro-inflammatory M1 or anti-inflammatory M2 phenotypes.183 Tumor-associated macrophages (TAMs) often polarize toward the M2 phenotype, which is characterized by immunosuppressive properties that facilitate tumor growth, invasion, and metastasis.184,185 Histone Kla influences the phenotypic transition of TAMs and immune remodeling. For instance, in monocyte-derived macrophages (MDMs), glucose-driven histone Kla increases interleukin 10 (IL-10) expression, suppressing T-cell activity and promoting GBM growth and progression.186 Similarly, lactate from patient-derived GSCs and microglia/macrophages triggers histone Kla, boosting transcriptional upregulation of CD47 in GBM cells, ultimately suppressing phagocytosis and inducing immunosuppressive programs.187 Additionally, H3K18la impedes retinoic acid receptor gamma (RARγ) expression, which interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6) and subsequently inhibits NF-κB-mediated inflammatory signaling within the TME. In turn, macrophage-derived IL-6 activates STAT3 signaling in CRC cells, facilitating c-Myc transcription and transforming macrophages into a pro-tumor M2-like phenotype, which promotes tumorigenesis.188 Coincidentally, tumor-produced lactate induces H3K18la in macrophages, thereby activating transcription and enhancing pro-tumor macrophage activity. Surprisingly, M2 macrophages inhibit CD8+ T cell enrichment and the proportion of interferon-γ+CD8+ T cells in the TME, resulting in immune evasion and anti-PD-1 resistance in HCC.136 Similarly, H3K18la in macrophages activates C-C motif chemokine ligand 18 (CCL18) expression and induces M2 polarization, thereby promoting ovarian cancer growth and metastasis.189 Moreover, prostate cancer (PCa) cell-derived lactate induces H3K18la in TAMs, inhibiting the activation and phagocytosis of PC cells, which ultimately promotes the occurrence of the PTEN/p53-deficient aggressive-variant PC.190 Additionally, Pan Kla is associated with the progression and metastasis of colon cancer cells via proprotein convertase subtilisin/kexin type 9 (PCSK9) through the regulation of epithelial‒mesenchymal transition (EMT), PI3K/AKT signaling, and macrophage polarization.191 Additionally, histone Kla affects mitochondrial dynamics, directing macrophage function and phenotype through metabolite regulation and gene expression.192 Likewise, B-cell adapter for PI3K (BCAP)-induced lactate accumulation facilitates the transition of inflammatory macrophages to reparative macrophages by stimulating histone Kla.28 Furthermore, PKM2-K62la promotes macrophages from pro-inflammatory and hinders the inflammatory to a reparative phenotype and hinders inflammatory metabolic adaptation.121T cells in the TME play a key role in cancer immune surveillance, impacting the occurrence, development, and treatment of cancer.193 Intriguingly, recent studies emphasize the role of lactylation in modulating T-cell function, particularly regarding immunosuppression and immune evasion.21 For example, lactate-induced H3K18la in CD4+ T cells and macrophages boosts CD39, CD73, and CCR8 gene expression, thereby leading to heightened regulatory T (Treg) cell infiltration in GBM and weakening chimeric antigen receptor (CAR)-T immunotherapy effectiveness.194 Similarly, H3K18la and H3K9la in CD8+ T cells initiate transcription of genes regulating their function. In addition, the modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways governs CD8+ T-cell antitumor immunity.21 Moreover, extracellular lactate-induced H3K18la in T helper 17 (Th17) cells, a subset of CD4+ T helper cells secreting IL-17, contributes to transforming pro-inflammatory T cells into Treg cells.195 Notably, non-histone Kla regulates Treg cell function. Specifically, the tumor metabolite lactate regulates the stability and function of Treg cells through lactylating MOESIN at lysine 72, enhancing its interaction with TGF-β receptor I and activating downstream SMAD3 signaling. However, chemical inhibition of lactate production via LDH inhibitors diminishes Treg cell function in the TME by suppressing MOESIN Kla, ultimately enhancing the HCC response to anti-PD-1 treatment.7Moreover, in acute myeloid leukemia (AML), high levels of signal transducer and activator of transcription 5 (STAT5) activate glycolytic genes and histone Kla, notably H4K5la, promoting PD-L1 transcription accompanied by the interaction of PD-1/PD-L1 and CD8+ T-cell activation, eventually leading to immunosuppression.104 In GBM cells, histone H3 lactylation, particularly H3K14/18la, facilitates Wnt/β-catenin, NF-κB, and PD-L1 expression, thereby enhancing CD8+ T-cell infiltration and contributing to immune evasion in GBM.67 Additionally, the elevated Pan Kla and H3K18la correlate with poor prognosis in NSCLC patients. H3K18la directly activates pore membrane protein 121 (POM121) transcription, which enhances MYC nuclear transport and direct binding to the CD274 promoter to induce PD-L1 expression in NSCLC cells, thereby causing CD8+ T-cell dysfunction and promoting immune evasion of NSCLC.196 Similarly, upregulated PRMT3-mediated H3K18la drives PD-L1-mediated immune escape by activating PDHK1-regulated glycolysis in HCC cells.197 Likewise, H3K9la in head and neck squamous cell carcinoma (HNSCC) cell lines initiates IL-11 expression, which transcriptionally activates immune checkpoint genes through JAK2/STAT3 signaling in CD8+ T cells, diminishing CD8+ T-cell killing and weakening the immunotherapy response.198 These findings underscore the intricate role of lactate and lactylation in the tumor microenvironment, influencing immune surveillance, immunosuppression, tumor behavior, and therapy response.Metabolic reprogrammingMetabolic reprogramming is a hallmark of cancer, where cancer cells predominantly utilize glycolysis to secure energy and metabolic intermediates necessary for tumor growth.199 Malignant cells are characterized by an accelerated tricarboxylic acid (TCA) cycle stimulated by an increase in acetyl-CoA synthesis, which accelerates efficient glucose use and ATP and lactate generation and ultimately leads to uncontrolled cell growth.8 This lactate accumulation, a key cancer biomarker, can be 5–20 times higher in tumors than in normal tissue (1.8–2.0 mM), correlating with tumor growth and metastasis.200,201Metabolism-derived lactylation in turn regulates metabolism by enhancing gene transcription, particularly in cancer. Histone Kla activates genes linked to energy metabolism, while lactate directly modifies metabolic enzymes, affecting their degradation, stability, and interactions and eventually leading to metabolic reprogramming. Additionally, lactylation of non-histone proteins influences enzyme activity and protein expression, further driving metabolic changes in cancer (Fig. 4).Histone Kla and metabolic reprogrammingHistone Kla-mediated gene expression associated with energy metabolism is a crucial mechanism for metabolic reprogramming in cancer. For instance, in NSCLC cells, elevated lactylation of histone H3 reduces glycolysis and maintains mitochondrial balance by altering mRNA levels of glycolytic enzymes (HK1, PKM) and TCA cycle enzymes (SDHA, IDH3G), highlighting the crosstalk between histone Kla and glucose metabolism in cancer progression.202 Similarly, lactate-derived histone Kla, particularly H3K18la and H3K9la, serves as a transcription initiator of key genes to manipulate the metabolic profiles and function of CD8+ T cells, which are vital for antitumor immunity.21Notably, histone Kla regulates gene expression beyond those directly involved in metabolism, affecting metabolism-associated proteins through alternative pathways, and establishing an indirect feedback loop with metabolic processes. For example, H3K18la activates the mitotic checkpoint regulators TTK and BUB1B in PDAC cells, which subsequently leads to the upregulation of p300, augmenting glycolysis. Concurrently, TTK phosphorylates LDHA, a pivotal enzyme in glycolysis, boosting lactate production and H3K18la levels.97 This positive feedback between glycolysis and histone lactylation drives oncogenesis in PDAC.Non-histone Kla and metabolic reprogrammingLactylation also occurs in enzymes related to metabolic pathways, forming a positive feedback loop to regulate metabolism. An integrative analysis of the lactylome and proteome in tumors and adjacent liver tissues in hepatitis B virus-related HCC revealed that lactylation predominantly affects enzymes in pathways such as the TCA cycle, carbohydrate, amino acid, fatty acid, and nucleotide metabolism, rather than histones for gene transcription.8 Notably, adenylate kinase 2 (AK2) is significantly lactylated at lysine 28, influencing its function and promoting HCC cell proliferation and metastasis. Similarly, lactylation of ALDOA at lysine 230/322 in liver cancer stem cells (LCSCs) facilitates the dissociation of ALDOA from DEAD-box helicase 17, ultimately enhancing glycolysis, proliferation, and migration of liver cancer.101 Moreover, proteomic analysis of HepG2 cells identified PKM2 lactylation at lysine 207 (K207la) and lysine 228 on ENO1, both critical enzymes in glucose metabolism. Additionally, lactylation of PKM2-K207la inhibits glycolysis and HCC cell proliferation by affecting its activity and function.203 Surprisingly, PKM2 at K62la inhibits its transition from tetramer to dimer and promotes its kinase activity, suppressing inflammatory metabolic adaptation in pro-inflammatory macrophages.121Furthermore, the lactylation of certain non-histone proteins that do not directly regulate metabolism affects cancer metabolism. For instance, lactylation of K436 at PTBP1, a key regulator of RNA processing, enhances its RNA-binding affinity and mRNA stabilization in GSCs, which in turn accelerates glycolysis and glioma tumorigenesis.127 Additionally, NUSAP1 interacts with c-Myc and HIF-1α to form a transcriptional regulatory complex to enhance LDHA expression. Interestingly, lactylation of NUSAP1 at lysine 34 prevents its protein degradation and increases its expression in PDAC cells, establishing an NUSAP1-LDHA-glycolysis-lactate loop that promotes PDAC metastasis.83 Similarly, in pancreatic adenocarcinoma (PAAD), lactylation of NMNAT1 at lysine 128 enhances its nuclear localization and enzymatic activity in PAAD cells, activating the NAD+ salvage pathway and promoting cell survival, linking Kla to NAD+ metabolism.92Lactylation has also been implicated in the PPP. Specifically, lactylation of DCBLD1 in SiHa cells directly stabilizes DCBLD1 by inhibiting its protein degradation and further upregulates G6PD to stimulate PPP, promoting cervical cancer progression.117 Intriguingly, G6PD also undergoes lactylation, which inhibits cervical cancer cell proliferation. However, human papillomavirus 16 E6 inhibits G6PD lactylation at lysine 45, promoting G6PD dimerization and PPP activation, thus encouraging the proliferation of PHKs and C33A cells.122Additionally, lactylation regulates lipid metabolism. Concretely, APOC2-K70la stabilizes APOC2 and promotes extracellular lipolysis in NSCLC cell lines, thus leading to free fatty acid release, regulatory T-cell accumulation, immunotherapy resistance, and metastasis in NSCLC.88Moreover, lactylation has been linked to serine metabolism reprogramming. Specifically, in lenvatinib-resistant cells, increased glycolysis and lactate levels induce IGF2BP3 lactylation at lysine 76, enhancing its m6A reader function and stabilizing PCK2 and NRF2 mRNA translation. This upregulated PCK2 reshapes redox homeostasis and drives serine metabolism reprogramming in liver cancer, contributing to lenvatinib resistance in HCC.14 These findings highlight the crucial role of lactylation as the bridge between metabolic reprogramming and epigenetic regulation in oncogenesis, metastasis, and chemotherapy resistance in cancer.Programmed cell deaths (PCDs)PCD mechanisms such as autophagy, pyroptosis, ferroptosis, and cuproptosis are crucial for maintaining cellular homeostasis.204 Disruption of PCD pathways is a common feature in cancer, enabling cancer cells to evade death and sustain uncontrolled proliferation, thus contributing to tumorigenesis and progression.205 Strikingly, recent studies highlight the implication of lactylation in altering the PCD of cancer (Fig. 4).Autophagy, a process where cells digest their own constituents in response to stress or nutrient deprivation, facilitates cellular component recycling and damaged organelle and protein removal.206 Autophagy plays a complex role in cancer.207 Recent studies have indicated that lactylation is implicated in autophagy, influencing tumor cell survival. For instance, lactate-induced H3K18la promotes RUBCNL/Pacer transcription, facilitating autophagosome maturation through the Beclin1 interaction, which contributes to CRC cell survival and resistance to bevacizumab treatment.208 This unveils the involvement of lactylation in transcriptional activation and interplay with autophagy proteins in cancer progression. Additionally, in lung cancer cells and osteosarcoma cells, LDHA phosphorylation at serine 196 by ULK1 promotes lactate generation, which subsequently induces PIK3C3 and Vps34 lactylation at lysine 356 and lysine 781, respectively. Intriguingly, PIK3C3/VPS34 lactylation augments its interaction with Beclin1, Atg14L, and UVRAG, increasing its lipid kinase activity and promoting macroautophagy/autophagy and endolysosomal degradation. This process contributes to skeletal muscle homeostasis maintenance and lung cancer progression, implying the integration of two highly conserved life processes: glycolysis-induced lactylation and autophagy.70 Moreover, in tissues of PDA patients, lactylation of TFEB at lysine 91 has been identified, which prevents its ubiquitination and proteasome degradation by hindering its interaction with the E3 ubiquitin ligase WWP2, enhancing TFEB activity and autophagy flux, which promotes pancreatic cancer progression.12Pyroptosis is an inflammatory PCD involving cell rupture and pro-inflammatory cytokine release, aiding cancer elimination by activating the antitumor immune response.209,210 Notably, lactylation has been identified as a critical regulator of pyroptosis. Gambogic acid eliminates lactylation of CNPY3, altering its localization and recruiting SIRT1, which activates caspase-1 and gasdermin D (GSDMD) through lysosomal rupture and cathepsin B (CatB) release, ultimately triggering pyroptosis in PCa cells.108 Moreover, pyroptosis-associated proteins undergo lactylation directly in non-cancer conditions. Lactylation of NLRP3 at lysine 245 enhances its stability, triggering cardiomyocyte pyroptosis and promoting myocardial ischemia‒reperfusion (I/R) injury.119 Additionally, lactylation also participates in the Caspase-11-mediated non-canonical pyroptosis pathway. Concretely, lactylation of NEDD4, a negative regulator of Caspase-11, impedes Caspase-11 ubiquitination by decreasing its interaction with Caspase-11, thereby triggering pyroptosis in macrophages and exacerbating acetaminophen-induced liver injury (AILI).91Ferroptosis, a cell death process regulated by iron and lipid peroxidation, has garnered significant interest in cancer research.211 Intriguingly, lactylation was recently identified to regulate ferroptosis in tumorigenesis and metastasis. Specifically, histone Kla, especially H3K18la, enhances the transcriptional activity of NFS1 cysteine desulfurase (NFS1), a key player in iron‒sulfur cluster biosynthesis, thereby reducing the susceptibility of HCC to ferroptosis and promoting metastasis.212 Similarly, H4K12la enhances glutamate-cysteine ligase (GCLC) expression, which is crucial for glutathione synthesis and inhibiting lipid peroxidation, leading to chemoresistance in CRC stem cells by inhibiting ferroptosis.213,214 In addition, non-histone lactylation modulates cancer cell ferroptosis. For instance, lactylation of K508 on NSUN2, a typical methyltransferase responsible for RNA m5C modification, enhances its activity, facilitating GCLC m5C methylation and stabilizing GCLC mRNA, which enhances GSH production and reduces oxidative stress, thereby promoting gastric cancer cell survival.75 Additionally, lactylation of K412 on HDAC suppresses FTO and ALKBH5 activation, decreasing the m6A modification of FSP1 mRNA and promoting its degradation, thereby weakening ferroptosis sensitivity in CRC cells.144Cuproptosis, a novel PCD involving copper dependence, accumulation of acylated proteins, and the reduction of Fe-S cluster proteins, is associated with the occurrence and development of cancer.215 Intriguingly, lactylation has been reported as a key regulator of cuproptosis, as seen in gastric cancer. For example, in HGC-27 cells, lactylation of METTL16 at lysine 229 promotes cuproptosis via m6A modification of the mRNA of ferredoxin 1 (FDX1), a key factor encoding a reductase known to convert Cu2+ to its more toxic form Cu1+, indicating the promising therapeutic potential of targeting Kla and cuproptosis in cancer.142 Additionally, mucin 20 (MUC20), a member of the mucin family encoded by human genes, represses CDKN2A expression by suppressing IGF-1R lactylation, triggering MET inactivation and cuproptosis to hinder proteasome inhibitor resistance in multiple myeloma cells.216Epigenetic rewiringEpigenetic rewiring refers to the transformation of heritable gene expression regulation patterns without altering the DNA sequence, comprising transcription factor regulation, histone modification, and RNA epigenetic modification. It is crucial in the occurrence, development, drug resistance, and potential therapeutic strategies of cancer.217,218,219 Intriguingly, accumulating studies have revealed the key role of lactylation in cancer epigenetic rewiring (Fig. 4).Lactylation of transcription factors is crucial in cancer because it affects transcription activation, signal transduction, DNA binding, and protein interactions. Direct lactylation of these factors plays a significant role in cancer progression. For instance, AARS1-mediated lactylation of p53 at lysine 120 and lysine 139 promotes breast cancer by disrupting its phase separation, DNA binding, and activation of p21 and PUMA.22 Similarly, in mouse gastric cancer tissue, lactylation of YAP at lysine 90 and TEAD at lysine 108 mediated by AARS1 activates the YAP-TEAD complex, promoting Hippo pathway gene expression and gastric cancer cell proliferation.13 Additionally, lactylation of TFEB at lysine 91 in tissues of PDA patients prevents its interaction with the E3 ubiquitin ligase WWP2, reducing TFEB ubiquitination and degradation, and thereby increasing its activity and autophagy flux, contributing to pancreatic cancer.12 Moreover, in PCa cells, HIF-1α lactylation boosts its transcriptional activity, enhancing KIAA1199 transcription to promote angiogenesis and vasculogenic mimicry in PCa.24 Histone Kla governs gene expression by regulating transcriptional activation of transcription factors. For example, H4K8la and H4K16la in LUAD cells promote telomerase reverse transcriptase (TERT) expression by modulating Sp1-related transcriptional activity, constraining cellular senescence in lung adenocarcinoma.109 These findings fully reveal the crucial role of lactylation in regulating transcription factor expression and activity and downstream target gene expression.Increasing studies have unveiled the essential influence of lactylation on regulating RNA epigenetic modification, especially RNA methylation, including m1A, m6A, and m5C, in cancer. Histone Kla significantly influences RNA m6A and m1A modifications by regulating RNA methylation-associated enzyme expression. For instance, H3K18la upregulates RNA methyltransferase METTL3 expression, which further facilitates m6A modification and potently enhances the immunosuppressive function of TIMs, thereby promoting CRC immune evasion.63 Similarly, H3K18la in melanoma tissue and cells promotes m6A methylation of PER1 and TP53 mRNAs and m1A demethylation of SP100A by enhancing the expression of reader YTHDF2 and eraser ALKBH3, consequently driving ocular melanoma oncogenesis progression.62,141 These findings underscore the pivotal role of histone Kla in RNA methylation enzymes within tumors.Certain RNA methylation-related enzymes undergo lactylation, impacting cancer progression and treatment resistance. For example, in gastric cancer cells, METTL16 lactylation at lysine 229 promotes cuproptosis via m6A modification of FDX1 mRNA.142 Likewise, IGF2BP3 lactylation at lysine 76 drives m6A of PCK2 and NRF2 mRNAs and serine metabolism reprogramming, forming the IGF2BP3-PCK2-SAM-m6A loop and contributing to lenvatinib resistance in HCC.14 Additionally, in gastric cancer cells, NSUN2 lactylation at lysine 508 facilitates GCLC mRNA m5C, increasing GSH production and lipid peroxidation inhibition and ultimately inducing ferroptosis resistance.75 Intriguingly, lactylation of NSUN2 at K356 in CRC cells boosts m5C-modified ENO1 mRNA capture, linking metabolic reprogramming and epigenetic changes.143 These findings convincingly elucidate the interplay between lactylation and RNA methylation in cancer.Stemness maintenanceCancer stem cells (CSCs) are cancer cells with stem cell-like traits, including robust self-renewal and tumorigenic capabilities, that are crucial for tumor initiation, progression, metastasis, and recurrence. Stemness is vital for their survival and proliferation.220 Interestingly, lactylation is intricately associated with stemness maintenance and self-renewal of CSCs (Fig. 4).In general, histone Kla levels in LCSCs have been observed to be elevated. Notably, H3K56 and H3K9 are identified as the predominant histone Kla sites in LCSCs and are associated with tumorigenesis and stemness.101,102 H3K18la facilitates the transcription of stemness-related genes such as ALDH1A3, SOX2 and KLF4, contributing to tumorigenesis in prostate and lung cancers.98Moreover, lactylation of specific stemness-related proteins directly manipulates cancer stemness. For instance, elevated glycolysis-induced lactylation of SRY-related high mobility group-box 9 (SOX9), a transcription factor belonging to the SOX family, promotes stemness, migration, and invasion of NSCLC cells.23 The Wnt/β-catenin signaling pathway governs CSC markers and self-renewal genes. Interestingly, hypoxia-induced β-catenin lactylation promotes CRC cell proliferation and stemness by stabilizing β-catenin protein and activating the Wnt signaling pathway.114 Furthermore, lactylation of c-myc, a downstream target of the Wnt/β-catenin pathway, increases its protein stability and stemness, thereby facilitating HCC progression.118In addition, lactylation of some other non-histone proteins influences stemness and cancer progression. For instance, in LCSCs, ALDOA lactylation attenuates its binding with DDX17, enhancing the regulatory function of DDX17 in maintaining stemness and promoting tumorigenicity and progression of HCC.101 In addition, hypoxia-induced lactylation of serine hydroxymethyltransferase 2 (SHMT2) upregulates its protein level, enhancing methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) expression and the stemness of esophageal squamous cell carcinoma cell lines, thus accelerating the malignant progression of esophageal cancer.221 Furthermore, PTBP1 hyperlactylation in GSCs promotes glioma progression and supports the maintenance of GSCs by inhibiting its interaction with TRIM21 and enhancing its RNA-binding affinity and stabilizing PFKFB4 mRNA, which in turn accelerates glycolysis, eventually forming a feedback loop that exacerbates tumorigenesis.127Invasion and metastasisThe invasion-metastasis cascade is the defining phenotype of tumor cell proliferation and is recognized as the most lethal aspect of tumor progression.222 It is important to note that lactylation is involved in regulating the invasion and metastasis of cancer cells by promoting EMT and angiogenesis223 (Fig. 4).EMT is crucial for cancer metastasis, aiding cell invasion and migration.224 Interestingly, recent studies link lactylation to EMT regulation in cancers. For instance, H3K18la transcriptionally activates VCAM1, which subsequently activates the AKT-mTOR-CXCL1 axis, ultimately provoking EMT and migration of gastric cancer cells and resulting in immunosuppression and unfavorable prognosis.225 Furthermore, in CRC cells, lactylation enhances cell differentiation and metastasis via the activation of the PI3K/AKT signaling pathway and Snail-mediated EMT, driven by PCSK9.191 In addition, lactylation of non-histone proteins such as YY1-K183la drives FBXO33 activation, promoting invasive metastasis in GBC by regulating p53 polyubiquitination and the subsequent EMT.111 Additionally, enhanced PKM2-mediated glycolysis in pancreatic cancer promotes Snail lactylation and its nuclear translocation, boosting N-cadherin and vimentin expression, and eventually promoting EMT and pancreatic cancer progression.130Angiogenesis is a critical process involving the formation of new blood vessels that supply cancer cells with essential oxygen and nutrients, establishing the material foundation for tumor growth and creating pathways for tumor cell invasion and metastasis.226,227 Recent research highlights the involvement of lactylation in angiogenesis within PCa. Concretely, enhanced glycolysis in PCa cells leads to HIF-1α lactylation, upregulating KIAA1199, accompanied by increased secretion of VEGFA, ultimately advancing angiogenesis and vasculogenic mimicry.24Lactylation of cell cycle regulatory proteins plays a role in tumor invasion and metastasis. Specifically, hypoxia-induced glycolysis in PDAC cells provokes the lactylation of lysine 34 on NUSAP1, a spindle microtubule regulator, which enhances its expression by hindering its degradation, consequently establishing an NUSAP1-LDHA-glycolysis-lactate feedforward loop and facilitating metastasis in PDAC.83 Moreover, H4K12la in PC9-BrM3 cells facilitates CCNB1 transcriptional activation, which accelerates DNA replication and the cell cycle, promoting acquired resistance to pemetrexed in lung cancer-derived brain metastasis.107 Additionally, histone Kla is also implicated in cancer cell metastasis from the primary tumor to distant sites. For instance, pyrroline-5-carboxylate reductase 1 (PYCR1) triggers H3K18la at the insulin receptor substrate 1 (IRS1) promoter, ultimately promoting liver cancer cell proliferation and lung metastasis.228 Similarly, H3K18la in CRC cells leads to CXCL1 and CXCL5 upregulation, thereby promoting liver metastasis.229 In addition, histone Kla, especially H3K18la, facilitates USP39 expression to target PI3K/AKT/HIF-1α signaling pathway in endometrial carcinoma (EC) cells, thereby promoting malignant progression of EC.230In summary, these findings underscore the significant role of lactylation in regulating metabolism, epigenetics, immunosuppression, cell death, stemness, and invasion and metastasis of cancer cells, offering valuable insights into the molecular mechanisms through which lactylation governs cancers and paving the way for the development of cancer intervention strategies that target lactylation.Lactylation in neuropsychiatric disordersGlucose and lactate serve as the principal energy substrates for the nervous system due to the significant energy requirements of the brain.231 Consequently, a growing body of evidence suggests that lactate-derived lactylation plays a critical role in various biological processes of neurological disorders such as Alzheimer’s disease (AD), cerebrovascular diseases, brain tumors, traumatic injuries, and psychiatric disorders232,233,234 (Figs. 5, 10 and Table 2).ADAD is a neurodegenerative disorder primarily characterized by the formation of tau neurofibrillary tangles and amyloid-β (Aβ) plaques.235,236,237 Dysregulation of glucose metabolism has been demonstrated to play a pivotal role in the pathogenesis of AD.238,239 Consequently, aberrant lactylation associated with impaired glucose metabolism is implicated in the onset and progression of AD and may also represent a potential therapeutic target. For instance, lactylation of Aβ precursor protein (APP) has been identified to ameliorate AD pathology and cognitive function. Specifically, APP lactylation at lysine 612 regulates APP trafficking and metabolism, accompanied by enhanced APP endosomal-lysosomal degradation with CD2AP, thereby inhibiting Aβ generation and repairing spatial learning and memory deficits.240 Meanwhile, tau hyperphosphorylation drives AD progression. Tau lactylation at lysine 677 (K677) is decreased in AD mouse brains and Aβ-induced BV2 cells. Mutating K677 to inhibit tau lactylation affects iron metabolism factors such as NCOA4 and FTH1, hindering ferroptosis linked to the p38 MAPK pathway.241 In AD pathology, glucose metabolism is disrupted, particularly affecting the TCA cycle.238,242 Isocitrate dehydrogenase 3β (IDH3β), a pivotal rate-limiting enzyme in the TCA cycle, is downregulated, leading to oxidative phosphorylation uncoupling and lactate accumulation in the brains of AD patients and AD transgenic mice. Lactate subsequently triggers histone lactylation, especially H4K8/12la, as well as H3K18la, enhancing paired-box gene 6 (PAX6) expression, which in turn inhibits IDH3β, creating a feedback loop of IDH3β-lactate-PAX6-IDH3β that worsens AD progression.243Microglial activation and senescence are key features of AD and are linked to abnormal glycolysis and inflammation.244,245 In 5xFAD mice and AD patients, increased microglial glycolysis enhances H4K12la, boosting glycolytic gene transcription and creating a feedback loop that worsens microglial dysfunction. Notably, disrupting this loop by knocking down PKM2 improves Aβ pathology and cognitive function.25 Additionally, H4K12la activates NEK7 transcription, triggering NLRP3 inflammasome activation, pyroptosis, and neuroinflammation, thereby intensifying cognition and memory in AD mice.106 Similarly, lactate levels are significantly higher in senescent microglia of aged and APP/PS1 mice, leading to increased histone Kla, particularly H3K18la. This enhances IL-6 and IL-8 expression via the NF-κB pathway, worsening neuroinflammation.64 These findings emphasize the multifarious roles of lactylation in AD and aging, implying the potential of targeting lactylation as a therapeutic strategy.Cerebrovascular diseasesCerebral ischemia, a common cerebrovascular disease, involves reduced blood flow to the brain, causing hypoxia and nutrient shortages, which can lead to tissue necrosis.246,247 This condition triggers increased glycolysis and lactate production, contributing to histone and non-histone lactylation248 (Figs. 5, 10 and Table 2). Histone Kla is elevated in oxygen–glucose deprivation/reoxygenation (OGD/R)-treated N2a cells and middle cerebral artery occlusion (MCAO) rat brains, facilitating HMGB1 transcription and the subsequent neuron pyroptosis, eventually causing cerebral I/R injury.249 Non-histone protein lactylation is also implicated in ischemic stroke. For instance, global and LCP1 lactylation are both prominently enhanced in MCAO rat brains and OGD/R-induced PC12 cells. However, suppressing glycolysis diminished lactylation levels of LCP1 and led to LCP1 degradation, mitigating cerebral ischemia progression.115 In addition, Yao et al. identified 1003 lactylation sites in 469 proteins in the cortex of rats with cerebral I/R injury using 4D label-free quantitative proteomics and lactylation-specific proteomics analysis.250 Coincidentally, the latest study found that lactylation of ADP-ribosylation factor 1 (ARF1) in astrocytes aggravates I/R injury by inhibiting mitochondrial transfer from astrocytes to neurons. Astrocytic low-density lipoprotein receptor-related protein 1 (LRP1) can promote astrocyte-to-neuron mitochondria transfer by inhibiting glycolysis and ARF1-K73la, thereby mitigating cerebral ischemia.251 All these findings imply a potentially significant correlation between lactylation and ischemic stroke pathology. Moreover, in hypoxic-ischemic encephalopathy (HIE), elevated ECAR, an indicator of glycolysis, increases Pan Kla and cGAS lactylation and shifts microglia to the M1 phenotype, releasing pro-inflammatory factors such as IL-1β, iNOS, and TNF-α in microglia stimulated by OGD.252 Another study also indicated that lactylation may be involved in neonatal HIE.253Lactylation also plays a role in subarachnoid hemorrhage (SAH) pathology (Figs. 5, 10 and Table 2). Concretely, astrocytes undergo polarization toward the neurotoxic A1 phenotype under SAH, which is mitigated by H4K8la.99 However, knockdown of bromodomain-containing protein 4 (BRD4), an essential member of the bromodomain and extra-terminal domain (BET) family and epigenetic reader, markedly reduces H4K8la level, increasing A1 polarization in astrocytes and promoting neuronal death by pro-inflammatory factors such as IL-6, IL-1β, and TNF-α.254 Moreover, H3K18la in astrocytes contributes to bilirubin encephalopathy by upregulating nucleotide-binding oligomerization domain 2 (NOD2) expression, which boosts downstream MAPK and NF-κB signaling pathway activation, exacerbating astrocytic neuroinflammation and pyroptosis.255GBMGBM is the most common aggressive malignant brain tumor in adults and is known for its high recurrence and lethality.256 The prognosis remains pessimistic due to the insensitivity to current treatments, even after gross total resection and aggressive postoperative chemoradiotherapy.257 A recent study suggested that lactylation is involved in chemotherapy resistance in GBM (Figs. 5, 10 and Table 2). For example, H3K9la in recurrent GBM tissues and TMZ-resistant cells confers temozolomide (TMZ) resistance in GBM by triggering LUC7L2-mediated retention of intron 7 in MLH1, which reduces its expression and inhibits mismatch repair, ultimately contributing to TMZ resistance in GBM.100 Similarly, H3K14la and H3K18la in GBM cells promote cell proliferation, immune evasion, and brain tumor growth. Specifically, EGFR activation triggers ERK-mediated phosphorylation and nuclear translocation of ACSS2, which binds to KAT2A, functioning as a lactyltransferase to promote H3K14/18la and facilitating Wnt/b-catenin, NF-kB, and PD-L1 expression.67 Notably, this study firstly proposes KAT2A as a lactyltransferase and ACSS2 as a lactyl-CoA synthetase of lactylation. Furthermore, GTPSCS-mediated H3K18la contributes to human glioma malignancy and radioresistance by upregulating growth differentiation factor 15 (GDF15) expression and subsequent cell proliferation.96 Of note, GTPSCS functions as a lactyl-CoA synthetase in the nucleus and interacts with p300 to form a histone lactyltransferase complex to synergistically modulate H3K18la in this process. Additionally, H3K18la promotes malignant glioma progression by inducing M2 macrophage polarization through TNFSF9 expression.258GSCs reside atop the cellular hierarchy of GBM and contribute to tumor growth, invasion, resistance, metabolic adaptations, and evasion of immune surveillance.259,260 Metabolic reprogramming toward glycolysis in GSCs facilitates epigenetic reprogramming of GBM cells and immune evasion by promoting lactate-derived histone Kla and the subsequent transcriptional upregulation of CD47.129,261 H3K18la triggers the upregulation of USP4 in GSCs, which is also a key factor leading to the maintenance and therapeutic resistance of GBM.262 Elevated expression of aldehyde dehydrogenase 1 family member A3 (ALDH1A3) and enhanced glycolytic activity are linked to treatment resistance in GBM, contributing to poor prognosis in GBM.263,264 Furthermore, ALDH1A3-induced PKM2 tetramerization reprograms glycometabolism and increases lactate production in GSCs, leading to lactylation of XRCC1 at K247. Lactylated XRCC1 increases its binding to importin α, which facilitates nuclear translocation and DNA repair, consequently leading to the chemoradiotherapy resistance of GBM.124 Furthermore, PTBP1 hyperlactylation in GSCs supports GSC maintenance and promotes glioma progression by impeding its proteasomal degradation via the disruption of interaction with tripartite motif-containing 21 (TRIM21). Additionally, PTBP1-K436la enhances its RNA-binding affinity and stabilizes PFKFB4 mRNA, boosting glycolysis and, in turn, forming a feedback loop, exacerbating tumorigenesis.127In addition, lactylation in monocyte-derived macrophages (MDMs) contributes to GBM pathology. Mechanistically, high glycolysis of MDMs expressing GLUT1 drives histone Kla, which further promotes IL-10 production and subsequently induces T-cell suppression, ultimately exacerbating GBM progression.186 These findings shed light on the mechanism of lactylation in immunosuppression, metabolic reprogramming, and chemoradiotherapy resistance in GBM, suggesting that targeting glycolysis-derived lactylation could be a potential combined therapeutic strategy for GBM.Traumatic neurological disordersTraumatic neurological disorders involve damage to the brain or spinal cord from external forces, with traumatic brain injury (TBI) and spinal cord injury (SCI) being the most common.265,266 TBI is increasingly recognized as a metabolic disorder, with lactate accumulation linked to poor prognosis.267 Notably, recent research has highlighted that lactylation, particularly of Tufm at lysine 286, exacerbates TBI by disrupting its interaction with Tomm40 on mitochondria and subsequently inhibiting Tufm-mediated mitophagy while promoting mitochondria-associated neuronal apoptosis.128 In addition, histone Kla, especially H3K18la, facilitates proteasome 26S subunit, non-ATPase 14 (PSMD14) upregulation, leading to neuronal PANoptosis and improved TBI prognosis by deubiquitinating PKM2 to activate PINK1-mediated mitophagy.268 These innovative findings offer a new insight into the role of lactylation in TBI and propose potential therapeutic targets through epigenetic modification. SCI, a major central nervous system disorder, often impairs autonomic, sensory, and motor functions.269 Emerging evidence indicates that inflammation following SCI is linked to the development of microglial scar formation.270,271 A recent study demonstrated increased lactate and lactylation in the spinal cord following SCI.272 Notably, exogenous lactate augments H4K12la in microglia, subsequently enhancing PD-1 transcription, microglial proliferation, scar formation, axon regeneration, and locomotor function recovery, thereby facilitating injured spinal cord repair.Psychiatric disordersLactate is linked to psychiatric disorders such as anxiety and major depression.32,273 Peripheral administration of lactate can alleviate anxiety and depression-like behaviors in chronic stress-induced depression mouse models.274 Notably, histone Kla is also involved in neural excitation and social stress (Figs. 5, 10 and Table 2). The increased lactate in the prefrontal cortex affects histone lactylation, particularly histone H1. Elevated histone Kla enhances the expression of neuronal activity markers such as c-Fos, leading to reduced social behavior and increased anxiety. Additionally, 63 lysine-lactylated proteins have been identified in stressed mouse brains.9Likewise, the biological mechanism of lactylation in the anti-anxiety effect mediated by exercise has also been revealed by the latest study. Concretely, exercise-induced lactate enhances lactylation of synaptic proteins, particularly synaptosome-associated protein 91 (SNAP91) at K885, in the medial prefrontal cortex. Interestingly, this process strengthens synaptic structures and neural activity, endowing it with resistance to chronic restrictive stress and alleviating anxious behavior.275 These findings indicate the crucial role of lactate-lactylation in neural excitation and anxiety, implying that lactate supplementation and exercise could be potential therapeutic strategies.Collectively, these findings unveil the essential role of lactylation in neurological diseases. However, further research is required to fully comprehend the molecular mechanisms of lactylation in the central nervous system, involving the lactylated proteins and corresponding sites that contribute to which biological processes, and to develop targeted interventions.Lactylation in cardiovascular diseases (CVDs)The involvement of lactylation in the pathogenesis of CVDs, particularly atherosclerosis and myocardial infarction, as well as in conditions such as vascular calcification, neointimal hyperplasia, pulmonary hypertension, heart failure, and radiation-induced heart damage (RIHD), is becoming increasingly elucidated. Importantly, distinct lactylation patterns demonstrate variable effects at different stages of these cardiovascular diseases, either aggravating or mitigating the progression of the disease (Figs. 6, 10 and Table 2).AtherosclerosisAtherosclerosis is the most common vascular disease and the dominant pathological basis of various cardiovascular diseases, and is characterized by lipid deposition, inflammatory cell infiltration, and fibrous tissue proliferation.276 Abnormal glucose metabolism is an independent risk factor for the occurrence and development of atherosclerosis.277 Recent studies have revealed the essential role of histone Kla in the progression and improvement of atherosclerosis. H3K18la drives atherosclerosis by promoting EndMT via p300/anti-silencing function 1A (ASF1A)-mediated transcriptional activation of snail family zinc-finger 1 (SNAI1) in ECs, which could be attenuated by pharmacological inhibition of glycolysis.278 Similarly, the enriched histone Kla, particularly H4K12la, is detected in vascular smooth muscle cells (VSMCs), activating senescence-associated secretory phenotype (SASP) transcription and exacerbating VSMC senescence.86 Conversely, histone Kla in macrophages contributes to the improvement of atherosclerosis. Specifically, deficiency of MCT4, a key lactate efflux mediator, enhances H3K18la, promoting reparative gene expression and inflammatory resolution, thereby ameliorating atherosclerosis.279 These findings illustrate the different roles of specific lactylation in regulating atherosclerosis.Intriguingly, non-histone protein lactylation is also associated with atherosclerosis. Exercise-generated lactate in mouse aortic endothelial cells (MAECs) triggers MeCP2-K271la, which alleviates atherosclerosis by regulating inflammatory cytokines and adhesion molecules via Ereg-mediated MAPK signaling pathway.280 Likewise, MeCP2-K271la in aortic root plaque macrophages facilitates macrophage M2 polarization by augmenting its interaction with H3K36me3 and promoting chromatin accessibility and RUNX1 transcriptional repression, thereby mitigating atherosclerosis.89Myocardial infarctionMyocardial infarction is a highly prevalent cardiovascular disease characterized by ischemia and hypoxia and is closely related to energy metabolism disorders.281 Essentially, lactate could exacerbate cardiac fibrosis and cardiac dysfunction after myocardial infarction by promoting EndMT.282 Intriguingly, lactylation is involved in cardiac fibrosis and cardiac dysfunction following myocardial infarction. Mechanistically, elevated lactate in mouse myocardial tissue and HUVECs triggers Snail1 lactylation, activating the TGF-β/Smad2 signaling pathway and eventually promoting EndMT and cardiac dysfunction.282 Similarly, lactylation of malate dehydrogenase 2 (MDH2), a key enzyme of the TCA cycle, induces ferroptosis of cardiomyocytes by inhibiting the TCA cycle and impairing mitochondrial function, thereby resulting in myocardial ischemia‒reperfusion injury (MIRI).283 Notably, 1026 sites of lactylated proteins were identified in myocardial tissues from I/R rats by lactylation modification omics and were prominently enriched in the TCA cycle pathway. In addition, NLRP3 lactylation also contributes to MIRI. Specifically, hypoxia/reoxygenation promotes lactylation of NLRP3 at lysine 245 and subsequently enhances its stability, leading to pyroptosis of cardiomyocytes. However, knockdown of LDHA diminishes NLRP3 K245la and reverses cardiomyocyte pyroptosis to alleviate MIRI.119 Intriguingly, researchers have identified lactylation-related genes (AMPD2, PYGL, SLC7A7, SAT1) that are significantly expressed in acute myocardial infarction (AMI), highlighting their potential as early diagnostic biomarkers.284Conversely, lactylation of distinct proteins in specific cells contributes to the repair of ischemia-induced cardiac injury. For instance, during early myocardial infarction, monocytes undergo metabolic reprogramming, increasing glycolysis and lactate, which triggers H3K18la and activates genes such as Lrg1, Vegf-a, and IL-10 for cardiac repair.66 Notably, this process is catalyzed by IL-1β-dependent GCN5 recruitment, confirming that GCN5 serves as a writer of lactylation. In addition, lactylation of Serpina3k at K351 in cardiac fibroblasts during I/R enhances protein stability, protecting cardiomyocytes from apoptosis.285 These findings highlight lactylation’s varied effects on different cells and stages of cardiac repair, offering novel insights into myocardial infarction treatment.Other CVDsVascular calcification is the pathological deposition of minerals in the form of calcium salts and phosphates in vascular tissues.286,287 It is a condition distinct from atherosclerosis and common in diabetes, chronic kidney disease, and aging, and involves lactylation. For instance, in calcified aortic tissues, increased NR4A3 boosts glycolysis by activating ALDOA and PFKL, leading to elevated H3K18la. This, in turn, raises phospho1 expression, enhancing calcium deposition and causing vascular calcification.288 Additionally, H3K18la increases CHI3L1 expression, activating the IL-13-IL-13Ra2-JAK1-STAT3 pathway, which promotes arterial VSMC calcification in diabetes.289Transdifferentiation of VSMCs into macrophage-like cells plays a role in vascular hyperplasia and atherosclerosis during chronic inflammation.290 Intriguingly, lactylation is implicated in vascular inflammation and neointimal hyperplasia. Specifically, TNF-α induces lactylation of sex-determining region Y (SRY)-related HMG-box gene 10 (Sox10) via PI3K/AKT signaling, driving VSMC transdifferentiation and pyroptosis.291 Additionally, VSMC transdifferentiation and apoptosis are common pathogenic mechanisms in aortic aneurysm/dissection and are associated with lactylation.292 Reduced membrane-associated RING finger protein 2 (March 2) disrupts its interaction with PKM2, altering glucose metabolism and increasing lactate production, which enhances H3K18la and p53-mediated apoptosis in VSMCs, worsening aortic aneurysm/dissection.293Glycolytic shift, driven by mitochondrial reactive oxygen species (mtROS), is a common denominator in pulmonary hypertension.294,295 Glycolysis-induced lactylation is implicated in hypoxic pulmonary hypertension by promoting the pulmonary artery smooth muscle cell (PASMC) glycolytic switch and proliferation through histone lactylation. Hypoxia-induced mROS inhibits HIF-1α hydroxylation and upregulates the HIF-1α/PDK1&PDK2/p-PDH-E1α axis, enhancing lactate production and histone lactylation. Subsequently, the increased histone lactylation facilitates the transcriptional activation of HIF-1α targets such as Bmp5, Trpc5, and Kit, thereby promoting PASMC proliferation and vascular remodeling.296 Inhibiting PDK1&2 reduces histone lactylation, alleviating PASMC proliferation and vascular remodeling in hypoxic pulmonary hypertension rats, suggesting the implication of lactate-lactylation in anti-remodeling therapy of pulmonary hypertension.Evidence suggests that lactate within myocardial cells protects the myocardium, with increased consumption in heart failure patients.297,298 Additionally, lactate and its analogs can significantly ameliorate acute heart failure.299,300 Notably, lactylation plays a favorable role in mitigating heart failure. Specifically, lactylation of α-MHC at lysine 1897 disrupts its interaction with Titin, impairing cardiac structure and function. However, enhancing lactate levels or inhibiting MCT4, a pivotal lactate transporter, promotes α-MHC-K1897la and α-MHC-Titin interaction, alleviating heart failure.26 This highlights that lactylation is an important determinant in maintaining sarcomeric structure and function, providing novel therapeutic insights. Further research is needed to further understand the role of lactylation in heart failure.Lactylation is linked to RIHD, a condition frequently resulting from cancer radiation therapy and predominantly characterized by cardiac fibrosis.301 A recent study demonstrated that lactylation of P4HB plays a crucial role in RIHD progression. Specifically, radiation-induced lactate accumulation in cardiomyocytes triggers P4HB lactylation at lysine 311 (K311la), which subsequently initiates inflammatory cascades and mitochondrial autophagy. Mechanistically, P4HB-K311la activates SH3GLB1 expression by promoting p-GSK3B transcription, enhancing interactions between P4HB, PTGS2, and SH3GLB1. This process regulates mtROS accumulation via SH3GLB1, kynurenine metabolism via GOT2, and NDP52-induced mitochondrial autophagy. Ultimately, P4HB-K311la exacerbates cardiac injury in RIHD through the PTGS2/SH3GLB1/NDP52 pathway, worsening RIHD progression.126In summary, lactylation plays a crucial role in various stages of cardiovascular diseases by affecting cardiac metabolism and acting as a signaling molecule. While its multifaceted impact is evident. Nonetheless, further comprehensive studies are necessary to elucidate its underlying mechanisms and develop targeted intervention strategies related to lactylation.Lactylation in ophthalmic disordersLactate metabolism serves as a critical regulatory factor in maintaining ocular homeostasis. Notably, evidence indicates that lactate-derived lactylation is implicated in diverse biological processes of various ocular disorders, such as myopia, intraocular malignancies, neovascularization-induced retinopathy, and autoimmune uveitis (Figs. 7, 10 and Table 2).MyopiaMyopia is the most prevalent global eye disorder and is characterized by sclera elongation.302 During myopia progression, hypoxia and increased lactate from anaerobic glycolysis lead to enhanced histone lactylation, particularly H3K18la.303 This facilitates Notch1 expression and ultimately triggers fibroblast-to-myofibroblast transdifferentiation (FMT) in the sclera of mice with form-deprivation myopia.27 Essentially, hypoxia and increased sugar consumption heighten myopia susceptibility through the lactate-histone lactylation-Notch1 pathway in the sclera.Ocular melanomaOcular melanoma is the most frequent and life-threatening malignant eye cancer and is resistant to standard chemotherapy.304 It is characterized by active glycolysis and epigenetic changes, such as abnormal histone lactylation and mRNA methylation.305,306 For instance, histone Kla, especially H3K18la, facilitates the expression of the m6A reader protein YTHDF2, leading to the degradation of m6A-modified mRNAs such as PER1 and TP53, which promotes tumor growth in OCM1 and CRMM1 cells.62 Additionally, H3K18la boosts the expression of the m1A eraser protein ALKBH3 and simultaneously attenuates tumor-suppressive promyelocytic leukemia protein (PML) condensates by removing m1A methylation from SP100A, driving tumorigenesis in ocular melanoma cells and orthotopic xenografts derived from ALKBH3-deficient 92.1 cells.141 These findings collectively highlight the noticeable relationship between high histone Kla levels and poor prognosis in ocular melanoma, emphasizing its pivotal oncogenic role in ocular malignancy.RetinopathyThe intricate interplay between histone Kla and RNA modifications emerges as a momentous accelerator in the pathogenesis of diabetic retinopathy, a major microvascular complication of diabetes that causes irreversible vision loss in working-age populations.307 Mechanistically, histone Kla upregulates FTO, a m6A demethylase, which enhances CDK2 mRNA stability. This promotes EC cycle progression and tip cell formation, influences EC-pericyte interactions causing diabetic microvascular leakage, and mediates EC-microglia interactions leading to retinal inflammation and neurodegeneration, ultimately driving angiogenesis in diabetic retinopathy.140 Correspondingly, H3K9 exhibits remarkable hyperlactylation in VEGF-induced ECs and oxygen-induced retinopathy mouse retinas, leading to increased expression of angiogenic genes, including NECTIN1, TGFBR2, ABL1, PTGFR, LAMA4, CLASP2, PRCP, and EGFR. Simultaneously, elevated H3K9la inhibits HDAC2 expression, forming a feedback loop of H3K9la/HDAC2 in ECs that regulates angiogenesis in retinopathy. Pharmacological inhibition of glycolysis diminishes H3K9la and angiogenesis, representing a novel therapeutic method for pathological neovascularization.85 Unimaginably, beyond histone Kla, lactate-mediated non-histone Kla is also involved in retinal neovascularization. For instance, YY1, a key transcription factor, undergoes lactylation at K183 in hypoxic retinal microglia. Hyperlactylated YY1 directly stimulates FGF2 transcription and promotes angiogenesis, driving oxygen-related retinal neovascularization and proliferative retinopathy.110Autoimmune uveitisAutoimmune uveitis is the most common autoimmune disease that causes blindness in the eyes.308 In experimental autoimmune uveitis (EAU) mice, CD4+ T cells display high lactate levels, leading to hyperlactylation of Ikzf1 at K164, which further modulates the expression of Th17-related genes, including Runx1, Tlr4, IL-2, and IL-4, consequently promoting Th17 differentiation.112 Conversely, reducing lactylation at Ikzf1 K164 hinders Th17 differentiation and improves EAU, implying the involvement of lactylation in autoimmune disease pathology.Taken together, these findings collectively underscore the significance of lactate metabolism and protein lactylation in ocular disorders, offering novel insights into the study of lactylation in ocular diseases and providing promising therapeutic strategies that target lactate-lactylation signaling pathways.Lactylation in immunoinflammatory diseasesPrevious studies have indicated a sophisticated interplay between lactate and the immune-inflammatory response.309 Activated immune cells preferentially utilize lactate to enhance their functionality. Moreover, lactate accumulation within the tissue microenvironment serves as a signaling molecule that constrains immune cell activity.310 Notably, lactylation has gradually been confirmed to play an important role in the pathogenesis of immunoinflammatory diseases, including sepsis, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and asthma (Figs. 8, 10 and Table 2).SepsisSepsis, a systemic immune disease caused by infection, disrupts the inflammatory response and is closely related to serum lactate levels.311 Elevated serum lactate is a biomarker for sepsis prognosis and mortality.312 Lactylation has emerged as a critical factor in sepsis and its common complications, including sepsis-induced acute lung injury (S-ALI) and sepsis-induced acute kidney injury (S-AKI). Specifically, macrophages absorb extracellular lactate, promoting HMGB1 lactylation via the p300/CBP-dependent pathway during sepsis.6 This lactylated HMGB1 is released from macrophages via exosome secretion, which increases endothelium permeability, thereby exacerbating polymicrobial sepsis progression.The lung is the most vulnerable target organ in sepsis, with S-ALI often occurring in the early stages of sepsis.313 S-ALI is the leading cause of poor prognosis in sepsis patients and is positively correlated with high lung lactate levels.314 Intriguingly, lactylation plays an important role in S-ALI. For instance, H3K18la boosts METTL3 expression, promoting ferroptosis by upregulating acyl-CoA synthetase long-chain family member 4 (ACSL4) and exacerbating S-ALI. Mechanistically, elevated lactate-triggered H3K18la in alveolar epithelial cells enhances ACSL4 m6A methylation and stabilizes ACSL4 mRNA by binding to the METTL3 promoter, leading to mitochondria-associated ferroptosis.315 Moreover, H3K18la promotes early growth response 1 (EGR1) transcription, with increased lactylation of EGR1 at lysine 364, enhancing its nuclear localization by binding with importin-α, eventually leading to heparinase upregulation and glycocalyx degradation in pulmonary microvascular ECs during S-ALI.68 Besides, lactylation of cold-inducible RNA-binding protein (CIRP) contributes to S-ALI. Concretely, the accumulated lactate promotes CIRP lactylation and consequently leads to CIRP release in macrophages, which then binds to ZBP1 in pulmonary vascular endothelial cells (PVECs). Internalized CIRP effectively blocks the interaction between ZBP1 and tripartite motif-containing 32 (TRIM32), an E3 ubiquitin ligase targeting ZBP1 for proteasomal degradation, thereby enhancing ZBP1-dependent PANoptosis of PVECs and exacerbating ALI in sepsis.131Furthermore, S-AKI is another common complication in patients with sepsis. Notably, lactate-derived lactylation correlates with higher S-AKI incidence and poor prognosis in clinical sepsis patients. Specifically, lactate triggers mitochondrial fission 1 (Fis1) lactylation at lysine 20, which promotes excessive mitochondrial fission, leading to ATP depletion, mtROS overproduction, and mitochondrial apoptosis, exacerbating S-AKI.132IBDIBD is a chronic, relapsing condition with two subtypes, ulcerative colitis (UC) and Crohn’s disease (CD).316 Lactate has been identified as an active signaling molecule in the immune system and UC pathology.317 Consequently, lactate-triggered histone Kla becomes an essential regulator in UC. Specifically, a specific deficiency of the B-cell adapter for PI3K (BCAP) in macrophages reduces lactate production and histone Kla, consequently leading to tissue repair-associated gene downregulation and impairing tissue repair following UC.28 However, Gegen Qinlian decoction (GQD) triggers histone lactylation such as H3K18la and H4K12la, subsequently inhibiting M1 macrophage polarization, inflammation, oxidative stress, and ulcerative colitis progression.318 In Crohn’s disease, a disease characterized by intestinal immune dysfunction319 accompanied by metabolic abnormalities,320 disrupted lactate metabolism results in abnormal lactylation.321 In addition, the lactylation level of intestinal immune cells correlates with inflammation, revealing a relationship between lactylation and Crohn’s disease.321RARA is a type of immune-mediated chronic inflammatory arthritis characterized by synovial hypertrophy and progressive joint destruction.322 Adopting diverse activation states of macrophages is associated with RA. Metabolic reprogramming is a key factor in macrophage effector diversity and inflammatory disease onset.323,324 Lactate-derived lactylation is consequently involved in modulating inflammation in RA. Specifically, RNA-binding motif protein 25 (RBM25) influences the splicing of ATP citrate lyase (Acly) pre-mRNA, creating two isoforms: Acly Long (Acly L) and Acly Short (Acly S). Interestingly, Acly L undergoes lactylation at K918/995, which influences its metabolic substrate affinity, metabolic activity, and immunoregulatory ability in pro-inflammatory macrophages, thereby controlling inflammation in spontaneous arthritis.139 This finding implies that targeting the RBM25-Acly splicing axis and lactylation could be a potential strategy for modulating macrophage responses in RA and aging-associated inflammation.AsthmaAsthma is characterized as an immunoinflammatory disorder marked by persistent airway inflammation, airway remodeling, and bronchial hyperresponsiveness.325 Metabolic pathways, such as glycolysis, play a role in regulating the immune response during airway inflammation.326,327,328 Notably, there is a significant increase in protein lactylation observed in the lungs and THP-1 cells when induced by ovalbumen, which is linked to the activation of the HIF-1α-glycolysis axis and elevated lactate levels. However, dexamethasone mitigates ovalbumen-induced eosinophilic airway inflammation, including airway hyperresponsiveness, leukocyte infiltration, goblet cell hyperplasia, Th2 cytokine production, and the expression of pyroptosis markers, by inhibiting the HIF-1α-glycolysis-lactate axis and subsequent protein lactylation.329Lactylation in metabolic disordersLactylation, as one of the novel PTMs derived from metabolism, interacts with various metabolic pathways and plays an important role in the occurrence and development of metabolic diseases, such as diet-induced obesity, fatty liver disease, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and osteoporosis (Figs. 8, 10 and Table 2).ObesityResearch is focused on whether lactylation from glucose metabolism contributes to diet-induced obesity. In hypothalamic pro-opiomelanocortin (POMC) neurons, knockdown of family with sequence similarity 172 member A (Fam172a) stimulates glycolysis and increases the levels of peptidylglycine α-amidating monooxygenase (PAM), which affects the synthesis of α-melanocyte-stimulating hormone (α-MSH) via H4K12la, eventually exerting an anti-obesity effect.108Fatty liver diseasesNAFLD is a common liver disease linked to metabolic dysfunctions in lipid metabolism.330 In fact, metabolic dysfunction-associated fatty liver disease (MASLD) has been identified as an alternative nomenclature for NAFLD, reflecting the role of metabolic issues in fatty liver disease.331 Emerging evidence suggests that lactylation is implicated in NAFLD, where FASN, a pivotal enzyme in lipid synthesis and accumulation, undergoes lactylation to ameliorate NAFLD. Specifically, MPC1 upregulation restricts lactate production and the subsequent lactylation of FASN at lysine 673, hindering FASN activity and resulting in lipid deposition in the liver tissue of patients and mice with NAFLD.123 Conversely, MCP1 knockout induces FASN-K673la and mitigates NFALD, suggesting the significance of lactylation in NFALD. Furthermore, histone lactylation is involved in MASLD. HK2 upregulation induces H3K18la, which promotes glycolysis and M1 polarization of liver macrophages by enriching glycolytic gene transcription in MASLD patients and mouse models, thereby establishing a positive feedback loop that exacerbates MASLD.332NASH, now termed metabolic dysfunction-associated fatty hepatitis (MASH), is characterized by hepatic steatosis, inflammation, hepatocellular injury, and varying degrees of fibrosis and is linked to lipid metabolism disorders.331 Notably, histone Kla has been identified to regulate NASH pathogenesis by facilitating the transcription of genes driving ferroptosis, such as ATF3, ATF4, and CHAC1, thereby promoting hepatocyte ferroptosis. However, tectorigenin counteracts NASH by inhibiting histone Kla induced by HDAC1.333 These findings elucidate the interplay between liver metabolic disorders and metabolism-coupled lactylation.OsteoporosisOsteoporosis is a metabolic bone disease characterized by low bone mass and degeneration of bone tissue microstructure, leading to increased bone fragility and susceptibility to fractures.334 Endothelial cells (ECs) covering the inner walls of blood vessels have recently been found to control osteogenesis.335 Glycolysis of ECs controls bone blood vessel formation and attenuates osteoporosis.29 Interestingly, aberrant histone Kla emerges in osteoporosis pathogenesis. Concretely, EC-derived lactate induces histone Kla, particularly H3K18la, which promotes the differentiation of bone mesenchymal stem cells (BMSCs) into osteoblasts by activating osteogenic genes such as COL1A2, COMP, ENPP1, and TCF7L2. Conversely, deleting PKM2 in ECs reduces serum lactate, which affects histone Kla in BMSCs, ultimately impairing osteogenesis and exacerbating osteoporosis.29In summary, lactylation plays an indispensable role in various metabolic disorders, implying crosstalk between metabolism and epigenetics. In-depth research on lactylation is expected to provide new diagnostic targets and treatment strategies for these diseases.Lactylation in other diseasesLactylation of histones and non-histone proteins is also linked to other various diseases, including liver diseases such as fibrosis, liver ischemia/reperfusion injury (LI/R) injury, and acetaminophen (APAP)-induced liver injury (AILI), lung fibrosis, acute and chronic kidney injuries, skin injuries such as flap necrosis and hyperplastic scarring, skeletal issues such as osteoarthritis and intervertebral disc degeneration (IDD), and sHLH (Figs. 9, 10 and Table 2).Lactylation plays an essential role in liver diseases such as fibrosis, LI/R injury, and AILI, encompassing multiple biological mechanisms. The overactivation of hepatic stellate cells (HSCs) is a dominant contributor to liver fibrosis. Intriguingly, HK2-induced glycolysis boosts histone Kla, especially H3K18la, which facilitates the transcription and expression of HSC activation-induced genes, including α-SMA, Col1a1, and Timp1, thereby governing HSC activation and leading to liver fibrosis.84 Additionally, lactylation of SORBS3, especially at lysine 479, abolishes its LLPS, which enhances its interaction with flotillin 1 and selectively sorts FBXO2 into “lactate bodies”, leading to hepatocyte apoptosis, activation, and liver fibrosis.16 Moreover, non-histone lactylation is involved in LI/R injury. Specifically, downregulated heat shock protein A12A (HSPA12A) in hepatocytes increases glycolysis and lactate production, which leads to HMGB1 lactylation and exosomal secretion of hepatocytes, exacerbating hepatocyte damage–macrophage chemotaxis/activation.336 Additionally, a recent study has identified that lactylation of PCK2 at lysine 100 (K100la) exacerbates hepatic ferroptosis during LI/R injury. Mechanistically, PCK2-K100la augments its kinase activity and competitively inhibits the Parkin-mediated polyubiquitination of 3-oxoacyl-ACP synthase (OXSM), thereby altering mitochondrial fatty acid synthesis and boosting oxidative phosphorylation and the TCA cycle.337 Moreover, lactate is an adverse prognostic factor for AILI.338 Whether lactate-derived lactylation is involved in AILI has attracted the attention of researchers. Surprisingly, lactylation of NEDD4 in macrophages has been found to worsen AILI by facilitating non-canonical pyroptosis. Mechanistically, lactylation of NEDD4 at lysine 33 decreases its binding affinity with Caspase-11 and the subsequent ubiquitination of Caspase-11, leading to non-canonical pyroptosis and advancing AILI.91Moreover, histone Kla has also been reported to be involved in lung fibrosis, serving as a dominant contributor to promoting macrophage profibrotic activity in lung myofibroblasts. Metabolic reprogramming of the lung leads to enhanced glycolysis, which is crucial for the fibrotic phenotype of myofibroblasts. Lactate in TGF-β1-induced lung myofibroblasts and in BAL fluids (BALFs) from TGF-β1- or bleomycin-induced mice induces histone Kla, particularly histone 3, in profibrotic gene promoters in macrophages, contributing to lung fibrosis.339 Additionally, PFKFB3-driven glycolysis also promotes histone Kla and boosts profibrotic gene expression in silica-treated mice, a process that can be inhibited by activating glucagon-like peptide-1 receptor (GLP-1R), disrupting the interaction between the NLRP3 inflammasome and PFKFB3, and intensifying pulmonary fibrosis progression.340Acute kidney injury (AKI) and chronic kidney disease (CKD) are prevalent disorders characterized by renal dysfunction. Recent studies have intriguingly highlighted the role of lactylation in AKI and CKD pathogenesis. In maleic acid-induced AKI mice and renal cells, mitochondrial dysfunction shifts metabolism to glycolysis and increases lactate production. Notably, lactate-induced ALDH2-K52la in renal cells disrupts its interaction with PHB2, a critical mitophagy receptor, leading to PHB2 degradation, impaired mitophagy, and worsened kidney damage.95 Similarly, in a unilateral ureteral obstruction (UUO)-induced CKD mouse model, elevated PKM2 induced the glycolytic pathway and lactate generation, which triggered histone Kla. The increased histone Kla facilitates TGF-β1 expression and the accompanying Smad3 pathway activation, driving macrophage-myofibroblast transition and exacerbating renal fibrosis.341Skin flap necrosis, a rising factor in the poor prognosis of patients after flap transplantation, is closely related to endothelial-to-mesenchymal transition (EndoMT), which is exacerbated by glycolysis-derived lactate production.342,343 Intriguingly, lactate-derived lactylation plays a critical role in EndoMT in flap ischemia. Specifically, lactylation of Twist1 at K150 intensifies flap fibrosis and ischemia by promoting flap necrosis and the fibrotic response. Mechanistically, lactate accumulation, driven by PKM2, enhances Twist1-K150la, which in turn facilitates Twist1 phosphorylation, nuclear translocation, and regulation of TGFB1 transcription, thereby inducing an EndoMT-associated fibrotic phenotype in ischemic flaps.129 In addition, lactylation contributes to hyperplastic scars by increasing Pan Kla and H3K18la levels, activating SLUG, suppressing PTEN, and inhibiting autophagy, which boosts collagen deposition and cell viability in scar fibroblasts.344Furthermore, lactylation is implicated in the progression of musculoskeletal diseases such as osteoarthritis (OA), intervertebral disc degeneration (IDD), and tendinopathy. In the synovial fluid of individuals with OA, increased lactate facilitates lactylation of UDP-glucose dehydrogenase (UGDH) at lysine 6, disrupting its interaction with signal transducer and activator of transcription 1 (STAT1), suppressing its enzymatic activity and glycosaminoglycan synthesis, and altering its nuclear-cytoplasmic distribution, activating the MAPK signaling pathway and ultimately contributing to OA progression.345 In IDD, high TNF-α in degenerative nucleus pulposus (NP) tissues enhances glycolysis, which subsequently induces AMPKα lactylation. This modification inhibits its phosphorylation and deactivates the AMPK pathway, resulting in diminished matrix synthesis, increased degradation, reduced autophagy, and accelerated cellular senescence.346 Additionally, elevated glycolysis and the resultant lactate promote H3K18la, which facilitates ACSL4 transcription while also enhancing ACSL4 lactylation at K412. This histone Kla-induced ACSL4 expression and self-lactylation cause NP dysfunction via ferroptosis.347 In addition, protein lactylation affects matrix and cholesterol metabolism within tendinopathy, a condition intricately linked to lactate metabolism.348 A comprehensive multi-proteomic analysis of the lysine lactylome identified lactylation at 872 Kla sites on 284 proteins, predominantly associated with extracellular matrix organization and cholesterol metabolism, suggesting a correlation between lactylation and protein expression in these areas and offering insight into the potential biophysical mechanisms and impact of lactylation on tendon function.349In addition, lactylation contributes to sHLH. Specifically, circMETTL3-156aa, a novel peptide encoded by circMETTL3 derived from METTL3 in sHLH patient plasma exosomes, promotes M1 macrophage polarization by binding with LDHA and enhancing macrophage glycolysis. The resulting lactate upregulates SRSF10 via H3K18la, eventually forming a feedback loop involving circMETTL3/METTL3-156aa/LDHA/Lactate/SRSF10 that triggers cytokine storms in sHLH.137Collectively, the emerging role of lactylation in diseases is gaining clarity, with its changes potentially serving as diagnostic and prognostic markers and aiding in identifying therapeutic targets. Nonetheless, further in-depth research is needed to understand the molecular mechanisms of lactylation for developing therapies targeting lactate-lactylation pathways.Clinical application potential of lactylationLactylation orchestrates diverse cellular processes, impacting gene expression, metabolism, immune regulation, and signal transduction. Current evidence demonstrates its critical involvement in maintaining physiological homeostasis while simultaneously contributing to the pathogenesis and progression of multiple diseases. Comprehensive investigation of its molecular networks and pathophysiological implications is expected to uncover novel diagnostic and prognostic biomarkers and therapeutic targets, positioning it as a pivotal frontier for clinical application and disease management (Table 3).Table 3 Therapeutic strategies directly or indirectly targeting lactylationFull size tableBiomarker discovery of diseasesAn increasing number of lactylated proteins and sites have been identified, revealing their potential as biomarkers for the early diagnosis and monitoring of diseases. Notably, proteomics and mass spectrometry have been pivotal for identifying protein lactylation.350 A global lactylome and proteome analysis profiling of a hepatitis B virus-related HCC cohort identified 9256 non-histone and 19 histone protein lactylation sites in tumors and adjacent livers, demonstrating the ubiquitous nature of lactylation in tumor biology beyond histones and transcriptional regulation.8 Similarly, using proteomic analysis coupled with mass spectrometry, researchers have identified 637 lysine lactylation sites in 444 proteins in FHC and SW480 cells, predominantly involving metabolic enzymes. These lactylation modifications modulate metabolic processes by influencing enzyme activity, indicating a feedback mechanism constituted by lactate-lactylation-metabolic reprogramming.351 A global lactylome profiling of cancerous and adjacent tissues from 40 patients with gastrointestinal cancer also identified 11698 Kla sites, highlighting its role in cancer processes, including epigenetic rewiring, metabolic perturbations, and genome instability.352 In addition, a lysine lactylome analysis in gastric cancer AGS cells identified 2375 Kla sites in 1014 proteins, with a higher prevalence in tumors linked to poor prognosis, highlighting its potential as a prognostic marker. These discoveries, based on proteomics and mass spectrometry, establish a foundational basis for exploring lactylation-modified proteins as biomarkers.Furthermore, machine learning has been instrumental in predicting novel biomarkers for diagnosis and prognosis linked to lactylation. By employing machine learning techniques on databases, researchers have determined lactylation-related gene expression levels and constructed a gene signature.353 Likewise, a lactylation-related model for GC predicts lactylation-related genes and scores, indicating GC prognosis.354 Additionally, a novel lactylation-related prognostic signature has also predicted the survival of patients with pancreatic cancer, indicating these genes as potential PAAD biomarkers.355Overall, integrating proteomics, mass spectrometry, and bioinformatics facilitates the construction of more effective diagnostic and detection models based on lactylation, thereby contributing to disease prevention and treatment strategies. Future research is expected to investigate the application of lactylation in personalized medicine, such as by developing tailored treatment plans that consider individual differences in lactylation.Targeted therapeuticsThe dynamic interplay between lactate metabolism and lactylation-driven epigenetic reprogramming has emerged as a hallmark of diverse pathological processes, such as cancer, inflammatory disorders, and metabolic syndromes. Consequently, the development of therapeutics targeting lactylation holds significant transformative potential. Currently, a limited number of studies have commenced the exploration of therapeutics that directly target lactylation. Most of the studies predominantly concentrate on targeting lactate, including its production and transport. In addition, interventions targeting lactylation-associated enzymes, such as the p300 inhibitor C646, might be emerging as promising therapeutic strategies for regulating lactylation (Table 3).Direct targeting of lactylationCurrent research on intervention strategies directly targeting Kla remains limited. A few preliminary studies have explored the potential of inhibiting lactylation to ameliorate diseases. For instance, demethylzeylasteral (DML) has been shown to suppress liver cancer stem cell tumorigenicity by inhibiting H3K9la and H3K56la, while royal jelly acid (RJA) inhibits tumor invasion, migration, proliferation, and apoptosis in HCC by targeting H3K9la and H3K14la.102,356 Furthermore, evodiamine, a natural compound, has been identified to impair H3K18la to inhibit angiogenesis and ferroptosis in PCa.357 Notably, a recent study has surprisingly identified that isosafrole, an anti-epileptic drug, targets histone Kla to enhance the brain tumor response to immunotherapy.358 These findings suggest that inhibition of histone Kla could be a promising candidate for cancer therapy. Nevertheless, the underlying precise regulatory mechanisms require further elucidation.Furthermore, the direct suppression of non-histone lactylation presents a potential avenue for the development of targeted clinical therapeutics. For instance, microtubule glycoside A (TubA), a small molecule compound identified based on analyzing the protein crystal structure of ABCF1-K430la and screening for drugs, mainly targets ABCF1 lactylation to promote HCC cell growth and organoids, inhibiting HCC progression.87 Moreover, β-alanine, a non-essential amino acid structurally similar to lactate, suppresses breast cancer tumorigenesis by competing with lactate for binding to AARS1 to interfere with p53 lactylation.22 Additionally, K673-peptide-3# (K673-pe), a peptidic inhibitor, suppresses MRE11 K673 lactylation to block DSB repair-mediated HR hyperactivation and sensitize CRC cells to chemotherapy, resulting in a synergistic tumor-suppressive effect.155 The anti-APOC2-K70-lac antibody, developed based on the lactylation of K70 at APOC2, enhances anti-PD-1 therapy efficacy in NSCLC, suggesting its potential in combination immunotherapy in cancer.88 Nevertheless, research into intervention strategies directly targeting lactylation remains limited, necessitating further in-depth studies to elucidate these strategies and their regulatory mechanisms, which hold significant practical importance for clinical applications.Inhibition of lactate production and transportThe lactate-rich microenvironment is a prerequisite for lactylation, primarily driven by glycolysis. Consequently, inhibiting glycolysis with 2-deoxy-d-glucose (2-DG), which is a glucose analog that competitively binds to hexokinase, postpones the malignant progression of endometrial cancer mediated by histone lactylation by suppressing cell proliferation and migration and inducing apoptosis.230 Additionally, preclinical studies in triple-negative breast cancer (TNBC) models have demonstrated that the LDHA inhibitor DCA and sodium oxamate reduce histone Kla levels and suppress tumor growth by reactivating antitumor immunity.359 Oxamate also suppresses lactate production to inhibit the oncogenesis of ocular melanoma.62 Moreover, small molecule inhibitors of LDHA, such as GSK2837808A, FX-11, galloflavin, and N-hydroxyindole-based compounds, inhibit pyruvate-to-lactate conversion, and may possess the potential to regulate lactylation.360,361,362,363,364,365,366The proteolysis targeting chimeras (PROTAC) degrader of LDH, MS6105, has shown antitumor effects in multiple pancreatic cancer cell lines through inhibiting proliferation.367 Moreover, LDH-targeted therapy can also achieve therapeutic effects when used in combination with adjuvant therapy. LDH acts as an immunotherapy sensitizer with oxime esters and inhibitors.136,194,368 In addition, D34-919, an inhibitor of pyruvate kinase by ALDH1A3, suppresses downstream XRCC1 lactylation, reversing chemoradiotherapy resistance in patients with high ALDH1A3-expressing GBM.In addition, the cellular uptake of lactate via MCTs significantly influences lactylation levels. For instance, MCT1-mediated lactylation stabilizes HIF-1α and enhances KIAA1199 transcription, thereby facilitating tumor angiogenesis.24 Within the tumor microenvironment, MCT-mediated influx of lactate triggers histone Kla, especially H3K18la, which subsequently promotes TIM polarization toward the M2 phenotype.63 Conversely, inhibiting MCTs impedes lactate efflux and diminishes intracellular lactate levels, thereby affecting lactylation levels. For instance, inhibiting MCT1 prevents cGAS lactylation, thus restoring innate immune function.77 MCT1 inhibitors, such as AZD3965, have progressed to phase I/II clinical trials, demonstrating tolerability in patients with advanced solid tumors and lymphomas through regulating tumor cell energy metabolism.369 AZD3965 has been proven to regulate antitumor immunity in bladder cancer by reducing H3K18la and H3K9la in activated CD8+ T cells.21 Conversely, the MCT4 inhibitor VB124 increases α-MHC K1897 lactylation, mitigating Ang II-induced heart failure.26 These findings indicate that the impact of MCT inhibitors on lactylation varies by cell type and inhibitor subtype. In general, lactylation can be regulated by targeting enzymes that affect lactate metabolism and transport.Intervention of lactylation-related enzymesThe majority of lactylation is mediated by enzymes, making the targeted intervention of these key regulatory enzymes, particularly the writers, a crucial focus for research into targeted therapy strategies for lactylation. The p300/CBP inhibitors have been employed in lactylation research, including both histone and non-histone lactylation, to validate their effects and alterations on other factors. For instance, C646 treatment inhibits pancreatic cancer progression by suppressing H3K18la-mediated cell proliferation, migration, and invasion.97 CPI-1612, a potent and selective oral p300 inhibitor, abrogates lactylation and subsequent IL-10 expression in tumor-educated BMDMs without affecting acetylation, thereby countering immunosuppression in GBM.186 Additionally, A-485, a CoA-competitive p300 inhibitor, decreases YY1 lactylation in human microglial clone 3 cells, ultimately hindering retinal neovascularization.110 However, treatment with A-485 lowers H3K18la levels and suppresses osteogenic gene expression in BMSCs, thereby exacerbating osteoporosis.29 These findings suggest the therapeutic potential of targeting p300-mediated Kla alterations, although in certain contexts, they may also promote disease occurrence and progression. Moreover, MG149, an acetyltransferase inhibitor targeting the MYST domain of KAT8, reduces Pan Kla levels in CRC cells, highlighting the tumor-suppressive potential of KAT8 inhibitors in high-lactate TME.72However, the principal regulatory enzyme responsible for lactylation is interchangeable with other PTMs, such as acetylation, leading to a lack of specificity. Consequently, targeting these enzymes could inadvertently affect other PTMs. Hence, it is imperative to conduct more detailed analyses of the specific regulatory enzymes involved in lactylation and to explore targeted intervention strategies accordingly.Conclusion and perspectivesLactylation has emerged as a multifaceted regulatory mechanism that not only modulates gene transcription and signal transduction but also profoundly influences protein characteristics and functions.370 As a metabolic-epigenetic interface, lactylation provides novel insights into how cellular metabolism dynamically shapes epigenetic landscapes and broader biological processes.371,372 While Kla is not an inevitable consequence of lactate accumulation, the presence of lactate does not necessarily result in Kla. This is because Kla requires the participation of specific enzymes, whose activity is regulated by numerous factors. Furthermore, cellular metabolism is inherently complex, and the fate of accumulated lactate can be influenced by multiple variables, potentially diverting it away from Kla.373 It is also important to note that Kla exhibits a degree of reversibility, as eraser enzymes can remove Kla, thereby restoring the protein to its unmodified state. Exploring the functions and regulatory mechanisms of Kla offers novel insights into the pivotal role of lactate in various physiological and pathological processes in mammalian biology.To date, numerous studies have investigated the protein substrates, modification sites, molecular regulatory mechanisms, and biological functions of lactylation, demonstrating its significant potential in biomedical research and clinical applications. Moreover, thousands of lactylation sites on hundreds of proteins have been identified.8,374,375 Nevertheless, research on protein lactylation remains in its nascent stages, and its causal relationship with specific phenotypes remains elusive. Several critical questions warrant further investigation, such as whether lactylation occurs on residues beyond lysine. The key regulatory enzymes of lactylation require further exploration. What are the definitive writers, erasers, and readers governing lactylation dynamics, and how do they achieve substrate specificity? The complex network of interactions, competition, and collaboration between lactylation and other PTMs across temporal and spatial dimensions, as well as the detailed operational mechanisms involved, remains unclear. Additionally, establishing causal links between lactylation and phenotypes remains a critical challenge. The precise synergistic regulation of gene expression by lactylation and other PTMs across different cell types and biological states requires further exploration.With the advancement of multi-omics sequencing technologies, including proteomics, transcriptomics, and metabolomics, alongside genetic code extension and machine learning, the mapping of lactylation networks, including lactylated proteins, specific modification sites, and protein function in various physiologies and pathologies, is anticipated to be elucidated more comprehensively.120,376 By utilizing 4D labeling quantitative proteomics technology, multiple lactylated proteins with multitudinous modification sites have been gradually identified.250,285 Moreover, integrating spatial transcriptomics with mass spectrometry analysis is expected to uncover the spatiotemporal distribution patterns of lactylation with tissue- and subcellular-localized roles. Moreover, the combination of single-cell transcriptomics and mass spectrometry is projected to elucidate the functional variations of cell type-specific lactylation.350 Additionally, molecular studies on lactylation should concentrate on investigating its specific effects on protein structure and the precise molecular mechanisms through which these effects are mediated, which will contribute to clarifying the orchestration of lactylation on protein function and its subsequent biological significance.Comprehensive and detailed investigations aid in identifying novel biomarkers for early disease diagnosis, monitoring treatment responses, and prognosis. Furthermore, by pinpointing key lactylation proteins, sites, and regulatory enzymes, these studies contribute to the development of novel targeted intervention strategies for various diseases. Significantly, a major challenge currently lies in the selective targeting of lactylation without affecting other PTMs, as they are intricately linked and share a common set of regulatory enzymes, such as p300, HDACs, and Sirts, complicating the specific inhibition of lactylation.82,94,377 Consequently, further research and development of selective inhibitors are necessary to achieve specific targeted inhibition of lactylation without affecting other modifications.Considering that certain small glycolysis inhibitors, gene editing techniques, and epigenetic therapies have been demonstrated to effectively normalize aberrant lactate and lactylation levels, their clinical potential warrants further investigation across a range of diseases.27 Nevertheless, the feasibility, effectiveness, and safety of targeted Kla therapy in clinical practice are still unknown and need to be further validated through in-depth studies and clinical trials. It is imperative to acknowledge that, with the progressive exploration of lactylation, therapeutic strategies targeting lactylation may evolve from elucidating molecular mechanisms to achieving clinical application, ultimately transitioning from bench to bed.In conclusion, advancements in lactylation research provide innovative perspectives and research trajectories for exploring biological processes such as metabolic regulation, epigenetic reprogramming, and immunological remodeling. As a bridge connecting metabolism and epigenetics, lactylation provides new paradigms for investigating various diseases, such as cancer, AD, and sepsis, and holds great potential for novel diagnostic and treatment strategies for various diseases. Nonetheless, further comprehensive in-depth studies are imperative to prioritize mechanistic depth, technological innovation, and translational validation to harness the full diagnostic and therapeutic potential of lactylation.ReferencesZhang, D. et al. 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We appreciate Prof. X.Z. and L.C.J. for the revisions of the figures and tables in this manuscript.Author informationAuthor notesThese authors contributed equally: Yue Yang, Ying HeAuthors and AffiliationsDepartment of Pharmacology, School of Pharmacy, China Medical University, Shenyang, ChinaYue Yang, Ziyi Zhang, Yuehua Zhang, Rui Gao, Ke Du, Yuqiang Wu, Minjie Wei & Mingyan LiuDrug and Food Inspection and Testing Center, China Medical University, Shenyang, ChinaYue Yang, Yuqiang Wu & Minjie WeiThe First Department of Medical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, ChinaYing HeShenyang Key Laboratory of Chronic Disease Assessment and Nutritional Intervention for Heart and Brain, Shenyang Medical College, Shenyang, ChinaJi WuThe Second Affiliated Hospital of Shenyang Medical College, Shenyang, ChinaJi WuLiaoning Medical Diagnosis and Treatment Center, Shenyang, ChinaMinjie WeiAuthorsYue YangView author publicationsSearch author on:PubMed Google ScholarYing HeView author publicationsSearch author on:PubMed Google ScholarZiyi ZhangView author publicationsSearch author on:PubMed Google ScholarYuehua ZhangView author publicationsSearch author on:PubMed Google ScholarRui GaoView author publicationsSearch author on:PubMed Google ScholarKe DuView author publicationsSearch author on:PubMed Google ScholarYuqiang WuView author publicationsSearch author on:PubMed Google ScholarJi WuView author publicationsSearch author on:PubMed Google ScholarMinjie WeiView author publicationsSearch author on:PubMed Google ScholarMingyan LiuView author publicationsSearch author on:PubMed Google ScholarContributionsY.Y., Y.H. and M.Y.L. designed and wrote the manuscript. Z.Y.Z., Y.H.Z. and R.G. performed the literature search and organized the tables. K.D. and Y.Q.W revised the figures and tables. M.J.W. and J.W. revised the manuscript. All authors listed have made a substantial contribution to the work. All authors have read and approved the article.Corresponding authorsCorrespondence to Ji Wu, Minjie Wei or Mingyan Liu.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.Rights 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. 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