IntroductionHistone deacetylases (HDACs), also known as lysine deacetylases (KDACs), are key epigenetic regulators that, together with histone acetyltransferases (HATs), regulate the reversible acetylation of histone lysine residues.1 Dynamic modification of histone acetylation regulates chromatin structure and gene transcription by affecting the interaction between histones and DNA, thereby controlling gene expression and playing pivotal roles in numerous biological processes. Additionally, HDACs modulate the acetylation of non-histone proteins involved in vital cellular processes, thereby profoundly influencing their functions, including activity, stability, and localization.2 Thus, the modifying effects of HDACs on non-histone proteins indicate that their functions extend beyond epigenetic regulation. Notably, recent studies have revealed that HDACs are also involved in regulating other acylations, including several newly identified types, such as succinylation,3 butyrylation,4 crotonylation,5,6 2-hydroxyisobutyrylation,7 β-hydroxybutyrylation,8,9 and lactylation,10,11,12,13,14 which broaden the functional spectrum of HDACs. Furthermore, accumulating evidence suggests that HDAC modulators hold therapeutic potential for treating various diseases, highlighting the critical roles of HDACs. Recently, an increasing number of studies have shown that HDACs are involved in various physiological and pathological processes, including tumors and diseases of the cardiovascular, respiratory, digestive, nervous, endocrine, motor, and urogenital systems. Based on their catalytic mechanisms, HDACs are classified into two categories: zinc-dependent HDACs (classes I, II, and IV; HDAC1–11) and nicotinamide adenine dinucleotide (NAD+)-dependent HDACs (class III, SIRT1–7). Previous studies have discussed the roles of SIRTs in multiple diseases. However, a comprehensive review of zinc-dependent HDACs is currently lacking. In this review, we aim to summarize the roles and mechanisms of HDAC1-11 in health and disease, providing a comprehensive understanding of their functions and therapeutic potential.Overview of the HDAC familyIn 1969, the enzyme activity responsible for catalyzing the removal of acetyl groups from histones was first detected in an extract derived from calf thymus.15 Subsequently, numerous studies characterized the biochemical properties and mechanism of action of HDACs, leading to the discovery that they comprise multiple members. With advances in technology, research on HDACs has gained increasing attention. To date, 18 members have been identified in humans. According to their catalytic mechanisms, these enzymes are classified into two categories: zinc-dependent HDACs (HDAC1–11), which require Zn2+ for catalytic activity, and sirtuins (SIRT1–7), which depend on NAD+.16,17 Based on sequence similarities to their yeast orthologs, the 18 identified proteins are further grouped into four classes (I–IV), which share similar structures and functions.18,19,20 In this review, we specifically focus on zinc-dependent HDAC members (Classes I, II, and IV), which are also called classical HDACs. In the following text, all HDACs denote zinc-dependent HDACs.Class I HDACs include HDAC1, HDAC2, HDAC3, and HDAC8, which share sequence similarity with the yeast Rpd3 protein. In 1996, HDAC1 (initially named HD1) was successfully purified and cloned and was shown to possess histone deacetylase activity.21 Subsequently, HDAC2 (initially called mRPD3), which exhibits high homology with yeast Rpd3, was identified as a transcription regulator.22 HDAC3 was subsequently discovered by searching the GenBank database for DNA and protein sequences similar to those of HDAC1 and HDAC2.23 Similarly, HDAC8 was identified by searching GenBank for protein sequences homologous to HDAC1, HDAC2, and HDAC3.24 Class I HDACs, which exhibit high homology to one another, are predominantly localized in the nucleus and display strong enzymatic activity toward histone substrates. Notably, HDAC2, HDAC3, and HDAC8 have also been found in the cytoplasm, indicating that class I HDACs exert broader functional roles by modifying non-histone proteins. Class II HDACs are divided into two subgroups: class IIa (HDAC4, HDAC5, HDAC7, and HDAC9) and class IIb (HDAC6 and HDAC10). These members share sequence similarity with the yeast Hda1 protein. In 1999, HDAC4, HDAC5, and HDAC6 were simultaneously identified through a GenBank search for human HDACs homologous to the yeast Hda1 protein.25 HDAC7 was discovered in 2000, and HDAC9 was identified through a homology database search using the amino acid sequence of human HDAC4.26,27 Class IIa HDACs share 48%–57% sequence identity with one another.28 In 2002, HDAC10 was independently discovered by multiple research groups and shares 55% overall sequence identity with HDAC6.29 Considering that both HDAC6 and HDAC10 possess a unique putative second catalytic domain not present in other HDACs, they are subclassified as class IIb. The conserved deacetylase domains of Class II HDACs share 23%–81% amino acid sequence identity with one another and are predominantly localized in both the nucleus and cytoplasm.28 Additionally, HDAC11, also discovered in 2002, is the sole member of class IV HDACs, sharing sequence similarity in its catalytic core regions with both class I and II HDACs.18 Interestingly, HDAC11 has been identified as the most proficient defatty acylase in the HDAC family, suggesting its extensive functions and physiological implications, thereby warranting further investigation (Fig. 1) (Table 1).30Fig. 1Full size imageHistorical timeline of milestones in HDAC family members. HDAC activity was first identified in 1969. In 1996, HDAC1 became the first HDAC enzyme to be cloned and purified, followed by the discovery of HDAC2. HDAC3 was identified in 1997. In 1999, HDAC4, HDAC5, and HDAC6 were characterized as human homologs of yeast Hda1. In 2000, HDAC8—the last member of class I HDACs—was identified, along with HDAC7 and HDAC9 from class IIa. Finally, in 2002, HDAC10 and HDAC11 were discovered, completing the human HDAC family. The figure was created with BioRender under an academic license (https://www.biorender.com/)Table 1 Classifications, location, and functions of the HDACs familyFull size tableThe HDAC family can act by affecting the expression and functions of substrate proteins. These substrates include histones, which are indispensable components of chromosomes and form nucleosomes in association with DNA. Histone acetylation plays a vital role in regulating gene expression.31 The HDAC family removes acetyl groups from histone lysine residues, leading to a more compact chromatin structure that suppresses transcription. In addition to histones, HDACs regulate the acetylation of non-histone proteins, affecting their stability, enzymatic activity, subcellular localization, and interactions with other macromolecules.32 As mentioned above, HDACs are also involved in regulating various types of acylation beyond acetylation. In addition, HDACs can also exert non-enzymatic functions; for example, HDAC6 can promote NLRP3 inflammasome activation through its scaffolding function, independent of catalytic activity.33 Notably, increasing evidence indicates that HDACs play critical roles in diverse cellular processes, contributing to the maintenance of cellular homeostasis and the regulation of disease pathogenesis.The regulatory roles of HDACs in cellular biologyHDACs play pivotal roles in diverse cellular processes. In this section, we systematically review the roles of HDACs in key biological processes, including inflammation, metabolism, multiple forms of regulated cell deaths (RCDs)—such as apoptosis, autophagy, ferroptosis, necroptosis, NETosis, PANoptosis, and cuproptosis, as well as oxidative stress, cell proliferation, migration and invasion, and cell senescence. These processes interact closely and collectively regulate cellular processes. By modulating these pathways, HDACs are critically involved in both physiological and pathological conditions. A more comprehensive elucidation of how HDACs regulate these cellular responses will provide novel insight for understanding underlying molecular mechanisms and facilitate the development of targeted therapeutic strategies.The roles of HDACs in inflammationInflammation is a double-edged sword that plays a critical role in host defense and tissue repair, yet its dysregulation is implicated in the pathogenesis of various diseases. Current studies have revealed that HDACs play crucial roles in regulating inflammation, including the modulation of inflammatory mediators, immune cells, and key signaling pathways. In this section, we summarize the roles and underlying mechanisms of HDACs in inflammation. A schematic summary of HDAC-mediated regulation of inflammatory mediators, immune cells, and signaling pathways is presented in Fig. 2.Fig. 2Full size imageRoles of HDACs in inflammation. a HDACs in inflammatory mediators and the NF-κB pathway. In inflammatory pathways, HDACs primarily activate the NF-κB and NLRP3/IL-1β axes, promoting the release of pro-inflammatory cytokines such as TNF-α. Additionally, HDACs suppress the expression of the anti-inflammatory cytokine IL-10. b HDACs exert dual effects on the MAPK pathway in different cell types. c HDACs exert isoform-specific effects on innate immune responses by modulating macrophage phagocytosis, bactericidal activity, and polarization, as well as dendritic cell (DC) maturation. The figure was created with BioRender under an academic license (https://www.biorender.com/)The roles of HDACs in inflammatory mediatorsThe inflammatory response involves a cascade of interactions between pro-inflammatory and anti-inflammatory mediators. Here, we discuss the roles of HDACs in regulating inflammatory mediators, especially the pro-inflammatory cytokine TNF-α and the anti-inflammatory cytokine IL-10.The regulation of TNF-α by HDACs is bidirectional and varies with cell type, resulting in either anti-inflammatory or pro-inflammatory effects. First, HDACs increase histone deacetylation, thereby inhibiting the binding of transcription factors such as NF-κB to the TNF-α promoter, which suppresses its transcription and exerts anti-inflammatory effects.34 For instance, in LPS-induced macrophages, HDAC1 is recruited to the TNF-α promoter by Bcl-3/p50 complexes, thereby suppressing its transcription and reducing inflammatory factor release.35 In contrast, increased reactive oxygen species (ROS) activate HDAC3 by c-Src, promoting its nuclear translocation. Thus, HDAC3 enhances TNF-α transcription and exacerbates LPS-induced inflammation in cardiomyocytes.36 Furthermore, the HDAC inhibitor KBH-A42 (see Table 3 and Fig. 17) reduces TNF-α in macrophages by inhibiting AP-1 binding to DNA.37HDACs also regulate IL-10, a key anti-inflammatory cytokine that modulates immune responses and suppresses inflammation. Inhibition of HDAC3 restores IL-10 expression by recruiting acetylated histone H3 to the IL-10 promoter, thereby exerting an anti-inflammatory effect.38 Additionally, overexpression of HDAC11 suppresses IL-10 production, promoting activation of inflammatory antigen-presenting cells that stimulate naïve T cells and impair tolerance of CD4+ T cells.39In summary, different HDACs exhibit distinct functions and, in some cases, exert opposing effects on inflammatory mediators. Recent studies have primarily focused on class I HDACs, whereas research on class II HDACs remains limited. Consequently, this area of HDAC-mediated regulation of inflammatory mediators remains largely underexplored and requires more in-depth investigation.The roles of HDACs in immune cellsThe regulation of immune cells is essential for controlling the inflammatory response. Numerous studies have shown that HDACs are involved in regulating the function of macrophages and dendritic cells (DCs).HDACs can regulate the phagocytosis and bactericidal functions of macrophages. Inhibition of HDACs by trichostatin A (TSA; see Table 3 and Fig. 17) and valproic acid (VPA; see Table 3 and Fig. 17) has been shown to reduce the expression of phagocytic receptors (Msr1, CD11c, CD14), NADPH oxidase, and inducible nitric oxide synthase (iNOS), thereby impairing macrophage phagocytosis and antimicrobial activity through decreased ROS and NO production.40 Additionally, pretreatment with HDAC inhibitors, either TSA or vorinostat (suberoylanilide hydroxamic acid, [SAHA]; see Table 3 and Fig. 17), before infection has been shown to reduce macrophage bactericidal function, whereas selective HDAC6 inhibition by tubastatin A (see Table 3 and Fig. 17) enhances phagocytosis and bacterial clearance by increasing mitochondrial ROS during infection, indicating that various HDAC isoforms exert different effects on the phagocytosis and bactericidal function of macrophages.41Additionally, HDACs play dual roles in macrophage polarization by regulating gene expression and signaling pathways, depending on the specific isoform and cellular context. For instance, in acute pancreatitis, the gut microbiota-derived metabolite norharman has been found to suppress HDAC activity, enhance H3K9/14 acetylation, and upregulate Raftlin 1 (Rftn1) expression, thereby inhibiting M1 macrophage activation and alleviating inflammation.42 Conversely, HDAC1 can deacetylate the TIR domain of TLR4, thereby inhibiting excessive activation of the TLR4/MAL/MyD88/NF-κB signaling axis and suppressing M1 polarization of macrophages.43 In addition, the HDAC10-signal transducer and activator of transcription 3 (STAT3) interaction has been shown to promote M2 polarization, thereby enhancing airway inflammation.44 Similarly, in tumor cells, inhibition of HDAC2 has been shown to suppress M2 polarization, promote M1 polarization, and enhance antitumor immunity.45In addition to macrophages, HDACs also modulate the maturation and functions of DCs. In a murine psoriasis-like inflammation model, elevated expression of HDAC1 was associated with increased levels of dendritic cell maturation markers, including CD80, CD83, and CD86.46 Additionally, in cutaneous inflammation, deletion of HDAC8 and HDAC9 has been shown to increase H3K9 and H3K27 acetylation at the MAP2K3 promoter, thereby elevating IFN-β secretion from keratinocytes. This activation stimulates DCs (CD86⁺) and promotes CD4⁺ and CD8⁺ T cell proliferation.47Overall, HDACs critically regulate immune cell functions, including macrophage phagocytosis, polarization, and dendritic cell activation. Different HDAC isoforms may exert distinct effects; therefore, investigating the function of specific HDAC members is of great significance.The roles of HDACs in inflammation-related signaling pathwaysThe regulation of inflammatory genes is governed by several intricate signaling pathways, including the NF-κB, NLR family pyrin domain-containing 3 (NLRP3) and mitogen-activated protein kinase (MAPK) pathways. Recent studies have increasingly shown that HDACs play a crucial role in modulating inflammation by modulating these pathways.HDACs are widely involved in the NF-κB signaling pathway that regulates inflammationThe NF-κB signaling pathway is widely regarded as the prototypical signaling pathway. Recent studies have increasingly highlighted the involvement of HDACs in regulating the NF-κB pathway through both direct and indirect mechanisms.HDACs can directly regulate the NF-κB pathway by deacetylating its subunits. For example, HDAC3 promotes the production of pro-inflammatory and profibrotic cytokines in macrophages by deacetylating NF-κB P65 at K122, thereby aggravating inflammation in chronic kidney disease.48 Additionally, HDACs can indirectly regulate the NF-κB pathway by modulating the acetylation of proteins involved in NF-κB signaling. For instance, HDAC3 inhibits the expression of Cathepsin B by deacetylating histones, thereby activating the RIP1/NF-κB pathway.49 Inhibition of HDAC3 modulates microglia polarization by STAT1-mediated acetylation within the NF-κB pathway, thereby attenuating the inflammatory response.50 In addition, inhibition of HDAC7 attenuates LPS-induced NF-κB activation and the subsequent inflammatory response in astrocytes by decreasing IKK deacetylation.51 Moreover, in normal hepatocytes, HDAC1 binds to RACK1 and suppresses histone H3K9 and H3K27 acetylation at the promoters of CXCL1 and S100A9, thereby reducing MDSC accumulation and ultimately attenuating MDSC-mediated NF-κB pathway activation.52Collectively, these findings highlight that HDACs serve as both activators and suppressors of NF-κB signaling, depending on subtype, context, and cellular environment. Their ability to maintain histone acetylation homeostasis and modulate pro- and anti-inflammatory signaling pathways underscores their therapeutic potential in treating inflammation-associated diseases.Other pathways involved in the HDAC-mediated inflammatory responseIn addition to regulating the NF-κB pathway, HDACs also modulate the inflammatory response by targeting the NLRP3 inflammasome and the MAPK pathway.HDAC2, HDAC6, HDAC9, and HDAC11 have been shown to promote NLRP3 inflammasome signaling. Specific inhibition of HDAC2 and HDAC6 effectively reduces NLRP3-mediated IL-1β release, thereby attenuating the inflammatory response.53,54 Recent studies have revealed that lysosomes activate the NLRP3 inflammasome via the Lamtor1 complex. In models of sepsis, HDAC6 enhances this interaction, thereby promoting inflammasome activation in sepsis, peritonitis, and gout.55 Additionally, HDAC9 has been found to promote inflammasome activation and lytic cell death by mediating the deacetylation of NLRP3 within the NACHT and LRR domains during vascular inflammation.56 Moreover, HDAC10 directly binds to NLRP3 and induces deacetylation at lysine (K) 496, thereby promoting NLRP3 ubiquitination and degradation, which alleviates the inflammatory response.57 Notably, HDAC11 expression is significantly increased in peripheral blood cells and THP-1 cells treated with palmitic acid (PA), which promotes the interaction between Yes-associated protein (YAP) and the NLRP3 inflammasome, ultimately enhancing the NLRP3-associated inflammatory response. Conversely, knockdown of HDAC11 effectively attenuates NLRP3 signaling.58MAPK, a member of the large family of serine-threonine kinases, represents a crucial signaling pathway involved in regulating the inflammatory response and has been extensively studied. To date, over 20 MAPK isoforms have been identified, including p38 MAP kinase, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK).59 Selective inhibition of HDAC6 suppresses ROS-MAPK-NF-κB signaling and activates the Nrf2/HO-1 pathway, thereby reducing inflammation in macrophages, whereas HDAC6 overexpression promotes MAPK activation, including ERK, JNK, and p38.60 Moreover, combined treatment with curcumin and the HDAC8 inhibitor PCI-34051 (see Table 3 and Fig. 17) downregulates phosphorylated p38 (p-p38), p-ERK, and p-JNK, alleviating airway inflammation, fibrosis, and remodeling in asthma models.61 Conversely, HDAC inhibition can also activate the MAPK pathway. HDAC inhibition by TSA activates p38 MAPK, promoting the proliferation and function of B10 cells, regulatory B cells that maintain immune balance through IL-10 production.62Collectively, recent studies have revealed that multiple HDACs play vital roles in regulating inflammation by regulating various inflammatory mediators, cells, and pathways. Notably, the roles of HDACs in inflammation are multifaceted, as they can either promote or suppress inflammation through diverse mechanisms. Furthermore, a single HDAC member can exert distinct or even opposing effects under different inflammatory conditions, possibly due to variations in its target protein and signaling pathways. Therefore, elucidating the roles and mechanisms of individual HDAC members under various inflammatory conditions is of great significance, as it may advance our understanding of inflammation pathogenesis and facilitate the development of novel therapeutics for precise modulation of inflammatory responses, such as selectively targeting specific subsets of immune cells through HDACs.The roles of HDACs in metabolismMetabolism refers to all reactions that occur within the cells of a living organism to sustain life.63,64 It is vital for growth, reproduction, structural maintenance, and adaptation to environmental changes. However, dysregulated metabolism contributes to various diseases. These processes are complex and regulated by diverse signaling pathways and proteins. Current studies have demonstrated the involvement of HDACs in metabolic regulation. In this section, we summarize the roles of HDACs in maintaining metabolic homeostasis, with a particular focus on their involvement in glucose and lipid metabolism. The roles and underlying mechanisms of HDACs in glucose, lipid, amino acid, and purine metabolism are presented in Fig. 3.Fig. 3Full size imageRoles of HDACs in metabolism. HDACs play pivotal roles in glucose, lipid, and other metabolisms by affecting key enzymes and genes. In glucose metabolism, HDACs can regulate glucose transport, anaerobic and aerobic glucose oxidation, the pentose phosphate pathway (PPP), gluconeogenesis, and glycogen metabolism. HDAC2, HDAC4, and HDAC5 repress the transcription and expression of glucose transporters (GLUTs). HDAC1, HDAC2, HDAC6, HDAC8, and HDAC11 participate in glycolysis by regulating the transcription and expression of glycolytic genes such as hexokinase-1 (HK1), pyruvate kinase M2 (PKM2), and the AMPK pathway. HDAC1 and HDAC7 suppress the tricarboxylic acid (TCA) cycle. In the PPP, HDAC4 reduces the enzymatic activity of 6GPD, while HDAC10 enhances G6PD transcription. Additionally, HDAC3, HDAC5, and HDAC7 are implicated in gluconeogenesis. In glycogen metabolism, HDAC2 and HDAC5 suppress insulin-stimulated glycogen synthesis, whereas TSA treatment improves this process. In lipid metabolism, HDAC1 represses CPT-1A expression and, together with HDAC3 and HDAC11, participates in FA oxidation (FAO). HDAC1, HDAC2, and HDAC6 inhibit lipogenesis, while HDAC3 exhibits dual roles. HDAC1, HDAC2, HDAC3, and HDAC9 are involved in various processes of cholesterol metabolism, including synthesis, accumulation, and efflux. HDAC5 has been reported to inhibit phospholipid-derived arachidonic acid production. Additionally, HDACs, particularly HDAC3, are implicated in amino acid and purine metabolism. The figure was created with BioRender under an academic license (https://www.biorender.com/)The effects of HDACs on glucose metabolismGlucose metabolism involves complex processes such as transport, anaerobic and aerobic oxidation, the pentose phosphate pathway (PPP), glycogen synthesis, and gluconeogenesis. Increasing evidence indicates that HDACs play pivotal roles in regulating these key steps.HDACs play crucial roles in glucose transport by affecting glucose transporters (GLUTs), which serve as gateways for cellular glucose uptake. Currently, several studies have identified class II HDACs as negative transcriptional regulators of GLUTs.65,66,67,68,69 For instance, HDAC4 represses GLUT1 expression and impairs glucose metabolism by inhibiting histone acetylation. Upon exercise, HDAC4 is phosphorylated by AMPK and exported from the nucleus, leading to increased H3K9 acetylation at the GLUT1 promoter, thereby enhancing GLUT1 transcription and improving glucose metabolism.65 Additionally, Weems et al.66 reported that HDAC4 and HDAC5 suppress GLUT4 transcription in response to elevated cAMP signaling in cultured adipocytes and fasting mice. Beyond class II HDACs, class I HDACs also regulate GLUT expression. HDAC2 knockdown was found to repress GLUT3 through miR-3189 in glioblastoma indirectly.70Moreover, HDACs are essential regulators of both anaerobic and aerobic glucose oxidation. HDAC1, HDAC2, HDAC6, HDAC8, and HDAC11 have been implicated in glycolysis, the common initial step of aerobic and anaerobic glucose oxidation, by modulating protein acetylation and the expression of glycolytic genes. For instance, HDAC2 was found to reduce K418 2-hydroxyisobutyrylation (Khib) of hexokinase-1 (HK1), thereby impairing its binding to glucose and leading to decreased production of glucose-6-phosphate and ATP.71 Additionally, HDAC8 could suppress the activity of pyruvate kinase M2 (PKM2), a key enzyme in glycolysis, by deacetylating it at K62, thereby reprogramming glucose metabolism in hepatocellular carcinoma (HCC).72 In addition, HDAC1 was shown to inhibit the transcription of the glycolytic regulators Pgam1, Pkm, and Pgk1 by decreasing H4 acetylation at their promoters in lung cancer.73 Additionally, loss of HDAC11 impaired glycolysis in HCC by enhancing LKB1 transcription through increased histone acetylation at its promoter region.74 For HDAC6, Dowling et al.75 demonstrated that HDAC6 inhibition could reduce glycolytic metabolism in triple-negative breast cancer. In addition to glycolysis, HDACs participate in the aerobic oxidation of glucose, including the tricarboxylic acid (TCA) cycle. For instance, HDAC7 suppresses the expression of TCA cycle-related genes by acting as a corepressor in renal cancer.76 In addition, HDAC1 was found to disrupt the TCA cycle by regulating Nur77 deacetylation in macrophages following hypoxia and regeneration.77 These findings suggest that HDAC-targeted therapies may represent a novel strategy for restoring TCA cycle function.HDACs also participate in regulating the PPP by modulating the expression or activity of 6-phosphogluconate dehydrogenase (6PGD) and glucose-6-phosphate dehydrogenase (G6PD), key PPP enzymes. For instance, HDAC4 deacetylates 6GPD at K76 and K294, thereby reducing its enzymatic activity.78 In contrast, the translocation of HDAC10 from the nucleus to the cytoplasm, mediated by tumor suppressor liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling, has been shown to enhance G6PD transcription.79HDACs are involved in glycogen metabolism. For instance, knockdown of HDAC2 and HDAC5 has been shown to enhance insulin-stimulated glycogen synthesis in muscle cells.80,81 Moreover, HDAC2 knockdown as well as TSA treatment improved insulin-stimulated glycogen synthesis.81Additionally, emerging studies have shown that HDACs, particularly class I and II members, play a crucial role in gluconeogenesis. For instance, Mihaylova et al.82 found that in the liver, class IIa HDACs (HDAC4, HDAC5, and HDAC7) are phosphorylated and excluded from the nucleus by AMPK family kinases. However, in response to glucagon, they undergo dephosphorylation and translocate back to the nucleus, where they recruit HDAC3 to promote the transcription of gluconeogenic enzymes such as glucose-6-phosphatase (G6Pase), partly by deacetylating and activating FOXO transcription factors. HDAC5 has been shown to promote hepatic gluconeogenesis through its interaction with the circadian factor BMAL1, which enhances FOXO1 activation.83 In contrast, AMPK-mediated phosphorylation and inactivation of HDAC5 were found to suppress hepatic gluconeogenesis by downregulating gluconeogenic gene expression.84 Moreover, Pan et al.85 demonstrated that HDAC7 activation in diabetes enhances FOXO1 transcriptional activity by suppressing its acetylation, thereby promoting hepatic gluconeogenesis. Hepatic HDAC3 has also been shown to promote gluconeogenesis by repressing lipid synthesis and sequestration.86The effects of HDACs on lipid metabolismLipid metabolism encompasses the synthesis, degradation, storage, and utilization of lipids, which are essential for energy homeostasis and cellular function. An increasing body of evidence shows that HDACs regulate the metabolism of various lipids, including triglycerides, cholesterol, and phospholipids.Triglyceride metabolism is essential for energy storage, thermoregulation, and hormone production. Increasing evidence indicates that HDAC members play vital roles in triglyceride breakdown, primarily by modulating key processes such as fatty acid (FA) transport into mitochondria and FA oxidation (FAO, β oxidation). For instance, HDAC1 can suppress CPT-1A gene expression by inducing H3K9 deacetylation at its promoter, thereby mediating ethanol-induced hepatic steatosis.87 CPT-1A is a rate-limiting enzyme in FA metabolism that controls the transport of FA into mitochondria for oxidation. Concerning FAO, HDAC1, HDAC3, and HDAC11 have been identified as key regulators of this process. For example, Zhang et al.88 demonstrated that reduced HDAC1 expression and increased H3K9ac promote FAO in the liver. Moreover, HDAC3, activated by the nuclear receptor corepressor (NCOR1), was found to regulate circadian metabolic gene expression essential for NCOR1-mediated metabolic function.89 In addition, decreased NCOR1 and HDAC3 levels in long-lived endocrine-mutant mice upregulate genes involved in oxidative phosphorylation and β-oxidation, including CPT2, ACADM, ECHS1, ACAA2, and HADH.90 HDAC11, the only HDAC with long-chain FA deacylase activity, has been identified as a novel regulator of FAO in skeletal muscle. It was localized in muscle mitochondria, and its depletion enhanced β-oxidation by activating the AMPK/acetyl-CoA carboxylase pathway.91 Moreover, HDAC11 knockout (KO) mice have shown elevated CPT1 activity and plasma adiponectin levels, further supporting the role of HDAC11 as a novel metabolic regulator.92HDAC1, HDAC2, HDAC3, and HDAC6 have been shown to regulate lipogenesis, the metabolic pathway responsible for triglyceride synthesis. Among these HDACs, HDAC1, HDAC2, and HDAC6 have been found to suppress lipogenesis. For instance, HDAC1 and HDAC2 contribute to Snail1-mediated suppression of lipogenesis by promoting H3K9 and H3K27 deacetylation.93 In addition, HDAC6 inhibition could activate lipogenesis in hepatocytes by increasing FOXO1 acetylation, thereby promoting lipid accumulation.94 However, HDAC3 has been shown to exert opposite effects depending on the tumor type. For example, in prostate cancer, HDAC3 is required for HOXB13-mediated suppression of de novo lipogenesis.95 In contrast, Lin et al. revealed that HDAC3 enhances de novo FA synthesis by mediating the deacetylation of FA synthase in HEK293T, HCT116, and ZR-75-30 tumor cell lines.96HDACs also regulate the metabolism of other lipids, including cholesterol, phospholipids, and sphingolipids. For example, HDAC3 can suppress cholesterol synthesis by repressing the expression of the lanosterol synthase gene.97 In addition, inhibition of HDAC1 and HDAC2 was found to significantly reduce cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts.98 Moreover, HDAC3 and HDAC9 were found to repress cholesterol efflux in T cells and macrophages, respectively.99,100,101 For example, HDAC9 deficiency in macrophages promotes cholesterol efflux by increasing the expression of ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) through the accumulation of acetylated H3 and H4 at their promoters.101 Additionally, HDACs participate in phospholipid and sphingolipid metabolism.102,103,104 For instance, HDAC5 deficiency enhanced phospholipid-derived arachidonic acid generation in pancreatic cancer by reducing GATA1 deacetylation, thereby relieving the repression of calcium-dependent phospholipase A2 (cPLA2).102The effects of HDACs on amino acid and purine metabolismHDAC3 promotes glutamine synthetase (GS) stabilization under glutamine starvation by mediating its deacetylation, thereby enhancing GS expression in liver cancer cells.105 Additionally, HDAC inhibitors, alone or in combination with sildenafil, significantly suppress purine metabolism by modulating PKM activity in pulmonary hypertension, highlighting the regulatory role of HDACs in purine metabolism.106In conclusion, HDACs play critical roles in metabolic regulation, particularly in glucose and lipid metabolism, by modulating key targets either by regulating the expression of associated genes or altering the acetylation levels of relevant proteins. Notably, their effects are often context dependent, varying across tissues and cell types, and the detailed mechanisms remain worthy of further investigation. Moreover, the regulation of many key metabolic proteins by HDACs remains poorly understood. Given the broad regulatory functions of HDACs, further elucidation of their roles in metabolic processes may provide valuable insights for the development of therapies targeting metabolic disorders.The roles of HDACs in regulated cell deathRCD refers to cell death resulting from the activation of one or more specific signal transduction pathways and can be pharmacologically or genetically modulated.107 Increasing evidence indicates that HDACs are critically involved in various RCDs, such as apoptosis, autophagy, ferroptosis, necroptosis, NETosis, PANoptosis, and cuproptosis. In this section, we summarize the roles and underlying mechanisms of HDACs in these RCDs, providing novel insights into their regulatory mechanisms underlying these cell death processes and potential therapeutic implications.The roles of HDACs in apoptosisApoptosis, a classical form of programmed cell death, is mediated by both intrinsic and extrinsic signals and is essential for development and organism homeostasis.108 Dysregulation of apoptosis, however, contributes to various diseases. Increasing evidence indicates that HDACs play critical roles in apoptosis by modulating the acetylation of apoptosis-related proteins and by influencing key signaling pathways. This section summarizes the functions and underlying mechanisms of HDACs in apoptosis, providing novel insights into the regulation of this fundamental process. The roles and underlying mechanisms of HDACs in apoptosis by regulating apoptosis-associated proteins are presented in (Fig. 4).Fig. 4Full size imageRoles of HDACs in apoptosis. HDACs play pivotal roles in regulating apoptosis, predominantly exerting anti-apoptotic effects. Class I HDACs, including HDAC1, HDAC2, HDAC3, and HDAC8, participate in apoptosis through their regulation of p53, a critical tumor suppressor that promotes apoptosis. These HDACs regulate p53 activity by regulating its acetylation, thereby influencing its transcriptional and apoptotic functions. Additionally, PTMs such as phosphorylation and SUMOylation can impact their enzymatic activity and, consequently, their effect on p53-mediated apoptosis. HDAC6 and HDAC5 also regulate apoptosis by modulating p53 acetylation. HDAC6 suppresses p53-mediated apoptosis by differentially regulating wild type and mutant p53. Additionally, HDAC6 inhibits p53 transcriptional activity through a runt-related transcription factor 2 (RUNX2)-dependent mechanism. Nuclear export of HDAC5 is accompanied by increased acetylation of p53 at the K120 residue, leading to the onset of p53-dependent apoptosis. Beyond p53, HDACs modulate apoptosis by affecting multiple transcription factors, such as FOXO, NF-κB, and MEF2. The interaction of HDAC2-FOXO3a can inhibit p21 expression by regulating histone acetylation. HDAC inhibitors such as trichostatin A and NaB induce apoptosis by suppressing NF-κB activity. However, HDAC9 promotes apoptosis by inhibiting MEF2. The figure was created with BioRender under an academic license (https://www.biorender.com/)Roles of HDACs in apoptosis by targeting p53The p53 protein, often referred to as a tumor suppressor protein, can promote apoptosis through both transcription-dependent and transcription-independent mechanisms. Recent studies have highlighted that HDACs significantly regulate apoptosis by modulating p53.Class I HDAC members—HDAC1, HDAC2, HDAC3, and HDAC8—have all been found to participate in apoptosis by regulating p53. For instance, HDAC1 inhibition caused by dephosphorylation at S421/423 can lead to p53 acetylation and activation in human primary aortic endothelial cells, suggesting that HDAC1 inhibition and subsequent p53 activation contribute to apoptosis.109 Additionally, Juan et al.110 showed that the deacetylation of p53 by HDAC1, HDAC2, and HDAC3 contributes to the regulation of p53 function. They revealed that p53 interacts with HDAC1 both in vitro and in vivo and that HDAC1 coexpression reduces p53 acetylation levels. Moreover, these HDACs suppress p53-mediated activation of the pro-apoptotic BAX promoter. In addition, deletion of HDAC1 and HDAC2 significantly increases apoptosis in activated GLI2-driven pre-basal cell carcinoma, which is partially rescued by p53 or p16 knockout.111 Moreover, Kanda et al.112 reported that HDAC1 negatively regulates apoptosis, at least in part, by inhibiting p53 expression during intestinal tumorigenesis. HDAC2 has been shown to suppress apoptosis by inhibiting p53 transcriptional activity through modulation of p53-DNA binding activity.113 Additionally, Brandl et al. revealed that sumoylation of HDAC2 at K462 facilitates its binding to p53, which subsequently mediates deacetylation of p53 at K320, ultimately suppressing apoptosis by blocking recruitment of p53 to promoter-associated complexes and inhibiting p53-dependent gene expression.114 PINK1-mediated phosphorylation of HDAC3 has been reported to suppress apoptosis by inducing hypoacetylation of p53 in experimental intestinal ischemia/reperfusion injury.115 Hua et al.116 revealed that HDAC8-deficient long-term hematopoietic stem cells display hyperactivation of p53 and increased apoptosis. Mechanistically, HDAC8 interacts with the p53 protein, modulating p53 activity through deacetylation. Inhibition of HDAC8 has been shown to induce apoptosis in human inv(16) + AML stem and progenitor cells by restoring p53 acetylation and activity.117HDAC6 plays a vital role in apoptosis by regulating the protein level and function of p53. For instance, Ryu et al.118 reported that HDAC6 inhibition promotes p53-mediated apoptosis by differentially regulating wild-type and mutant p53. The HDAC6-selective inhibitor A452 (see Table 3 and Fig. 17) increased wild-type p53 levels by destabilizing murine double minute-2 (MDM2) while reducing mutant p53 by inducing MDM2 expression and disrupting the Hsp90-mutant p53 complex. HDAC6 was also found to bind the C-terminal region of p53 and regulate its acetylation at K381/382, suggesting that HDAC6 modulates p53 function through both expression and acetylation. HDAC6 mediates runt-related transcription factor 2 (RUNX2)-dependent suppression of p53 transcriptional activity under DNA damage, and inhibition of HDAC6 by tubacin enhances ADR-induced p53 target gene expression.119HDAC5 participates in apoptosis by targeting p53. Sen et al.120 found that under prolonged genotoxic stress, HDAC5 undergoes nuclear export accompanied by increased acetylation of p53 at the K120 residue, leading to p53-dependent apoptosis.Roles of HDACs in apoptosis by targeting multiple transcription factorsHDACs also regulate apoptosis by influencing the function of multiple transcription factors involved in apoptosis, such as the FOXO family, NF-κB, and myocyte enhancer factor 2 (MEF2).FOXO transcription factors play crucial roles in apoptosis, and current studies have shown that HDACs regulate apoptosis by regulating the expression and activity of FOXO3a and FOXO1. For instance, Peng et al.121 found that oxidative stress reduces the HDAC2-FOXO3a interaction, increasing H4K16 acetylation at the p21 promoter, upregulating p21, and protecting neurons from apoptosis. Furthermore, they found that phosphorylation of HDAC2 at S394 by casein kinase 2 enhances the HDAC2-FOXO3 interaction, thus suppressing p21. Additionally, romidepsin (FK228, [Depsipeptide]; see Table 3 and Fig. 17), a novel HDAC inhibitor, induces apoptosis in lung cancer cells by acetylating FOXO1 and activating Bim.122 HDACs may also regulate apoptosis by affecting NF-κB and MEF2. For instance, Shu et al.123 found that HDAC inhibitors (trichostatin A and NaB) suppressed NF-κB activity by upregulating Zac1 transcription through enhanced chromatin acetylation at its promoter. Zac1 inhibits NF-κB by interacting with the C-terminus of the p65 subunit and reducing its phosphorylation at S468 and S536. Neuronal-specific deletion of HDAC9 reduces neuronal apoptosis in ischemic stroke injury by relieving HDAC9-mediated repression of MEF2, enhancing cGK II expression, and protecting neurons.124Collectively, various HDACs play pivotal roles in regulating apoptosis, generally exerting inhibitory effects. The underlying mechanisms are complex and involve the regulation of key apoptotic proteins and transcription factors. However, current studies mainly focus on the effects of HDAC inhibitors on apoptosis, whereas the distinct roles and mechanisms of individual HDACs remain largely unclarified. Furthermore, the target proteins through which HDACs regulate apoptosis are yet to be fully elucidated. Further studies are warranted to explore the distinct roles of HDACs in apoptosis under both physiological and pathological contexts, thereby providing a basis for advancing understanding and developing potential therapeutic strategies for apoptosis-associated diseases, such as tumors.The roles of HDACs in autophagyAutophagy is an intricately regulated process that degrades dysfunctional organelles and protein aggregates via lysosomal pathways, playing a critical role in cellular homeostasis.125 Impaired autophagy contributes to the pathogenesis of various human diseases. Recent studies have identified HDACs as key modulators of autophagy. In this section, we mainly focus on the roles and underlying mechanisms of the most studied members, HDAC1, HDAC4, and HDAC6, in the regulation of autophagy, aiming to provide novel insights into autophagy-targeted therapeutic strategies. An overview of the regulatory functions of HDACs, particularly HDAC6, HDAC1, and HDAC4, is presented in Fig. 5.Fig. 5Full size imageRoles of HDACs in autophagy. HDACs, particularly HDAC6, HDAC1, and HDAC4, play crucial roles in autophagy. a Roles of HDAC6 in autophagy. HDAC6 participates in autophagy by modulating the acetylation and expression of autophagy-related proteins, including cytoskeletal components (tubulin and cortactin) and autophagy-regulating proteins, as well as through non-deacetylase-dependent mechanisms. b Roles of HDAC1 in autophagy. HDAC1 exerts dual roles in autophagy, which can either promote or suppress autophagy depending on diverse conditions. c Roles of HDAC4 in autophagy. HDAC4 acts as a dual regulator of autophagy by influencing the transcription or activity of autophagy-associated proteins. d Roles of other HDACs in autophagy. HDAC2, HDAC8, HDAC9, and HDAC10 are also involved in regulating autophagy by various mechanisms. The figure was created with BioRender under an academic license (https://www.biorender.com/)The role of HDAC6 in autophagyHDAC6 is the most studied HDAC in autophagy, functioning through both deacetylation and non-enzymatic adaptor mechanisms.Regarding its deacetylation function, HDAC6 modulates the acetylation and expression of autophagy-related proteins, including cytoskeletal components and autophagy-regulating proteins. The cytoskeleton, comprising microtubules, microfilaments, and intermediate filaments, is essential for autophagosome formation, trafficking, and fusion. HDAC6 can mediate the deacetylation of tubulin, a major microtubule component, affecting microtubule dynamics and autophagy progression.126,127 For example, McLendon et al.128 demonstrated that HDAC6 inhibition promoted autophagy by tubulin hyperacetylation in cardiac proteotoxicity models. Similarly, in silicate-exposed mesenchymal stem cells, HDAC6 activation led to microtubule depolymerization and autophagic flux impairment through α-tubulin deacetylation.129 In addition to microtubules, HDAC6 also targets cortactin, an actin-binding protein involved in cytoskeletal remodeling, thereby contributing to the regulation of autophagy. For instance, HDAC6-mediated cortactin deacetylation, facilitated by ATP13A2 recruitment to lysosomes, enhanced actin polymerization and autophagosome-lysosome fusion.130 Similarly, HDAC6 inhibition has been found to increase cortactin acetylation, which disrupts cortactin and F-actin recruitment to lysosomes and impairs autophagosome-lysosome fusion.131 Additionally, HDAC6 can regulate the acetylation and expression of key regulators involved in autophagy. For instance, Zhang et al.94 revealed that the HDAC6-S100A11 interaction could prevent HDAC6-FOXO1 binding, leading to increased FOXO1 acetylation and autophagy activation. Additionally, HDAC6 inhibition by tubastatin A enhanced TFEB acetylation, promoting its nuclear translocation and upregulating the expression of Beclin 1, thereby promoting autophagy in a chronic kidney disease model.132HDAC6 also regulates autophagy through non-deacetylase mechanisms. Notably, HDAC6 links the ubiquitin–proteasome system (UPS) and autophagy by binding ubiquitinated misfolded proteins via its ubiquitin-binding zinc finger domain.133 HDAC6 also interacts with p62134, a scaffolding protein that mediates the delivery of protein aggregates and damaged organelles to autophagosomes.135 For instance, Kawaguchi et al.136 discovered that HDAC6 is a core component of aggresomes, binding polyubiquitinated proteins and dynein motors to mediate their transport to the microtubule-organizing center (MTOC) for autophagic degradation. Additionally, Pandey et al.137 revealed that HDAC6 is essential for linking autophagy and the UPS, rescuing degeneration in Drosophila models with impaired proteasome function. Additionally, HDAC6 participates in mitophagy by promoting mito-aggresome formation and mitophagosome-lysosome fusion.138The effect of HDAC1 on autophagyRecent studies have revealed dual roles of HDAC1 in autophagy regulation. On the one hand, HDAC1 acts as an autophagy suppressor.139,140,141 For instance, inhibiting HDAC1 and HDAC2 with hydroxytyrosol and valproic acid activates autophagy in stress-induced liver injury139 and gastric cancer140, respectively. Additionally, in high glucose-stimulated rat Schwann cells, HDAC1 inhibition enhanced the ratio of LC3-II/LC3-I, an effect reversed by Atg3 downregulation, suggesting Atg3 as a potential target of HDAC1.141 In addition, inhibition of the HDAC1-Sin3a complex and the transcription repressor protein ZBTB25 induces autophagy in Mycobacterium tuberculosis-infected macrophages by regulating IL-12B expression.142 Conversely, HDAC1 can promote autophagy. Moresi et al.143 reported that HDAC1 promotes autophagic flux by inducing autophagic gene expression and autophagosome formation in skeletal muscle. Furthermore, the interaction between HDAC1 and nuclear receptor corepressor 1 mediates the beneficial effects of TLR4 ablation by promoting autophagy, thereby attenuating aging-induced myocardial remodeling and contractile dysfunction.144 Intriguingly, dephosphorylation of HDAC1 by cholesterol derivatives results in its nuclear export, subsequently promoting autophagy.145 However, research on the effects of other post-translational modifications (PTMs) on HDAC1’s role in autophagy remains limited.The effect of HDAC4 on autophagyMost studies suggest that HDAC4 acts as a negative regulator of autophagy, although some report a promoting role. HDAC4 can inhibit autophagy by repressing the transcription of autophagy-related genes. For instance, Zang et al.146 reported that HDAC4 suppresses autophagy in gastric cancer by binding to the transcription factor MEF2A and inhibiting its transcriptional activation of ATG4B, a key enzyme essential for autophagy. Additionally, inhibition of HDAC4 by miR-145-3p induces autophagy in multiple myeloma by suppressing mechanistic target of rapamycin kinase complex 1 (mTORC1), a key autophagy repressor.147 HDAC4 also modulates autophagy by regulating autophagy-related proteins. In a model of contrast-induced kidney injury, inhibition of HDAC4 by berberine enhances autophagy by indirectly activating FoxO3a through negative regulation of SIRT1.148 Furthermore, HDAC4 interacts with and deacetylates STAT1, leading to its activation and translocation, thereby inhibiting autophagy in podocytes.149 However, several studies have reported that HDAC4 can promote autophagy. For example, HDAC4 enhances autophagy by deacetylating and activating FoxO3a, thereby upregulating LC3 and Atg5 expression in Ang II-induced vascular inflammation.150 Additionally, HDAC4 overexpression promotes autophagy in Kupffer cells by repressing the expression of Rubicon, a negative regulator of autophagy.151 Furthermore, HDAC4 phosphorylation and cytoplasmic translocation promote autophagy in cisplatin-resistant ovarian cancer by increasing ATG3 transcription.152 These dual effects of HDAC4 likely arise from differences in cellular or tissue context, as well as the diversity of their target proteins.The effect of other HDAC members on autophagyHDAC2,153 HDAC8,154 HDAC9,155 and HDAC10156,157,158 also play crucial roles in autophagy. For instance, Zhou et al.153 reported that HDAC2 protects against vascular calcification by activating autophagy in chronic kidney disease. Additionally, HDAC8, together with RELA, suppresses high glucose-suppressed neuronal mitophagy by downregulating PRKN protein expression by binding to its promoter region.154In summary, accumulating evidence highlights that multiple HDACs play distinct and diverse roles in the regulation of autophagy. Among them, HDAC6 serves as a pivotal autophagy modulator through deacetylation-dependent and adaptor-mediated mechanisms. HDAC1 and HDAC4 exhibit dual regulatory functions in autophagy, acting either as repressors or activators. Other HDAC members, such as HDAC2, HDAC8, HDAC9, and HDAC10, also contribute to autophagy regulation, although their mechanisms remain less defined. Overall, HDACs constitute a complex and finely tuned regulatory network that governs autophagy, contributing to a more comprehensive understanding of their regulatory mechanisms.The roles of HDACs in other RCDsHDACs play a pivotal role in other RCDs, including ferroptosis, necroptosis, NETosis, PANoptosis, and cuproptosis.Ferroptosis is a type of RCD triggered by uncontrolled iron-dependent lipid peroxidation.159 Factors affecting lipid metabolism, ROS levels, and iron homeostasis can contribute to the initiation and progression of ferroptosis. Notably, emerging evidence indicates that HDACs can modulate ferroptosis by regulating these factors. HDACs can regulate ferroptosis by modulating key proteins involved in ROS homeostasis, such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). GPX4 can reduce lipid hydroperoxides to nontoxic lipid alcohols using glutathione (GSH) as a reducing agent. This reduction process suppresses lipid peroxidation, thereby preventing ferroptosis. Zhang et al.160 revealed that HDAC3 could promote ferroptosis by inhibiting GPX4 in renal tubular epithelial cells. At the molecular level, HDAC3, together with KLF5, binds to the GPX4 promoter, leading to local histone hypoacetylation and repression of GPX4 transcription. SLC7A11, a crucial component of system Xc-, absorbs extracellular cystine for intracellular GSH biosynthesis, playing a critical role in preserving redox homeostasis and limiting lipid peroxidation, thereby suppressing ferroptosis. HDAC5 upregulates SLC7A11, thereby promoting ferroptosis resistance in pancreatic cancer. Mechanistically, HDAC5 could deacetylate STAT6 and enhance its transcriptional activity, ultimately upregulating SLC7A11 expression. HDACs also regulate ferroptosis by modulating lipid metabolism-associated enzymes. Acyl-CoA synthase long-chain family member 4 (ACSL4), a key enzyme in FA oxidation, can positively regulate ferroptosis by producing polyunsaturated FAs.161 Zhou et al.162 reported that HDAC2 could increase ACSL4 acetylation by inhibiting SIRT3 transcription. Acetylation of ACSL4 could prevent its ubiquitination-mediated degradation, thereby increasing ACSL4 protein stability and promoting ferroptosis. HDACs also regulate ferroptosis by modulating iron homeostasis. Hepcidin (encoded by the HAMP gene) mediates the internalization and degradation of ferroportin, reducing iron absorption. Hepatic HDAC3 has a protective role in the liver by maintaining systemic iron homeostasis and reducing ferroptosis, whereas loss of hepatic HDAC3 leads to iron overload via Yap-mediated suppression of Hamp expression.163 Collectively, these findings highlight the pivotal role of HDACs in modulating ferroptosis, suggesting novel strategies for its regulation.Necroptosis is a necrotic form of RCD that elicits a pro-inflammatory response. It is typically activated when apoptosis is compromised and is mediated by signaling pathways involving receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL).164 Current studies demonstrate that HDACs serve as key regulators of necroptosis, which can either positively or negatively modulate necroptosis. For instance, loss of HDAC2 sensitizes acute lymphoblastic leukemia (AML) cells to RIPK1-driven necroptosis by modulating transcription.165 Similarly, the HDAC inhibitor (HDACi) entinostat (MS275; see Table 3 and Fig. 17), synergistic with a Smac mimetic, was shown to trigger necroptosis in AML.166 These results suggest that either inhibition or promotion of HDAC may be beneficial in treating diseases associated with necroptosis, depending on the specific pathological condition.HDACs also regulate several newly discovered RCDs, including NETosis, PANoptosis, and cuproptosis. NETosis is a specialized form of cell death in neutrophils, characterized by the release of neutrophil extracellular traps (NETs), web-like structures composed of fibers, DNA, histones, and neutrophil granule proteins. Poli et al.167 found that inhibition of class I/IIb HDACs prevents NET formation by neutrophils, thereby reducing systemic inflammation. PANoptosis is a unique inflammatory cell death pathway involving interactions among pyroptosis, apoptosis, and necroptosis. In aristolochic acid nephropathy, specific inhibition of HDAC1 and HDAC2 by romidepsin suppresses PANoptosis, thereby mitigating kidney injury.168 Cuproptosis is a recently discovered form of RCD triggered by excess Cu2+, leading to proteotoxic stress and cell death. A recent study showed that HDAC2 exacerbates cuproptosis by mediating the delactylation of NUDT21 in esophageal squamous cell carcinoma.169 Conversely, depletion of HDAC2 restored cell viability under copper-induced stress.In summary, HDACs have emerged as important regulators of multiple RCD pathways, including apoptosis, autophagy, ferroptosis, necroptosis, and other novel types. These enzymes exert their influence by regulating various substrates, including key proteins involved in these processes. These findings suggest that targeting HDACs could represent a potential therapeutic strategy for diseases driven by dysregulated RCDs. However, because the functions of HDACs are context-dependent, large-scale studies are needed to evaluate this possibility.The roles of HDACs in oxidative stressOxidative stress, which results from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, contributes to inflammation, various forms of cell death, and numerous diseases.170 Emerging evidence indicates the crucial roles of HDACs in oxidative stress regulation through the modulation of key genes and signaling pathways. The roles of HDACs in oxidative stress by regulating the expression and activity of multiple oxidative stress-related proteins are presented in (Fig. 6).Fig. 6Full size imageRoles of HDACs in oxidative stress. HDACs play vital roles in oxidative stress by regulating the expression and activity of multiple oxidative stress-related proteins. HDAC2 and HDAC3 participate in oxidative stress by regulating nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor governing cellular antioxidant defense. HDAC2 and HDAC3 promote oxidative stress by suppressing the Nrf2 pathway. In addition, inhibition of HDAC3 by the selective inhibitor RGFP966 activates the Nrf2 pathway and confers protection against oxidative stress. However, the class I HDAC inhibitor MS-275 has been shown to increase cellular ROS through suppressing Nrf2 translation by enhancing acetylation of the RNA-binding protein YB-1. Moreover, HDAC1 and HDAC2 can aggravate oxidative stress by inhibiting Foxo3a, another critical transcription factor in the antioxidant response. HDAC6 can exacerbate the oxidative stress response by suppressing malate dehydrogenase 1 (MDH1), peroxiredoxin 1, and extracellular superoxide dismutase (SOD3). Additionally, several HDAC inhibitors, such as β-hydroxybutyrate (βOHB) and vorinostat (SAHA), have been shown to attenuate oxidative stress. The figure was created with BioRender under an academic license (https://www.biorender.com/)HDAC2 and HDAC3 play pivotal roles in oxidative stress by regulating nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor that governs cellular antioxidant defense. HDAC2 and HDAC3 have been found to promote oxidative stress by suppressing the Nrf2 pathway. For instance, Yue et al. reported that inhibition of HDAC3 increased the acetylation level of Nrf2, thereby reducing oxidative stress in myocardial ischemia injury.171 In addition, the HDAC3-specific inhibitor RGFP966 (see Table 3 and Fig. 17) has been revealed to exert a neuroprotective effect by activating the Nrf2 pathway following traumatic brain injury.172 However, the class I HDAC inhibitor MS-275 increased cellular ROS levels in sarcomas by promoting acetylation of the RNA-binding protein YB-1, thereby suppressing Nrf2 translation.173 Additionally, HDAC2 promotes oxidative stress by inhibiting the Nrf2 pathway. For example, Ma et al. demonstrated that HDAC2 reduces Nrf2 expression and antioxidant enzyme activity by deacetylating H3K27, thereby exacerbating ovariectomy-induced osteoporosis.174 However, the effects of other HDAC members on Nrf2 regulation warrant further investigation.HDACs also participate in oxidative stress by regulating FOXO, malate dehydrogenase 1 (MDH1), and peroxiredoxin 1. For instance, Shimazu et al.175 reported that inhibition of HDAC1 and HDAC2 activity by β-hydroxybutyrate (βOHB) induced local histone acetylation at the promoter of the oxidative stress-resistance genes Foxo3a and metallothionein 2, thereby protecting against oxidative stress. Additionally, inhibiting class I HDACs by the ketone body d-βOHB was shown to alleviate oxidative stress in spinal cord injury, and selective suppression of HDAC1 or HDAC2 attenuated H2O2-induced ROS production while upregulating FOXO3a.176 HDAC6 plays a vital role in oxidative stress by targeting redox-related enzymes. For example, HDAC6 can aggravate oxidative stress following intracerebral hemorrhage by interacting and deacetylating MDH1 at K121 and K298.177 MDH1 is a key enzyme in glucose metabolism, and its acetylation has been identified as a negative regulator of oxidative stress. In addition, HDAC6 contributes to oxidative stress by regulating peroxiredoxin 1, an enzyme that protects cells from oxidative damage. Upregulation of HDAC6 was shown to promote oxidative stress by suppressing peroxiredoxin 1 in cognitive impairment associated with obstructive sleep apnea178, while its inhibition by tubastatin A protected against oxidative stress by preserving peroxiredoxin 1 activity in photoreceptor cells.179 Furthermore, inhibition of HDAC6 upregulated extracellular superoxide dismutase (SOD3) through enhanced Sp1 acetylation, thereby mitigating Ang II-induced oxidative stress.180 Additionally, the pan-HDAC inhibitor SAHA was shown to reduce atherosclerotic lesion progression by inhibiting oxidative stress, suggesting that HDACs may serve as therapeutic targets in oxidative stress-related diseases.181In summary, the aforementioned findings indicate that HDACs are essential for maintaining cellular redox homeostasis and mitigating oxidative injury. Further studies are required to clarify the specific roles and mechanisms of each HDAC member under different conditions, thereby enhancing our understanding of oxidative stress and its pathological implications.The roles of HDACs in cell proliferationCell proliferation refers to an increase in the number of cells through division.182 It plays an important role in the growth, development, tissue repair, and regeneration of organisms.183,184 The effects of HDACs on cell proliferation can be categorized as promotive or bidirectional, and no HDAC has been identified as acting solely as an inhibitor of cell proliferation. HDAC family members exhibit diverse roles in cell proliferation, as illustrated in (Fig. 7).Fig. 7Full size imageRoles of HDACs in cell proliferation. HDAC family members exhibit diverse roles in regulating cell proliferation across diverse conditions. HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC9 have been reported to enhance cell proliferation, whereas HDAC4 and HDAC7 display bidirectional effects depending on the cellular context. HDAC1 promotes hepatocyte transformation into cancer cells by suppressing P21 expression and facilitates cancer cell proliferation through the Wnt-Smad signaling pathway. HDAC2 enhances cell proliferation through modulation of p53 and is implicated in the proliferation of cervical cancer cells. HDAC3 promotes the proliferation of multiple cancer cell lines, including HeLa, B16F10, QBC939, and SNU308, as well as cholangiocarcinoma and breast cancer cells. Inhibition of HDAC6 or HDAC8 significantly suppresses cancer cell proliferation. HDAC9 has been shown to promote gastric cancer cell proliferation. Notably, HDAC4 inhibits proliferation when localized in the nucleus but facilitates the proliferation of pulmonary artery smooth muscle cells (PASMCs) when translocated to the cytoplasm by increasing the acetylation of Runx2. HDAC7 promotes the proliferation of nasopharyngeal carcinoma cells by downregulating microRNA-4465, which in turn upregulates Ephrin-A receptor 2. It also promotes the proliferation of lung adenocarcinoma cells. Conversely, HDAC7 suppresses endothelial cell proliferation by preventing the nuclear translocation of β-catenin. The figure was created with BioRender under an academic license (https://www.biorender.com/)HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC9 enhance cell proliferation. HDAC1 influences cell proliferation by regulating protein expression and acetylation, which has been detected in various studies. Rivas et al. found that HDAC1 promoted cell proliferation by suppressing hepatocyte markers and p21 expression, leading to hepatocyte dedifferentiation and carcinoma progression.185 HDAC1 promotes fibroblast proliferation, the inflammatory response, and osteogenic differentiation through the Wnt–Smad pathway.186 Knockdown of HDAC2 has been found to suppress cell proliferation in a manner that is partially dependent on p53.113 Inhibition of HDAC2 activity by the HDAC2 inhibitor SAHA induces mitophagy through Parkin acetylation, thereby suppressing cervical cancer cell proliferation.187 HDAC3, a primarily nuclear histone deacetylase, also plays a positive role in regulating cell proliferation. HDAC3 inhibition in HeLa and B16F10 cell lines results in the obstruction of cell proliferation.188 Similar effects have also been observed in QBC939, SNU308, and cholangiocarcinoma cells.189 Furthermore, HDAC3 facilitates the proliferation of endocrine-resistant breast cancer cells.190 Selective HDAC6 inhibitors, such as compounds 59 and 17 (see Table 3 and Fig. 17), effectively suppress cancer cell proliferation and enhance cancer cell elimination.191,192 HDAC8 is essential for controlling cell proliferation in various cell types and is highly expressed in multiple tumor cells.193,194 Selective inhibitors such as 10a (see Table 3 and Fig. 17)195 and compounds 12a, 12b, and 12c (see Table 3 and Fig. 17) can significantly reduce tumor growth by initiating cell cycle arrest and differentiation.196 In addition, knockdown of HDAC9 inhibits the growth and proliferation of gastric cancer cells and induces their apoptosis.197HDAC4 and HDAC7 exhibit bidirectional effects. Under normal conditions, HDAC4 localized within the nucleus inhibits cell proliferation, whereas its translocation to the cytoplasm enhances proliferation. Cytoplasmic translocation of HDAC4 increases Runx2 acetylation, which subsequently promotes the proliferation of pulmonary artery smooth muscle cells (PASMCs).198 HDAC7, on the one hand, facilitates the proliferation of nasopharyngeal carcinoma cells by downregulating microRNA-4465, which subsequently upregulates Ephrin-A receptor 2.199 Conversely, HDAC7 suppresses endothelial cell proliferation by inhibiting β-catenin nuclear translocation and downregulating key cell cycle proteins.200The direct and indirect involvement of HDACs in cell proliferation provides new insights and opportunities for further research and therapeutic applications. This finding holds significant potential for the treatment of diseases associated with abnormal cell proliferation, thereby alleviating the disease burden. However, current research focuses on the role of HDACs in cancer, whereas other molecular mechanisms remain underexplored. Therefore, future studies should investigate these less well-understood pathways involved in cell proliferation.The roles of HDACs in cell migration and invasionCell migration and invasion, which involve cell movement within organisms, are vital for physiological processes such as embryonic development, wound healing, angiogenesis, and immune responses, as well as for pathological conditions including cancer metastasis and atherosclerosis.201 Increasing evidence shows that HDACs play key roles in regulating these processes. The following section summarizes the roles and molecular mechanisms of HDACs in cell migration and invasion, offering new insights into their regulatory functions.The roles of HDAC6 in cell migration and invasionAmong the HDAC family, HDAC6 is the most extensively studied for its involvement in cell migration and invasion under both physiological and pathological conditions. Emerging evidence indicates that HDAC6 regulates these processes through multiple mechanisms.HDAC6 regulates cell migration by modulating cytoskeletal acetylation. Cell migration is a highly dynamic process involving rearrangement of the cytoskeleton, which primarily consists of microtubules (composed of α-tubulin and β-tubulin dimers), actin microfilaments, and intermediate filaments.202 HDAC6 is recognized as a key tubulin deacetylase, and HDAC6 can regulate the acetylation levels of microtubule and actin networks, thereby influencing cytoskeletal stability and dynamics essential for cell motility.127,203 To target microtubules, Deakin et al.204 reported that inhibiting HDAC6 by paxillin could facilitate microtubule acetylation-dependent cell polarization and migration. Similarly, HDAC6 activation by the transcription factor Erg promotes endothelial cell migration and angiogenesis through cytoskeletal remodeling and tubulin acetylation.205 Moreover, inhibiting HDAC6 by cyclohexene carboxamide (MCC2344) exerts a negative effect on cell migration by inducing hyperacetylation of tubulin and HSP-90.206 Beyond its effects on microtubules, HDAC6 also modulates actin network function by targeting proteins such as cortactin and RAC1, thereby regulating cell migration and invasion. For instance, Zhang et al.207 uncovered that HDAC6 enhances actin-dependent cell migration by regulating the acetylation of cortactin, an actin-binding protein. Similarly, HDAC6 was found to promote endothelial cell migration by deacetylating cortactin.208 In addition, HDAC6 promotes rhabdomyosarcoma cell migration by modulating cytoskeletal dynamics through RAC1, a Rho family GTPase required for actin cytoskeletal reorganization.209HDAC6 also regulates cell migration and invasion by interacting with key signaling pathways and protein modifications. For instance, HDAC6 was found to promote the proliferation and migration of human peritoneal mesothelial cells by activating the JAK2/STAT3 signaling pathways, which play a critical role in cell migration and invasion. Intriguingly, phosphorylation of HDAC6 can modulate its functional activity. Williams et al.210 reported that phosphorylation of HDAC6 at S1035 by ERK1 stimulates cell migration by mediating the deacetylation of α-tubulin.The roles of other HDAC members in cell migration and invasionOther HDAC members also play essential roles in cell migration and invasion, including HDAC1-4, HDAC7, HDAC8, and HDAC10.Accumulating studies indicate that HDAC1 plays a significant role in cell migration and invasion by modulating diverse downstream targets. For instance, HDAC1 suppressed breast cancer metastasis by deacetylating p65 and inhibiting its transcriptional activation of MMP9,211 while inhibiting the SAP18/HDAC1 complex enhanced p65/RelA acetylation, activating NF-κB signaling and promoting invasion in Kaposi’s sarcoma.212Emerging evidence suggests that HDAC2 participates in cell migration and invasion by regulating various proteins. For instance, HDAC2 activates NF-κB signaling by upregulating IKK-β transcription, leading to p65 phosphorylation and nuclear accumulation and subsequently promoting osteosarcoma cell migration.213 Additionally, HDAC2 facilitates lung cancer progression by upregulating the transcription factor Ying Yang 1 (YY1), which subsequently enhances c-Myc expression.214 Intriguingly, the S-nitrosylation of HDAC2 promotes the radial migration of cortical neurons, which is vital in cortical development.215Current research mainly supports the role of HDAC4 in promoting cell migration and invasion. For example, Usui et al.216 found that HDAC4 promoted the proliferation and migration of vascular smooth muscle cells by activating mitogen-activated protein kinase/heat shock protein 27 signals. Additionally, Li et al.217 reported that activation of HDAC4 could mediate the migration of pulmonary artery smooth muscle cells. Additionally, the HDAC inhibitor apicidin (see Table 3 and Fig. 17) suppresses ovarian cancer cell migration by targeting HDAC4.218HDAC3, HDAC7, HDAC8, and HDAC10 also play promoting roles in cell migration and invasion. For HDAC3, Jeong et al.219 revealed that HDAC3 promoted the migratory and invasive properties of human fibroblasts under hypoxic conditions. At the molecular level, HDAC3 facilitated EMT by stabilizing HIF-1α through the AKT signaling pathway. HDAC7 has been found to promote cell migration and invasion. HDAC7 silencing altered endothelial cell morphology, thereby inhibiting migration.220 Notably, the effect of HDAC7 on cell migration and invasion has also been found to be associated with its phosphorylation status, which influences its subcellular location. Phosphorylation of HDAC7 by PKD1, which leads to its nuclear export, was associated with the activation of genes that promote cell migration.221 HDAC8 has also been implicated in promoting migration. HDAC8 cooperates with SMAD3/4 heterotrimers to suppress SIRT7 transcription, leading to hyperactivation of TGF-β signaling and enhanced cell migration.222 Additionally, Dong et al.223 found that HDAC10 promoted the migration of human hepatocellular carcinoma cells by inhibiting miR-223.In conclusion, the HDAC protein family has dual roles in regulating cell migration and invasion under both physiological and pathological conditions, predominantly exerting a promoting effect. HDACs function through diverse mechanisms, including regulating the activity of proteins involved in cell migration and invasion. Among them, HDAC6 plays a pivotal role by regulating cytoskeletal acetylation. In addition, PTMs, such as phosphorylation and S-nitrosylation, can significantly impact HDAC function. Further studies are required to elucidate the precise roles and mechanisms of HDACs in cell migration and invasion, thereby providing novel insights and methods for developing effective treatments for diseases driven by aberrant cell migration and invasion, particularly cancer.The roles of HDACs in cell senescenceCell senescence is an irreversible state of cell cycle arrest that occurs in response to various extrinsic and intrinsic stressors and can act as a pathological process contributing to aging and age-related diseases.224 Notably, an increasing body of research has underscored the pivotal role of HDACs as key regulators of cell senescence through diverse mechanisms, including regulation of the DNA damage response, expression of the senescence-associated secretory phenotype (SASP), and maintenance of intracellular homeostasis.DNA damage is a major inducer of cell senescence, and HDACs have been demonstrated to regulate this process by modulating the DNA damage response. For instance, Di Giorgio et al.225 revealed that HDAC4 could influence the DNA damage response and counteract cell senescence by assembling with HDAC1/HDAC2 to regulate H2BK120 acetylation. Furthermore, the essential roles of HDAC1 and HDAC2 during development have been highlighted, as their loss in podocytes leads to sustained DNA damage, cellular senescence, and podocyte depletion.226 Beyond DNA damage, HDACs also regulate the expression of senescence-associated proteins, including key cell cycle inhibitors such as p21 and p16. For example, HDAC1 condenses chromosomes and downregulates p21 expression, thereby protecting against vascular senescence.227 Moreover, HDACs regulate the activation of the SASP, a hallmark of senescent cells characterized by the secretion of diverse bioactive molecules. Li et al.13 found that HDAC3 inhibition led to upregulation of H4K12 lactylation, thereby activating the SASP and promoting smooth muscle cell senescence. Additionally, HDACs participate in cell senescence by regulating factors involved in maintaining intracellular homeostasis, such as autophagy. For instance, downregulation of HDAC3 was discovered to alleviate chondrocyte senescence in mice by promoting Parkin acetylation and subsequently activating excessive mitophagy.228 Furthermore, an increasing number of studies have shown that several HDACis exert protective roles in preclinical models of age-related diseases, including neurodegeneration, heart disease, and diabetes.229In summary, HDACs play critical roles in modulating cell senescence through multiple mechanisms. These findings provide valuable insights into the mechanisms of cell senescence and offer novel therapeutic strategies for age-related diseases targeting HDAC modulators.Regulatory roles of HDACs in human diseasesAs mentioned above, HDACs have been implicated in numerous pathological processes and play vital roles in various diseases. In this section, the roles and mechanisms of HDACs in diverse diseases are summarized, including tumors, cardiovascular diseases, respiratory system diseases, digestive system diseases, nervous system diseases, endocrine system diseases, motor system diseases, and urogenital system diseases. This section aims to provide a comprehensive overview of the roles and mechanisms of HDACs in common diseases and to provide a basis for the development and application of HDAC modulators. Notably, the functions of HDACs vary among diverse cell types, organs, and diseases. The same HDAC isoform may exert distinct effects on the same cellular process under different pathological conditions. Therefore, elucidating the specific roles and underlying mechanisms of various HDACs in diverse diseases is of great significance for advancing the application of HDAC-targeted strategies.HDACs and tumorsTumors represent a significant global health challenge, accounting for nearly one in six deaths worldwide.230 Recent studies have shown that HDACs play a significant role in tumor development, particularly in processes such as apoptosis, immune modulation, cell migration, proliferation, differentiation, drug resistance, autophagy, DNA damage response, and metabolism. This section summarizes the distinct roles of HDACs in the initiation and progression of various cancers. A summary of HDAC functions in various tumor types is presented in (Fig. 8).Fig. 8Full size imageHDACs and tumors. Generally, HDACs inhibit tumor cell apoptosis, promote proliferation and metastasis, enhance drug resistance, and suppress antitumor immune responses. However, exceptions exist in specific tumor types: in the respiratory system, HDAC10 functions as a tumor suppressor; in breast cancer, HDAC1 and HDAC2 suppress metastasis; in prostate cancer cells, HDAC5 loss confers resistance to CDK4/6 inhibitors. The figure was created with BioRender under an academic license (https://www.biorender.com/)Respiratory system tumorsLung cancers represent a major category of malignant tumors affecting the respiratory system. Increasing evidence indicates that HDACs critically influence the progression of these tumors through the regulation of tumor cell apoptosis, proliferation, migration and drug resistance.Multiple HDACs significantly impact lung tumor progression, primarily exerting a promotive role through their modulation of apoptosis, cell proliferation, and cell migration. For example, upregulation of HDAC6 suppresses the expression of GATA-binding factor 6, thereby promoting the proliferation and metastasis of lung squamous cell carcinoma cells.231 In contrast, HDAC6 inhibition enhances the activity of caspases 3, 8, and 9 and increases the DNA damage marker phosphorylated H2AX, thereby restraining lung cancer development.232 Moreover, downregulation of HDAC4, HDAC5, and HDAC6 promotes expression of the p21 (waf1) gene, thereby enhancing apoptosis in lung cancer cells.233 Similarly, HDAC3 inhibition activates the Bcl-2 interacting mediator of cell death protein, promoting apoptosis and inhibiting the progression of EGFR-mutated non-small cell lung cancer (NSCLC) harboring the BIM deletion polymorphism.234 In addition, activation of the DNA methyltransferase 3 alpha (DNMT3a)/HDAC7 pathway promotes proliferation and metastasis in lung adenocarcinoma cell lines.235 Notably, under stress and hypoxic conditions within the lung tumor microenvironment, HDAC6 expression is upregulated, promoting tumor cell migration. For instance, in isoproterenol-treated H1299 lung cancer cells, elevated HDAC6 expression correlates with reduced α-tubulin acetylation, thereby accelerating cell migration.236HDAC1, HDAC2, and HDAC4 also impact respiratory system tumor progression by modulating drug resistance. For instance, HDAC1 inhibition induces DUSP1 upregulation, inhibits EGFR signaling and resensitizes gefitinib-resistant NSCLC cells.237 HDAC4 downregulation reduces STAT1 phosphorylation and EGFR expression, thereby contributing to doxorubicin sensitivity and promoting apoptosis in lung cancer.238 Additionally, HDAC2 inhibition increases miR-130a-3p expression while suppressing Rad51, thereby reducing pemetrexed resistance in KRAS-mutant NSCLC and inhibiting its progression.239In recent years, the role of HDAC10 in regulating lung adenocarcinoma progression has drawn increasing attention. For example, in KRAS-driven lung adenocarcinoma models, HDAC10 functions as a tumor suppressor, and its loss enhances TGFβ–SOX9 signaling, thereby promoting cancer stemness and tumor progression.240Collectively, HDACs play crucial roles in lung cancer by regulating multiple pathophysiological processes. Specifically, HDAC6 exerts multifaceted functions. Future research should aim to elucidate the precise molecular mechanisms of HDACs to develop targeted drugs with enhanced therapeutic efficacy and reduced adverse effects in lung cancer treatment.Breast tumorsBreast cancer represents a heterogeneous group of malignant neoplasms, and HDACs critically shape its initiation and progression by orchestrating diverse processes, including cell proliferation, apoptosis, migration, and therapeutic resistance.HDACs can promote breast cancer progression by influencing the cell cycle, apoptosis, and cell viability. HDACs regulate cyclin-dependent kinase (CDK) activity to influence tumor cell cycle progression. For example, HDAC8 inhibition promotes apoptosis of breast cancer cells, thereby hindering tumor progression.241 Additionally, HDAC8 inhibition delays cell cycle progression and reduces viability in MCF-7 cells by preventing the deacetylation of structural maintenance of chromosome 3 (SMC3).242 Moreover, Nimal et al. reported that combined treatment with galangin and SAHA significantly downregulated HDAC1 and HDAC3, potentially inducing breast cancer cell death by causing cell cycle arrest at the Sub-G0/G1 phase.243 Furthermore, inhibition of HDAC3 and HDAC6 reduces the transcription and protein stability of key anti-apoptotic proteins, survivin and XIAP, leading to autophagy and decreased viability in MCF-7 and MDA-MB-231 breast cancer cells.244HDAC1 and HDAC2 also contribute to breast cancer progression by regulating cell migration. Inhibition of HDAC1 and HDAC2 upregulates heparin-binding epidermal growth factor expression, thereby promoting tumor cell migration and accelerating breast cancer progression.245 Under hypoxic conditions, HDAC2 forms a stable repressive complex with XBP1s and EZH2, facilitating the conversion of H3K27ac to H3K27me3, thereby repressing ΔNp63α transcription and ultimately promoting breast cancer metastasis.246 Additionally, HDAC2 promotes DNA damage repair and chemotherapy resistance in triple-negative breast cancer by mediating METTL3 delactylation.247 Notably, HDAC10 plays a central role in mediating metformin-induced sensitization of breast cancer cells to SAHA by regulating histone acetylation of FGFR4 and the expression of metabolism-related genes.248HDACs, especially HDAC1-3 and HDAC10, play pivotal roles in breast cancer development. Future research should elucidate the specific functions and mechanisms of individual HDAC subtypes, facilitating a shift from broad-spectrum inhibition toward selective therapeutic strategies that precisely target breast tumors.Digestive system tumorsDigestive system tumors represent a major group of malignancies affecting the digestive tract. Emerging evidence indicates that HDACs play critical roles in promoting the progression of multiple digestive system tumors, such as colorectal cancer (CRC), hepatocellular carcinoma (HCC), and cholangiocarcinoma (CCA).HDACs contribute to the progression of digestive system tumors through their involvement in cell death regulation, migration control, DNA damage response, immune modulation, macrophage polarization, and proliferation. For instance, HDACs inhibit apoptosis and ferroptosis in colorectal cancer cells. HDAC1 suppresses the expression of fat mass- and obesity-associated gene (FTO) and AlkB homolog 5 (ALKBH5) through deacetylation, leading to the activation of downstream ferroptosis suppressor protein 1 (FSP1) and thereby reducing the sensitivity of CRC cells to ferroptosis.10 In addition, HDAC2 inhibition upregulates BAX and TP53 expression to induce apoptosis and suppress colorectal cancer progression.249 Regarding cell migration, heightened HDAC1 activity activates the IL-8/STAT3/miR-370-3p/Twist1/Snail axis to promote HCC invasion.250 Additionally, suppression of HDAC6 increases the acetylation level of α-tubulin, which inhibits HCC cell migration and suppresses HCC progression.251 Regarding DNA damage control, HDAC4/6 inhibition enhances H3K9 acetylation while reducing DNA damage and telomerase activity, thereby suppressing HCC initiation.252 HDAC3 inactivation also upregulates CXCL9/CXCL10/CXCL11, recruiting CXCR3+ T cells to bolster antitumor immunity in HCC.253 Furthermore, HDAC6 activates the TAK1-p38 MAPK-ADAM17 axis to drive soluble IL-6R release and M2 polarization, thereby promoting colon cancer.254 In hepatocellular carcinoma cells, enhancer of zeste homolog 2 (EZH2) represses CXCL10 transcription by recruiting HDAC10, thereby inhibiting NK cell activity and promoting tumor progression.255 Moreover, HDAC3 inhibition by chidamide (see Table 3 and Fig. 17) promotes FOXO1 acetylation, thereby inducing cell autophagy in CCA.189 Additionally, HDAC3 stabilizes the c-Myc protein by deacetylating the K323 residue, thereby downregulating pyruvate metabolism, maintaining low pyruvate levels, and consequently promoting CCA proliferation.256HDACs, crucial for gene expression and function, are implicated in the development and progression of various digestive tumors, particularly HDAC1 and HDAC3. Consequently, the development of HDACis enables innovative, targeted strategies against specific HDACs to halt tumor progression and enhance the efficacy of existing cancer therapies.Urinary system tumorsAs major urological malignancies, prostate cancer, renal cell carcinoma, and urothelial carcinoma pose a considerable health burden. Increasing evidence indicates that HDACs facilitate their progression by modulating key cellular events, particularly cell migration and apoptosis.Several HDAC isoforms, notably HDAC1, HDAC2, HDAC6, and HDAC7, promote urological cancer progression by enhancing cell migration. For instance, inhibition of HDAC1 and HDAC2 in renal cell carcinoma (RCC) reduces the expression of E-cadherin and platelet-derived growth factor receptor-β, thereby impairing cellular adhesion and metastasis. This inhibition, in turn, suppresses RCC progression.257 Similarly, HDAC6 inhibition increases α-tubulin acetylation, which directly impedes cell migration and contributes to the suppression of prostate cancer development and progression.258 Moreover, HDAC7 promotes tumor metastasis and invasion by reprogramming branched-chain amino acid metabolism to upregulate the expression of Snail family transcriptional repressor 1.259HDACs also impact urinary system tumor progression by affecting cell proliferation and apoptosis. In urothelial carcinoma cells, the combination of TSA and paclitaxel significantly enhances paclitaxel cytotoxicity and promotes tumor cell apoptosis, as TSA inhibits paclitaxel-induced activation of ERK1/2.260 Moreover, loss of HDAC5 led to resistance to CDK4/6 inhibitors (such as palbociclib) in prostate cancer cells, potentially promoting cancer development and progression.261HDACs play pivotal roles in the pathogenesis of urological tumors, making HDAC inhibitors attractive candidates for novel therapeutic approaches. Nevertheless, extensive further investigation, especially in clinical trials, is needed to fully assess their efficacy and safety.LeukemiaLeukemia encompasses a group of hematological malignancies characterized by uncontrolled proliferation of abnormal white blood cells. Recent research has elucidated the complex interplay between HDACs and leukemogenesis. Specifically, HDACs influence leukemia progression by modulating apoptosis, proliferation, and differentiation.Class I and II HDACs, particularly HDAC1-3, HDAC6, HDAC8 and HDAC10, contribute to leukemia development by regulating apoptosis and proliferation pathways. In acute myeloid leukemia (AML), downregulation of HDAC3 induces acetylation of WISP2 at K6, preventing its degradation and thereby suppressing cell proliferation while promoting apoptosis.262 Similarly, HDAC2 inhibition leads to reduced c-Myc expression, thereby downregulating RCC1 and triggering apoptosis in AML cells.263 Concurrent downregulation of HDAC1 and HDAC3 disrupts their interaction with the transcription factor YY1, causing aberrant liquid‒liquid phase separation and METTL3 suppression, ultimately inhibiting AML proliferation.264 In chronic myeloid leukemia (CML), HDAC6 inhibition downregulates BCR-ABL expression and activates the caspase-dependent apoptotic pathway, thereby restraining disease progression.265 Additionally, pharmacological inhibition of HDAC10 has been shown to induce apoptosis specifically in lymphoid tumor cells, as HDAC10 helps maintain DNA replication processivity and genome integrity in malignant lymphoid cells.266 In addition, HDAC1 and HDAC8 also affect the progression of leukemia by influencing cell differentiation and antitumor immunity. Inhibition of HDAC1 and HDAC8 increases the acetylation of HSP90 and p53, thereby inhibiting AML development and progression by triggering apoptosis and inducing differentiation.267 In addition, HDAC1 interacts with exosomal circ_0006896, impairing CD8+ T-cell function and promoting AML cell proliferation and progression.268Collectively, HDACs exert multifaceted roles in leukemia pathogenesis. Understanding these diverse yet synergistic functions highlights their therapeutic potential, paving the way for novel targeted strategies.Gynecologic tumorsGynecologic tumors remain a major cause of cancer-related mortality in women worldwide. Recent research has revealed the involvement of HDACs in the progression of these cancers, including cervical and ovarian cancers.HDACs, particularly HDAC1, HDAC6, and HDAC8, play key roles in the progression of gynecologic cancers by modulating cell proliferation and apoptosis. For example, inhibition of HDAC1 enhances ROS production, facilitating HMGB1 translocation from the nucleus to the cytoplasm and thereby promoting apoptosis while hindering cervical cancer progression.269 Moreover, inhibition of HDAC6 and HDAC8 enhances p53 acetylation at the K381 site, increases the expression of pro-apoptotic proteins, and suppresses ovarian cancer progression.270 Additionally, HDAC8 promotes cervical cancer growth by mediating α-tubulin deacetylation.271HDAC1-3 have been reported to regulate antitumor immunity in gynecologic tumors. For instance, tumor-associated human leukocyte antigen (HLA) ligands derived from HDAC1 and HDAC2 stimulate CD8+ T-cell responses capable of lysing HLA-matched tumor cells.272 Moreover, the HDAC inhibitor entinostat enhances the sensitivity of patients with homologous recombination deficiency (HRD) to PARP inhibitor-based immunotherapy by inhibiting the deacetylase activity of HDAC1 and HDAC3 and promoting the expression of the HRD-associated functional phenotype (HRD-EXCUTE).273In summary, most current findings suggest that HDACs drive gynecologic tumor progression by influencing apoptosis, proliferation and immune responses. Therefore, targeting HDACs shows significant potential for treating gynecologic tumors.Nervous system tumorsNervous system tumors include a group of malignant neoplasms that affect the central and peripheral nervous systems. Recent research has revealed that HDACs regulate multiple nervous system tumors by modulating tumor apoptosis, proliferation, and metabolic processes.HDAC1 and HDAC2 suppress apoptotic processes in nervous system tumors. For instance, inhibiting HDAC1 and HDAC2 together with activation of ClpP synergistically suppresses glioblastoma cell viability by disrupting TCA cycle activity and oxidative metabolism, inducing apoptosis through Bcl-xL- and Mcl-1–regulated caspases, and significantly prolongs survival in GBM patient-derived xenograft models.274 Similarly, HDAC2 inhibition increases H4 acetylation, activating apoptotic pathways to inhibit medulloblastoma progression.275HDAC6 promotes nervous system tumor proliferation by distinct mechanisms. Its inhibition reduces LINC00461 levels, decreases cell division proteins, and induces cell cycle arrest in GBM.276 Additionally, HDAC6 promotes glioblastoma growth by stabilizing glutamine synthetase.277Additionally, HDAC1 and HDAC2 influence the DNA damage response and metabolic processes in GBM. For instance, inhibiting HDAC1 and HDAC2 downregulates the expression of DNA repair-related molecules, including breast cancer susceptibility gene 1, checkpoint kinase 1, RAD51, and O6-methylguanine-DNA methyltransferase, and upregulates the apoptosis pathway, thereby inhibiting GBM progression.278 In addition, HDAC2 knockdown upregulates miR-3189 and suppresses GLUT3 expression, impairing glucose metabolism and proliferation, thereby inhibiting glioblastoma tumorigenesis.70Studies have shown that HDACs, including HDAC1, HDAC2, and HDAC6, play crucial roles in the pathogenesis of neurological tumors, especially GBM. Their complex involvement highlights therapeutic potential, offering novel strategies to improve patient outcomes.Other tumorsBeyond the tumors mentioned above, HDACs have also been shown to regulate other malignancies, including nasopharyngeal carcinoma, multiple myeloma, and melanoma.In nasopharyngeal carcinoma, HDAC4 has been reported to promote malignancy by accelerating G1/S phase transition and inducing epithelial–mesenchymal transition, thereby enhancing proliferation, migration, and invasion.279HDAC1 and HDAC3 modulate proliferation in multiple myeloma. HDAC1 inhibition downregulates interferon regulatory factor 4 (IRF4) and PIM2, thereby suppressing tumor proliferation.280 Similarly, HDAC3 inhibition triggers c-Myc degradation and DNMT1 hyperacetylation, thereby downregulating DNMT1 and inhibiting myeloma growth.281The pathogenesis of melanoma involves HDAC1, HDAC2, HDAC3, and HDAC6, particularly in mediating chemoresistance and immune modulation. Combined HDAC1/2/3 inhibition downregulates RAD51 and FANCD2, compromising homologous recombination repair and sensitizing cells to alkylating agents.282 Additionally, HDAC6 inhibition elevates tumor antigen/MHC-I expression to enhance immune surveillance, increases acetylated tubulin, and reduces IL-10 levels, collectively suppressing tumor progression.283Collectively, aberrant HDAC activity plays a central role in driving malignancy across various tumors through multiple mechanisms. These findings offer novel insights into tumor biology and highlight the therapeutic potential of targeting HDACs. The development of isoform-specific inhibitors and the exploration of combination therapies involving HDAC inhibitors and other anticancer agents represent promising strategies for improving clinical outcomes in cancer treatment.HDACs and cardiovascular diseasesCardiovascular disease (CVD) remains the leading cause of death worldwide, placing a heavy burden on economies and societies.284 In recent years, the critical roles of HDACs in cardiovascular diseases have been increasingly recognized. In this section, we summarize current research on the roles and mechanisms of HDACs in cardiovascular diseases, including pulmonary arterial hypertension (PAH), atherosclerosis, cardiac hypertrophy, heart failure (HF), hypertension, myocardial infarction (MI), and myocardial ischemia‒reperfusion injury (IRI), to provide a scientific basis and new perspectives for future therapeutic strategies. The effects of HDACs in these CVDs are illustrated in (Fig. 9).Fig. 9Full size imageHDACs and cardiovascular diseases. Most HDACs are involved in promoting the progression of cardiovascular diseases, including atherosclerosis, hypertension, pulmonary arterial hypertension, myocardial IRI, myocardial infarction, heart failure, and cardiac hypertrophy. HDAC1, HDAC2, HDAC8, HDAC9, and HDAC11 have been implicated in promoting atherosclerosis, whereas HDAC3 plays a dual role. HDAC3 and HDAC6 contribute to the pathogenesis of hypertension. HDAC1 and class IIa HDACs are associated with the progression of pulmonary arterial hypertension. Both HDAC1 and HDAC4 play detrimental roles in myocardial IRI. HDACs also promote the progression of myocardial infarction. In heart failure, HDAC2 exerts harmful effects, whereas HDAC4 appears to be protective. In cardiac hypertrophy, HDAC2 and HDAC8 have a harmful role, while HDAC4 exhibits dual functions depending on context. The figure was created with BioRender under an academic license (https://www.biorender.com/)Pulmonary arterial hypertensionPAH is a progressive and debilitating cardiovascular condition characterized by elevated blood pressure in the pulmonary arteries. Recent research has illuminated the complex involvement of HDACs in the pathogenesis of PAH. Most HDAC isoforms are associated with the promotion of PAH.In the context of vascular remodeling, HDAC1 downregulates miR-34a expression and increases the ratios of MMP-9 to tissue inhibitor of metalloproteinases-1 (TIMP-1) and MMP-2 to TIMP-2. These changes promote extracellular matrix degradation, facilitating pulmonary arterial remodeling and contributing to the progression of PAH.285 Moreover, reduced HDAC activity alleviates pulmonary vascular remodeling associated with pulmonary hypertension by inhibiting activation of the insulin-like growth factor-1 (IGF-1)/phosphorylated AKT signaling pathway.286HDACs are actively involved in the pathogenesis of PAH through the regulation of inflammatory mediators, cellular proliferation, migration, and immune modulation. HDACs modulate the expression of cytokines that influence inflammatory responses. For instance, HDACs influence vascular cell proliferation and migration—two key mechanisms underlying PAH.287 Inhibition of HDAC1 leads to dephosphorylation of Akt within the platelet-derived growth factor (PDGF) signaling pathway and reduced Cyclin D1 expression, thereby suppressing cell proliferation and mitigating PAH progression.288 Additionally, decreased HDAC activity downregulates cyclin D1 (CCND1) and upregulates p21 expression, inducing G1 phase cell cycle arrest. These molecular changes, in turn, inhibit the proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), potentially alleviating PAH progression.289 Moreover, reduced activity of class IIa HDACs can restore the function of myocyte enhancer factor 2 (MEF2) and its transcriptional targets, thereby limiting the proliferation and migration of pulmonary artery endothelial cells (PAECs) and further contributing to PAH inhibition.290 HDACs are also implicated in immune regulation within the context of PH. Decreased HDAC activity has been associated with increased expression of regulatory T cells (Tregs), particularly those expressing Forkhead box P3, which helps to alleviate immune dysregulation and inflammation in PH.291Collectively, these studies highlight the critical involvement of HDACs in the pathogenesis of PAH through multiple interconnected mechanisms. These insights provide a promising foundation for the development of HDAC-targeted therapeutic strategies.AtherosclerosisAtherosclerosis is the most prevalent form of cardiovascular disease and is characterized by lipid accumulation and chronic inflammation in large arteries.292 Studies have found that HDACs promote the development of atherosclerosis.Multiple HDACs have been shown to regulate the development of atherosclerosis through different mechanisms. For instance, HDAC2 directly binds to the promoter region of the arginase 2 (Arg2) gene, represses its expression, and consequently reduces endothelial nitric oxide production, thereby contributing to endothelial dysfunction and the pathogenesis of atherosclerosis.293 Moreover, HDAC9 plays a proatherogenic role by enhancing the activation of the NF-κB signaling cascade, primarily through the deacetylation of IKKα and IKKβ, which are key mediators in inflammatory pathways.294 HDACs also regulate immune cell function, with a notable emphasis on their effects in macrophages. Elevated expression of class I HDACs suppresses Beclin 1 expression and impairs the autophagy process, resulting in excessive lipid accumulation within macrophages and thereby accelerating atherosclerotic progression.295 When HDACs were inhibited by SAHA, the expression of NADPH oxidase (Nox) isoforms in the aorta decreased, and NADPH-stimulated ROS production was reduced, thereby reducing oxidative stress and inflammation and finally inhibiting the progression of atherosclerosis.181 Pyroptosis is an inflammatory form of programmed cell death. In human umbilical vein endothelial cells induced by TNF-α, knockdown of HDAC11 alleviates pyroptosis by inhibiting both the NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways, thereby suppressing the progression of atherosclerosis.296 Additionally, suppression of HDAC9 reduces endothelial-to-mesenchymal transition, preserves endothelial identity, and decreases the extent of atherosclerotic plaque formation, thus decelerating disease progression.297 In contrast, HDAC3 has been discovered to exert a protective role in atherosclerosis. For example, HDAC3 was shown to protect against atherosclerosis by maintaining endothelial integrity through Akt activation in disturbed flow regions, whereas HDAC3 deficiency could trigger endothelial apoptosis and vessel rupture, thereby accelerating lesion formation.298 In addition, HDAC3 downregulation, resulting from lactate accumulation, has been found to exacerbate vascular smooth muscle cell senescence and atherosclerosis due to enhanced H4K12 lactylation.13Collectively, these studies demonstrate that HDACs are intricately involved in the pathogenesis of atherosclerosis through multiple molecular and cellular mechanisms.Cardiac hypertrophyCardiac hypertrophy is characterized by enlarged cardiac myocytes, resulting in thickened heart walls or dilated ventricles, which impair cardiac function and may lead to serious complications.299 Recent studies have found that HDACs play multiple roles in cardiac hypertrophy, with HDAC2, HDAC4, and HDAC8 exhibiting distinct functions.Downregulation of HDAC2 alleviates ventricular arrhythmias in a mouse model of cardiac hypertrophy by upregulating the expression of Kv channel-interacting protein 2 (KChIP2).300 HDAC8 plays a role in promoting cardiac hypertrophy. For example, downregulation of HDAC8 expression by binding MiR-21-3p to its 3’ untranslated region (3’UTR) inhibits the activation of the Akt-Gsk3β pathway, thereby suppressing the development of cardiac hypertrophy.301 HDAC4 exerts dual regulatory effects in cardiac hypertrophy, functioning as both a promoter and inhibitor of pathological myocardial enlargement. In response to increased cardiac preload, HDAC4 is exported from the nucleus, where it promotes H3K9 demethylation rather than deacetylation. This modification facilitates dissociation of HP1 from the promoter region and activation of the ANP gene, ultimately exacerbating heart failure.302 Conversely, HDAC4 can exert inhibitory effects on cardiac hypertrophy by suppressing MEF2 activity through protein kinase A (PKA)-dependent proteolysis, thereby contributing to the prevention of pathological cardiac enlargement.303 This evidence suggests that HDAC4 functions as a negative regulator of cardiac hypertrophy under certain conditions, potentially serving as a protective factor against pathological cardiac enlargement.In summary, recent studies have demonstrated that HDACs regulate cardiac hypertrophy through multiple mechanisms. HDACs and their associated regulatory pathways offer novel insights and promising targets for therapeutic intervention in cardiac hypertrophy.Heart failureHeart failure is a prevalent and critical cardiovascular condition characterized by the heart’s inability to pump blood effectively. Research indicates that HDACs, particularly HDAC2 and HDAC4, play critical roles in the initiation and progression of heart failure. A proteolytic fragment of HDAC4 protects the heart from failure by regulating the hexosamine biosynthesis pathway.304 Additionally, loss of HDAC2 leads to upregulation of inositol polyphosphate-5-phosphatase F (INPP5F), which subsequently deactivates AKT and 3-phosphoinositide-dependent protein kinase 1. This deactivation results in the activation of glycogen synthase kinase 3 beta (GSK3β), thereby attenuating cardiac hypertrophy and slowing the progression of heart failure.305 In summary, HDACs play a multifaceted role in the development of heart failure through diverse mechanisms. These contrasting functions underscore the complexity of HDAC-mediated regulation in heart failure and suggest that HDACs represent promising targets for future therapeutic strategies.HypertensionHypertension is a prevalent cardiovascular disorder characterized by persistently elevated arterial blood pressure. Recent research has demonstrated that HDACs play a significant role in the pathogenesis of hypertension. HDACs, particularly HDAC3 and HDAC6, play a promotive role in hypertension. For instance, HDAC inhibition by VPA attenuated inflammatory, hypertrophic, and hypertensive responses in spontaneously hypertensive rats by reducing reactive oxygen species and angiotensin II type 1 receptor expression in the heart.306 Meanwhile, inhibition of HDAC6 promotes the upregulation of cystathionine γ-lyase (CSEγ) and hydrogen sulfide (H2S), thereby preventing the development of hypertension.307 Additionally, knockdown or inhibition of HDAC3 has been shown to prevent the development of hypertension.308 These studies collectively highlight the involvement of HDACs in the pathogenesis of hypertension through distinct molecular pathways. These insights offer promising avenues for the development of HDAC-targeted therapeutic strategies aimed at managing or preventing hypertension.Myocardial infarctionMyocardial infarction (MI), commonly referred to as a heart attack, is a life-threatening cardiovascular event. Recent research indicates that HDACs play critical roles in the pathogenesis and progression of MI.HDACs influence the progression of MI through multiple mechanisms, including the regulation of macrophage polarization and angiogenesis. For instance, the downregulation of HDACs has been shown to enhance the recruitment and activity of M2 macrophages while reducing the expression of inflammatory immune cells, such as CD45(+)/CD11b(+), thereby mitigating the post-MI inflammatory response.309 Additionally, HDACs also impact angiogenesis in myocardial IRI.310 HDAC downregulation can promote cardiac repair and functional recovery after MI by upregulating the expression of WNT-inducible signaling pathway protein-1 (Wisp-1), contributing to beneficial cardiac-specific angiogenesis.311HDACs contribute to the pathogenesis of MI through multiple molecular pathways. These insights provide a promising foundation for the development of HDAC-targeted therapeutic strategies, which may support the treatment and prevention of MI.Myocardial ischemia/reperfusion injuryIRI refers to the paradoxical exacerbation of cellular damage and death that occurs upon the restoration of blood flow to previously ischemic tissues. HDACs have been increasingly recognized for their critical roles in the pathophysiology of IRI.Specifically, HDAC1 and HDAC4 have been implicated in promoting disease progression during IRI. HDAC1 is localized in the mitochondria of myocardial cells and is involved in early myocardial reperfusion injury.312 HDAC1 disrupts the TCA cycle by deacetylation of Nur77 and promotes inflammation in mice with ischemia‒reperfusion.77 Simultaneously, the overexpression of HDAC4 promotes IRI by elevating the levels of the autophagy-related protein LC3 and the apoptosis-related protein active caspase-3 while simultaneously reducing the antioxidant enzyme SOD-1, thereby exacerbating myocardial damage.313HDACs contribute to the pathogenesis of IRI through various molecular mechanisms. These findings offer new insights into the development of therapeutic strategies targeting HDACs.Other cardiovascular diseasesIn addition to the conditions discussed above, HDACs are also implicated in other cardiovascular diseases. Given their diverse biological functions, HDACs have been shown to contribute to disease progression across these conditions.HDACs are implicated in the pathogenesis of myocardial fibrosis and cardiac remodeling. For example, class I HDACs promote angiotensin II-dependent cardiac fibrosis through resident and circulating fibroblasts.314 However, inhibition of HDAC1 increases the acetylation of the tumor suppressor protein p53, particularly at K382, thereby effectively suppressing myocardial fibrosis.315 Thoracic aortic aneurysm (TAA) is a severe vascular disorder characterized by dilation of the thoracic aorta, often leading to aortic dissection or rupture. Inhibition of HDAC1 preserves vascular smooth muscle cell function, thereby protecting against TAA.316 Inhibition of HDAC3 prevents diabetic cardiomyopathy through epigenetic regulation of the DUSP5-ERK1/2 pathway in OVE26 mice.317 In summary, HDACs are indispensable for the regulation of myocardial fibrosis and various vascular diseases.This section elaborates on the intricate and multifaceted roles of HDACs across a range of cardiovascular diseases. Among the various isoforms, HDAC1 and HDAC2 have been the most extensively studied in cardiovascular research. HDACs represent complex and dynamic targets for therapeutic intervention in cardiovascular medicine. Their context-dependent effects underscore the importance of precise modulation strategies. Targeting HDACs holds significant promise for the development of innovative treatments aimed at improving clinical outcomes and reducing the socioeconomic burden associated with cardiovascular disease.HDACs and respiratory system diseasesRespiratory diseases pose a significant threat to both physical and mental health. HDACs play a crucial role in regulating histone and non-histone, thereby regulating the pathological responses that drive disease progression. The roles of HDACs and respiratory system diseases are presented in (Fig. 10).Fig. 10Full size imageHDACs and respiratory system diseases. Most HDACs contribute to the onset and progression of respiratory diseases, including chronic obstructive pulmonary disease, lung fibrosis, asthma, pneumonia, and acute lung injury. Specifically, HDAC2, HDAC5, HDAC7 and HDAC8 alleviate the progression of chronic obstructive pulmonary disease. Both HDAC2 and HDAC7 are involved in the development of lung fibrosis. HDAC1, HDAC8, HDAC9, and HDAC10 have been implicated in the progression of asthma. HDAC3 is associated with detrimental effects in pneumonia. Moreover, HDAC6 and HDAC10 contribute to the pathogenesis of acute lung injury. The figure was created with BioRender under an academic license (https://www.biorender.com/)Lung fibrosis (LF) is an interstitial lung disease characterized by a progressive fibrotic phenotype, high mortality, and poor prognosis, often of unknown etiology. The proliferation and apoptosis resistance of IPF fibroblasts are mediated by increased HDAC enzyme activity.318 Another study identified the HDAC2/Sin3A/methyl-CpG-binding protein 2 (MeCP2) corepressor complex as an endogenous inhibitor of connective tissue growth factor (CTGF), a key mediator of airway fibrosis, in human lung fibroblasts.319 Furthermore, reduced HDAC7 activity has been shown to restore function to misfolded CFTR in cystic fibrosis.320 An imbalance in HAT/HDAC activity is also associated with the heightened inflammatory response observed in cystic fibrosis airways.321 These findings suggest that pan-HDAC inhibitors may represent a novel therapeutic strategy for IPF, as confirmed by several animal and cell-based studies.322 In conclusion, HDACs appear to play a dual role in LF, and HDAC inhibitors hold promise as potential therapeutic agents.Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation and heterogeneous clinical features. Since 2005, studies have reported decreased mRNA expression of HDAC2, HDAC5, and HDAC8, along with reduced HDAC2 protein levels in patients with COPD, demonstrating a progressive decline in total HDAC expression that correlates with advancing disease stages.323 A study found that decreased HDAC7 levels may impair VEGF gene expression and contribute to the pathogenesis of COPD.324 Meanwhile, HDAC inhibition in patients with COPD leads to emphysema.325Asthma is a common respiratory disease characterized by chronic airway inflammation, hyperresponsiveness, and airway remodeling. Decreased HDACs may increase the inflammatory response in asthma.326 Paulina et al. reported that HDAC1 and HDAC9 expression levels were significantly elevated in bronchial epithelial cells of patients with asthma compared with controls.327 HDAC10 directs macrophage M2 polarization and promotes asthma through deacetylation of STAT3.44 HDAC8 inhibitors ameliorate airway hyperresponsiveness and airway inflammation in animal models of allergic asthma by simultaneously inhibiting galectin-3 expression and reducing M2 polarization.328 In conclusion, HDAC inhibitors hold significant potential as therapeutic agents for asthma management.Acute lung injury (ALI) is an acute inflammatory condition triggered by diverse pulmonary insults. Class I/IIb HDACs promote neutrophil extracellular trap formation, thereby exacerbating both local and systemic inflammation.167 HDAC10 promotes the expression of p62 and increases the production of inflammatory cytokines, which aggravate lung inflammation.329 Cigarette smoke (CS) is associated with the development of ALI. CS destroys the integrity of the pulmonary endothelial barrier through HDAC6 and increases susceptibility to acute lung injury.330In a Klebsiella pneumoniae mouse model, the pan-HDACi inhibitor sodium butyrate (NaB; see Table 3 and Fig. 17) enhanced acetylated histone 3 recruitment to the IL-10 promoter, thereby increasing IL-10 levels in the lungs. As IL-10 is an anti-inflammatory cytokine, this finding identifies a mechanism of persistent inflammation in pneumonia and highlights the therapeutic potential of HDAC inhibitors.38This section discusses the relationship between HDACs and respiratory diseases. Attempts to modulate HDAC activity for the treatment of respiratory diseases have thus far been limited to animal and cell-based models and lack specificity.HDACs and digestive system diseasesDigestive system diseases remain highly prevalent and burdensome despite therapeutic advances.331 For common digestive diseases such as nonalcoholic fatty liver disease (NAFLD), viral hepatitis, inflammatory bowel disease (IBD), and pancreatitis, effective and specific treatments remain limited. Interestingly, accumulating evidence supports a pivotal role for HDACs in various digestive system diseases, suggesting that targeting HDACs may provide novel therapeutic strategies and clinical insights. The various effects of HDACs across different digestive system diseases are presented in (Fig. 11).Fig. 11Full size imageHDACs and digestive system diseases. The effects of HDACs vary across different digestive system diseases, including NAFLD, viral hepatitis, IBD, pancreatitis, and other liver injuries. In NAFLD, HDAC3, HDAC4, and HDAC5 are protective, while HDAC1 and HDAC2 have dual effects. In HBV infection, HDAC1, HDAC2, HDAC3, and HDAC11 exert protective roles, whereas HDAC5 is deleterious. In contrast, HDAC1, HDAC2, and HDAC3 contribute to HCV-related liver damage. In IBD, HDAC2, HDAC5, HDAC6, HDAC7, and HDAC9 promote disease progression, while HDAC3 is protective; HDAC1 may have dual effects. HDAC1 contributes to injury in both acute and chronic pancreatitis. HDAC6 aggravates hepatic IRI and acetaminophen-induced liver injury, while HDAC3 alleviates intestinal IRI. HDAC2 worsens acute liver failure. HDAC4 and HDAC8 are implicated in cholestatic liver injury. The figure was created with BioRender under an academic license (https://www.biorender.com/)Nonalcoholic fatty liver disease (NAFLD)NAFLD is the most common liver disease, affecting approximately 25% of adults worldwide.332 It encompasses a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH), potentially progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Dysregulated lipid metabolism is central to its pathogenesis. Notably, HDAC1-5 have been implicated in NAFLD by modulating hepatic lipid metabolism.HDAC3, currently the most extensively studied HDAC in NAFLD, appears to play a protective role by modulating hepatic lipid homeostasis and inflammation. For instance, Feng et al.333 demonstrated that deletion of HDAC3 in the mouse liver resulted in hepatic steatosis. Mechanistically, HDAC3 was recruited to the genome in a circadian manner in the mouse liver, aligning with the expression pattern of the circadian nuclear receptor Rev-erbα, thereby maintaining normal hepatic lipid metabolism. Similarly, HDAC3 was reported to mediate the protective effects of RORα against diet-induced hepatic steatosis by repressing PPARγ transcriptional activity.334HDAC4 and HDAC5 are also involved in hepatic FA metabolism. HDAC5 was found to promote FA oxidation gene expression through interaction with PPARα, suggesting a potential protective role in NAFLD.335 Interestingly, the protective effect of HDAC4 in NAFLD appears to be sex dependent. Kang et al.336 reported that in male mice with obesity and nonalcoholic steatohepatitis, macrophage-specific Hdac4 deficiency exacerbated hepatic and white adipose tissue inflammation. However, this effect was not observed in female mice, indicating a sex-specific role of HDAC4.Both HDAC1 and HDAC2 exhibit dual roles in NAFLD. For instance, HDAC1 inhibition by NaB was found to alleviate NAFLD by stimulating FAO through increasing H3K9 acetylation at the PPARα promoter.337 Additionally, combined inhibition of HDAC2 and DNA methyltransferase 1 has been shown to improve fibrosis in a NASH minipig model.338 These findings suggest that targeting HDAC1 and HDAC2 may be beneficial for preventing NAFLD. However, HDAC1 and HDAC2 were discovered to protect against fatty liver disease by suppressing lipogenesis through catalyzing the deacetylation of H3K9 and H3K27 at the fatty acid synthase promoter.93The studies mentioned above demonstrate that HDACs play a regulatory role in NAFLD, with most current research focusing on HDAC1-5. Generally, HDAC3-5 exert protective effects in NAFLD, suggesting potential therapeutic applications, whereas HDAC1 and HDAC2 exhibit dual roles in disease progression.Viral hepatitisViral hepatitis, primarily caused by hepatitis A–E viruses (HAV–HEV), is a leading cause of liver cirrhosis and liver cancer. Despite available vaccines, it remains a global health burden. Emerging evidence reveals a key regulatory role of HDACs, particularly in HBV and HCV infections.HDACs exert both protective and detrimental roles in HBV infection. Several studies have demonstrated that HDACs can suppress HBV by inhibiting the transcription of covalently closed circular DNA (cccDNA), which is the molecular basis for HBV persistence and recurrence. For instance, HDAC1 and HDAC2 can be recruited to cccDNA, leading to H3K9 and H3K27 deacetylation and transcriptional suppression.339 Similarly, HDAC11 inhibits HBV transcription and replication by reducing acetylated H3K9 and H3K27 bound to cccDNA.340 These findings suggest that targeting H3K9 and H3K27 acetylation on cccDNA may serve as a potential therapeutic strategy against HBV. Beyond histone acetylation, HDACs regulate other epigenetic modifications of cccDNA. For example, Zhao et al. demonstrated that IFN-α suppresses HBV by enhancing HDAC3-mediated de2-hydroxyisobutyrylation of H4K8 on cccDNA, providing new insights into IFN-α’s antiviral effects.341 Conversely, HDAC5 promotes HBV infection and pathogenesis by increasing the stability and splicing of 3.5 kb HBV RNA, which plays a critical role in viral replication.342HDACs have also been implicated in HCV, with most studies indicating that HDAC inhibition exerts anti-HCV effects. For example, Zhou et al.343 demonstrated that the selective HDAC3 inhibitor RGFP966 suppresses HCV replication. Mechanistically, in HCV-infected cells, HDAC3 inhibition downregulates Apo-A, a protein essential for HCV particle formation and maintenance of infectivity. Additionally, RGFP966 stimulates the expression of LEAP-1, thereby mitigating HCV infection and chronic liver injury. Beyond direct antiviral effects, HDAC inhibition may also alleviate HCV-associated liver disease. Miura et al. reported that suppression of HDAC activity by TSA ameliorated chronic hepatitis C by upregulating hepcidin expression, which reduces liver injury by preventing iron deposition.344 Furthermore, HDACs are involved in the progression of HCV-associated hepatocellular carcinoma (HCC). Nie et al.345 reported that HDACs promote HCC metastasis through interactions among HCV, Snail, HDAC1 and HDAC2 at the E-cadherin promoter, leading to E-cadherin repression and increased hepatoma cell invasiveness. In summary, these findings suggest that HDAC inhibition represents a promising therapeutic strategy for treating HCV infection and HCV-associated liver diseases.The studies discussed above highlight the dual roles of HDACs in HBV infection while suggesting a predominantly detrimental impact in HCV infection and HCV-associated diseases. Therefore, further research is essential to elucidate the specific effects and underlying mechanisms of individual HDACs in HBV and HCV pathogenesis. Such insights could facilitate the development of precision therapies utilizing selective HDAC modulators. Moreover, given the significant regulatory influence of HDACs, future studies should also explore their roles in hepatitis caused by other viral pathogens.Inflammatory bowel diseaseInflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic, incurable digestive disorder that significantly diminishes the quality of life for millions worldwide.346 Despite ongoing research, effective treatment strategies for IBD remain limited. Notably, a growing body of evidence suggests that HDACs play a crucial regulatory role in IBD, exerting either detrimental or protective effects.HDAC6 and HDAC9 can exacerbate IBD. For instance, Lee et al.347 found that oral administration of CKD-506 (see Table 3), a highly selective HDAC6 inhibitor, improved experimental acute and chronic colitis in murine models, as evidenced by reduced weight loss, disease activity, and histopathologic scores. Mechanistically, CKD-506 was shown to inhibit NF-κB signaling in intestinal epithelial cells and macrophages. Additionally, HDAC9 has also been implicated in IBD pathogenesis. de Zoeten et al.348 found that HDAC9-knockout mice were resistant to colitis development, likely due to enhanced regulatory T-cell function, which plays a crucial role in preventing autoimmunity. HDAC1 and HDAC5 have been reported to play different roles in CD. Chervy et al.349 showed that HDAC1 protected against CD by limiting ileal colonization of pathobiont Enterobacteria, whereas HDAC5 had the opposite effect, indicating that HDAC5 may be a promising therapeutic target. However, HDAC1, together with HDAC2 and HDAC7, has been reported to have harmful effects by regulating epigenetic and metabolic reprogramming of fibroblasts in CD.350 In contrast, HDAC3 protects against IBD by maintaining intestinal homeostasis351 and regulating inflammation.352Consequently, these results suggest that targeting HDACs may represent a novel therapeutic strategy. However, various HDAC proteins may exhibit contrasting roles in IBD, highlighting the need for further research to elucidate the precise mechanisms and to develop targeted therapeutics.PancreatitisPancreatitis, a prevalent and potentially fatal digestive disease, remains a significant global health concern because of its high morbidity and mortality.353 Despite advancements in diagnostic techniques, effective therapeutic interventions are still urgently needed. Notably, multiple studies have demonstrated that HDACs are involved in both acute pancreatitis (AP) and chronic pancreatitis (CP).AP is characterized by early protease activation followed by inflammation and organ damage, with both inflammation and apoptosis being key contributors to this pathophysiology. Notably, emerging studies indicate that HDACs play a role in AP by regulating inflammation and apoptosis. For example, Zhou et al. found that inhibiting HDAC activity with the enterobacterial metabolite norharman attenuated the inflammatory response in AP by enhancing H3K9/14 acetylation, which promoted Rftn1 transcription, thereby suppressing M1 macrophage activation and restoring lipid metabolism homeostasis.42 In addition, HDACs are also implicated in AP through the regulation of apoptosis. Deng et al. reported that downregulation of HDAC1 protected against AP by suppressing the expression of NEP-mediated KLF4.354 These findings suggest that HDACs may represent promising therapeutic targets for AP by modulating both inflammation and apoptosis.CP is a progressive inflammatory disorder characterized by pancreatic fibrosis resulting from the deposition of extracellular matrix proteins by activated pancreatic stellate cells (PSCs). Notably, growing evidence suggests that HDACs may be promising therapeutic targets for CP, as their inhibition can attenuate pancreatic fibrosis. For instance, Yang et al. reported that HDAC1 was overexpressed in pancreatic tissue from patients with CP. Silencing HDAC1 alleviated cerulein-induced inflammatory cell accumulation and the upregulation of TGF-β and collagen 1 in a CP mouse model.355 TGF-β is a potent profibrotic factor in the pancreas that promotes PSC activation and fibrosis. Similarly, MS-275, a selective class I HDAC inhibitor, was found to suppress TGF-β expression and prevent fibrosis progression in vivo.356 These findings suggest that HDAC inhibition may provide therapeutic benefits in CP by attenuating pancreatic fibrosis.Recent studies mainly indicate that inhibiting HDACs exerts protective effects in pancreatitis. However, a study by Eisses et al. demonstrated that VPA, a broad-spectrum HDAC inhibitor primarily targeting class I HDACs, impaired pancreatic recovery following pancreatitis by disrupting acinar regenerative reprogramming.357Given that the HDAC inhibitors used in these studies lack selectivity, future research should focus on elucidating the precise roles and mechanisms of individual HDAC isoforms in pancreatitis, providing a foundation for developing targeted and more effective therapeutic approaches.Other digestive system diseasesHDACs are also implicated in various digestive disorders, including hepatic IRI, acute liver failure (ALF), cholestatic liver injury, drug- and toxin-induced liver damage, necrotizing enterocolitis (NEC), eosinophilic esophagitis, and intestinal IRI.Several studies have demonstrated that inhibiting HDAC6 exerts a protective effect in hepatic IRI. For instance, Pan et al.358 reported that HDAC6 expression was significantly upregulated in liver tissue from patients who underwent liver transplant, mice subjected to hepatic IR surgery, and hepatocytes exposed to hypoxia/reoxygenation (H/R) treatment compared with their respective controls. Further investigations revealed that global HDAC6-knockout mice exhibited reduced liver IRI, whereas adeno-associated virus-mediated, liver-specific HDAC6 overexpression resulted in aggravated injury. Mechanistically, HDAC6 deficiency alleviated hepatic IRI by suppressing inflammation and apoptosis through activation of the PI3K/AKT/mTOR signaling pathway. Additionally, Concors et al.359 demonstrated that TubA, an HDAC6 inhibitor with additional activity against HDAC10, significantly protected against hepatic IRI in mice.HDACs are also involved in other liver diseases. For instance, inhibition of HDAC2 exerts hepatoprotective effects in ALF.360,361 In cholestatic liver injury, both HDAC4 and HDAC8 have been identified as factors that exacerbate hepatic damage, and inhibition of their activity could reduce liver injury.362,363 HDACs are also implicated in liver injury induced by drugs. Zhang et al. reported that HDAC6 expression was significantly upregulated in acetaminophen-induced liver injury, and treatment with LT-630 (see Table 3 and Fig. 17), a novel HDAC6 inhibitor, attenuated liver damage by modulating malate dehydrogenase 1-mediated oxidative stress.364In other intestinal diseases, HDAC8 expression was reported to be upregulated in intestinal samples from both human and murine models of NEC, and its inhibition using PCI-34051 alleviated NEC. Mechanistically, increased HDAC8 levels disrupted arginine metabolism by modulating the expression of metabolic enzymes.365 Additionally, Zhang et al.115 demonstrated that the protective effects of dexmedetomidine in intestinal IRI were associated with the phosphorylation of HDAC3 by PINK1, which inhibited p53 activity and prevented apoptosis in enteric glial cells. In addition, HDACs have also been implicated in eosinophilic esophagitis,366 suggesting a broader role for HDAC regulation in intestinal pathologies.This section highlights the involvement of HDACs in digestive system diseases, in which they modulate various molecular pathways. Notably, the same HDAC may exert different effects on similar pathological phenotypes across diseases, reflecting its tissue- and cell-specific functions. Some HDACs have opposing roles within a single disease. Given their complex regulation of histone and non-histone proteins, further research is needed to clarify the specific roles of individual HDACs. Additionally, while current evidence mainly comes from cellular and animal models, clinical trials are crucial for evaluating the therapeutic potential of HDAC-targeting strategies.HDACs and nervous system diseasesRecent studies have shown that HDAC-driven deacetylation contributes to the onset and progression of neurological diseases through its involvement in pathological protein accumulation, oxidative stress, neuronal damage, and other mechanisms. In this section, we summarize the important roles and mechanisms of HDAC in the development and progression of nervous system diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic disease, Huntington’s disease (HD), ischemia-related disease, epilepsy, amyotrophic lateral sclerosis (ALS), depression, and schizophrenia. The aim is to gain insight into the therapeutic potential of HDAC-targeting strategies and to explore new avenues for developing more effective treatments for neurological diseases. The roles of HDACs in these nervous system diseases are summarized in (Fig. 12).Fig. 12Full size imageHDACs and nervous system diseases. Most HDACs act as detrimental factors in neurological disorders, including Alzheimer’s disease, Parkinson’s disease, neurological injury, Huntington’s disease, ischemia-related disease, epilepsy, amyotrophic lateral sclerosis, depression, and schizophrenia. HDAC2, HDAC3, HDAC6, and HDAC7 promote the development of AD, while HDAC1 and HDAC4 are involved in the pathogenesis of PD. In traumatic brain injury, HDAC3 and HDAC6 act as detrimental factors, whereas HDAC5 appears to have a protective role. Both HDAC4 and HDAC6 contribute to the progression of Huntington’s disease. HDAC2 and HDAC9 have been associated with ischemia-related neurological conditions. In epilepsy, the expression of HDAC1, HDAC2, and HDAC11 is decreased during acute seizures, whereas in chronic seizures, HDAC1 is increased and HDAC2, HDAC3, and HDAC8 are decreased. HDAC6 promotes the progression of amyotrophic lateral sclerosis, while HDAC4 exerts bidirectional effects. In depression and schizophrenia, HDAC1 exerts detrimental effects. The figure was created with BioRender under an academic license (https://www.biorender.com/)Alzheimer’s diseaseAD is the most common neurodegenerative disorder and the leading cause of dementia. The clinical and pathological heterogeneity of AD has prevented the development of any specific or curative treatment to date. In recent years, increasing attention has been directed toward the role of protein PTMs in AD, particularly the deacetylation activity mediated by HDACs, which has emerged as a focal point in the search for therapeutic targets.367,368HDACs play an important role in the aggregation and neurotoxicity of β-amyloid (Aβ), whose abnormal accumulation leads to the formation of senile plaques, a hallmark pathological feature of AD. HDAC2, for example, regulates histone acetylation and reduces the activity of neprilysin (NEP), an Aβ-degrading enzyme, thereby impairing Aβ clearance and aggravating Aβ-induced neurotoxicity.369 Additionally, HDAC6 expression is upregulated in AD transgenic mouse models and is implicated in Aβ formation.370 Moreover, HDAC3 overexpression has been shown to contribute to Aβ aggregation, reduce dendritic spine density, enhance microglial activation, and impair spatial memory.371 These findings collectively suggest that targeting HDACs may enhance Aβ clearance and mitigate the pathological progression of AD.HDAC6 and HDAC7 deacetylate tau, impairing its clearance and promoting its aggregation and neurotoxicity. Tau is a major microtubule-associated protein in mature neurons, and its excessive phosphorylation, which leads to neurofibrillary tangle formation, represents another key pathological hallmark of AD. HDAC6-mediated deacetylation of α-tubulin reduces microtubule stability, thereby disrupting intracellular transport and contributing to the formation of pathological protein aggregates.372 Notably, selective inhibition of HDAC6 using compound W5 has been shown to increase acetylated α-tubulin levels while reducing phosphorylated tau levels, suggesting a therapeutic benefit.373 Studies have shown that upregulation of HDAC7 induces AD-like tau pathology by deacetylating transcription factor EB (TFEB) and suppressing lysosomal biogenesis in astrocytes. In contrast, downregulation of the HDAC7-TFEB signaling pathway holds promise for preventing AD and other tauopathies.374 Thus, HDAC6 and HDAC7 may be promising therapeutic targets for treating neurodegenerative disorders.Additionally, the transcriptional repression mediated by HDACs can lead to decreased expression of synapse-related genes, thereby impairing synaptic function. Yamakawa et al. demonstrated that HDAC2 negatively regulates gene expression at synapses and in neurons and that the transcription factor SP3 promotes the recruitment of HDAC2 to these sites.375 In addition, apolipoprotein E4, a known genetic risk factor for AD, has been found to accelerate the nuclear translocation of HDAC6, where it binds to the brain-derived neurotrophic factor (BDNF) promoter, leading to reduced BDNF expression, synaptic loss, and exacerbation of synaptic dysfunction.376HDAC2 has been discovered to regulate memory formation in AD. HDAC2 plays a key role in suppressing genes involved in synaptic plasticity. Neuroligin-1 (NLGN1), a postsynaptic protein essential for regulating synaptic excitability and functional plasticity in the central nervous system, has been identified as one such target. HDAC2 deacetylates histones and promotes their interaction with methyl-CpG-binding protein 2 (MeCP2), which enhances methylation of the NLGN1 promoter and represses its expression.377 Furthermore, a study by Singh et al. found increased HDAC2 binding to the promoters of neuronal immediate early genes in aged mice, and memory impairments were reversed following the suppression of HDAC2 expression.378However, contrary to previous findings, a clinical study reported decreased HDAC2 protein levels in cholinergic neurons of the nucleus basalis of Meynert (nbM) in patients with AD, along with reduced nuclear localization of HDAC2. These changes were associated with exacerbated cholinergic neuronal degeneration.379 Similarly, reduced expression of class I HDACs, particularly HDAC2, has been observed in both patients with AD and transgenic mouse models.380 These findings present an opposing view to earlier studies suggesting HDAC2 overexpression in AD pathology. The molecular mechanisms underlying HDAC2 expression changes at different stages of disease progression and in distinct brain regions warrant further investigation.While current research highlights the critical role of HDACs in AD, most evidence is derived from animal studies, and their function in human pathology remains to be fully validated in clinical settings. Therefore, further investigation into the role and mechanisms of individual HDAC family members in AD is necessary and may offer promising therapeutic strategies to improve clinical outcomes.Parkinson’s diseasePD is the second most common neurodegenerative disorder after AD. Its hallmark pathological features include the progressive degeneration of dopaminergic (DA) neurons and the formation of Lewy bodies, which are primarily composed of aggregated α-synuclein.381Recently, the potential pathogenic role of HDACs in PD has gained increasing attention. In PD, the progressive loss of DA neurons is a central pathological feature and a major cause of motor symptoms. In a mouse model of PD, HDAC1 interacts with protein phosphatase 1 (PP1) to promote the inactivation of CREB, leading to reduced expression of its downstream target, nuclear receptor-related 1 protein (Nurr1), which in turn contributes to dopaminergic neuronal damage and disease progression.382 In PD models, increased nuclear accumulation of HDAC4 has been shown to suppress CREB and myocyte enhancer factor 2 A (MEF2A), thereby dysregulating neuronal gene expression and inducing apoptosis, further contributing to neurodegeneration.383In summary, members of the HDAC family contribute to the pathogenesis of PD by promoting dopaminergic neuronal damage and suppressing the expression of neuron-related genes.Neurological injuryCentral and peripheral nervous system injuries are devastating conditions that can cause long-lasting or permanent damage to the nervous system, particularly motor function, and often lead to long-term neurological deficits. Following such injuries, a cascade of pathological events occurs, including apoptosis and the release of pro-inflammatory cytokines, all of which contribute to the severity of secondary damage to the nervous system. Notably, the increased expression of HDAC proteins plays an important role in the neuroinflammatory response.HDAC3 plays a central role in regulating the inflammatory response following spinal cord injury (SCI) by regulating inflammation. HDAC3 contributes to neuroinflammation by deacetylating the STAT1–NF-κB p65 complex and NF-κB p65 itself, thereby activating the NF-κB signaling pathway and promoting the transformation of microglia from the M2 (anti-inflammatory) to the M1 (pro-inflammatory) phenotype, which initiates central inflammatory responses.50 Notably, specific deletion of HDAC3 in microglia significantly reduces pro-inflammatory responses and brain inflammation while also decreasing axonal and myelin damage.384After peripheral axonal injury, HDAC5 nuclear export in dorsal root ganglion (DRG) neurons is promoted by calcium influx, leading to increased cAMP levels and activation of downstream signaling pathways. Once exported, HDAC5 regulates microtubule-associated proteins and enhances histone acetylation, thereby supporting growth cone dynamics and facilitating axon regeneration.385 HDAC6 is also a target for protection and regeneration after nervous system injury. Selective inhibition of HDAC6 prevents oxidative stress-induced neurodegeneration and enhances neurite outgrowth, highlighting its potential as a therapeutic target.386Huntington’s diseaseHD is a neurodegenerative disorder characterized by movement abnormalities, psychiatric symptoms, and progressive cognitive decline. Transcriptional dysregulation is a central feature of its pathogenesis. HDACs are involved in this process and play a pathogenic role by altering gene expression.387The pathological accumulation of mutant huntingtin (mHTT) protein is a hallmark of HD progression.388 In HD mouse models, HDAC4 has been shown to interact with other protein complexes, leading to increased mHTT aggregation, defects in vesicle trafficking and recycling, and impaired synaptic transmission.389 Inhibition of HDAC4 expression can restore BDNF levels, enhance synaptic function, and improve clinical manifestations of HD. HDAC4 may also interact indirectly with mutant huntingtin through coprecipitation and cytoplasmic localization.390 HDAC6 deacetylates tubulin, disrupts protein trafficking, and promotes huntingtin aggregation. Like HDAC4, it suppresses BDNF expression and contributes to neuronal damage. HDAC6 inhibitors restore trafficking, increase tubulin acetylation, and enhance BDNF release in Huntington’s disease.391Ischemia-related diseaseCerebral ischemic diseases are characterized by a high incidence and poor prognosis. In recent years, the role of the HDAC family in cerebral ischemia has gained increasing attention.The roles of HDAC2 and HDAC9 in ischemia-related diseases have been extensively studied. Kirenol promotes synaptic plasticity by regulating HDAC2-mediated BDNF expression, thereby reducing cerebral ischemic injury.392 In a large genome-wide association study of ischemic stroke, HDAC9 was identified as being significantly associated with large-vessel ischemic stroke.393 HDAC9 promotes neuronal ferroptosis after stroke by stabilizing HIF-1 to upregulate TfR1 and degrading Sp1 to downregulate GPX4, thereby exacerbating ischemic brain injury.394 Ethanolic extract of Arctium lappa leaves alleviates inflammatory injury induced by cerebral IR through the HDAC9-mediated NF-κB pathway.395 Meanwhile, HDAC inhibition activates the transcription factor Nrf2 and protects against cerebral ischemic injury.396Other nervous system diseasesIn addition to the more extensive diseases studied above, HDACs are associated with epilepsy, amyotrophic lateral sclerosis, depression, and schizophrenia.Epilepsy is a complex symptom caused by a variety of risk factors and genetic factors, and the mechanism is complex and still unclear. In two mouse models of temporal lobe epilepsy, distinct temporal changes in HDAC expression were observed. In the kainic acid (KA)-induced model, the expression of HDACs 1, 2, and 11 was significantly reduced during the acute phase. In contrast, transcription and expression of class I HDACs increased between 12 and 48 h post-seizure. A similar pattern was observed in the pilocarpine-induced model.397 These dynamic changes in HDAC expression across the acute, interictal, and chronic phases of temporal lobe epilepsy suggest their involvement in the epigenetic regulation of epilepsy-related genes and proteins. In the KA-induced seizure model, GluA2 expression is downregulated, promoting neuronal injury and seizure progression. This reduction is associated with decreased histone acetylation at the GluA2 promoter, suggesting that HDAC-dependent deacetylation suppresses GluA2 transcription, particularly during the later stages of epileptogenesis.398Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by muscle weakness, with most patients eventually dying from respiratory failure due to respiratory muscle involvement.399 Pigna et al. reported that HDAC4 deletion accelerates ALS onset by modulating the uncoupling protein (UCP1) gene network.400 However, Bruneteau et al. demonstrated that upregulation of HDAC4 in muscle accelerates neuromuscular dysfunction and may serve as a potential risk factor for ALS.401 Furthermore, inhibiting HDAC6 improves neurite outgrowth and regeneration, as well as the morphology of neuromuscular junctions, thereby ameliorating the progression of ALS.402The incidence of mental disorders has been rising steadily in recent years, drawing increasing concern. Growing evidence suggests that epigenetic mechanisms, particularly histone modifications, play an important role in the pathogenesis of psychiatric conditions. In patients with depression and other psychiatric disorders, elevated levels of HDACs lead to histone deacetylation and alterations in chromatin structure, which contribute to disease development.403 Additionally, HDAC1 overexpression has been identified in both mouse models and peripheral blood samples from patients with schizophrenia, and inhibition of HDAC1 has been shown to improve related pathological outcomes.404In conclusion, the HDAC family in neurological diseases has garnered increasing attention, with different HDAC subtypes exhibiting distinct functions across various disease contexts. The current understanding of the underlying molecular mechanisms remains limited. Additional research is needed to identify novel mechanisms of action and to elucidate the molecular pathways that link different regulatory processes. Most studies on HDACs in neurological disorders have thus far been conducted using cellular and animal models. Therefore, expanding clinical research will be essential to validate these findings and to facilitate their translation into effective therapies.HDACs and endocrine system diseasesThe endocrine system plays a pivotal role in maintaining homeostasis and regulating diverse physiological processes; its dysregulation can lead to various diseases. Notably, a growing body of research has identified the involvement of HDACs in the onset and progression of various endocrine-related diseases, particularly diabetes mellitus (DM) and its complications, obesity, and other metabolic diseases. This section summarizes current research progress on the roles and mechanisms of HDACs in these conditions, aiming to provide a foundation for future studies exploring HDAC-targeted therapeutic strategies. The complicated roles of HDACs in endocrine system diseases are presented in (Fig. 13).Fig. 13Full size imageHDACs and endocrine system diseases. HDACs play complicated roles in endocrine system diseases, including diabetes mellitus (DM) and its complications, obesity, and other metabolic diseases. HDAC1 and HDAC3 promote T1DM. In T2DM, HDAC3, HDAC4, and HDAC7 exert a detrimental effect; HDAC6 shows dual roles, while phosphorylated HDAC5 protects against T2DM. Multiple HDACs aggravate DM-related complications, such as diabetic kidney disease (DKD), diabetic cardiomyopathy (DCM), diabetic neuropathy (DN), diabetic retinopathy (DR), neurovascular dysfunction, diabetic osteoporosis, and diabetic foot ulcers (DFUs), although HDAC4 appears to be protective. HDAC3, HDAC8, HDAC9, and HDAC11 contribute to obesity. HDAC4 and HDAC6 exert complex effects in obesity depending on conditions, while HDAC5 is protective. Notably, various HDAC inhibitors have shown therapeutic potential in metabolic diseases, including Cushing’s syndrome, hypothyroidism, and Niemann-Pick type C disease. The figure was created with BioRender under an academic license (https://www.biorender.com/)Diabetes mellitusDM is an endocrine disorder characterized by abnormally elevated blood glucose levels due to impaired insulin production and/or insulin resistance.405 It can cause long-term damage to multiple organs, leading to decreased quality of life and increased mortality. DM is primarily classified into type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), and accumulating evidence indicates that HDACs play a crucial role in the pathogenesis of both types.T1DM is caused by the autoimmune destruction of pancreatic β-cells, leading to absolute insulin deficiency and dependence on exogenous insulin for survival. Accumulating evidence suggests that HDACs play a critical role in regulating both the number and function of pancreatic β-cells. Current research primarily focuses on the use of HDAC inhibitors, which have demonstrated protective effects in T1DM models. For example, treatment with NaB significantly enhanced β-cell proliferation and function while reducing β-cell apoptosis in streptozotocin (STZ)-induced juvenile diabetic rats.406,407 Similarly, the HDACi ITF2357 was found to protect islet β-cells from injury by inhibiting inflammation and oxidative stress.408 These results indicate that HDAC inhibition exerts a protective role in T1DM by preserving β-cell mass and function. For the role of individual HDACs, HDAC1 and HDAC3 have been found to affect β-cells. Lundh et al.409 demonstrated that inhibiting HDAC1 and HDAC3 could reduce cytokine-induced β-apoptosis, and HDAC1 knockdown significantly restored insulin secretion. Furthermore, in pancreatic β-cells from children with newly diagnosed T1DM, HDAC1 was upregulated, while HDAC3 was downregulated compared to five pediatric controls, directly demonstrating altered HDAC expression in β-cells. Collectively, these findings indicate that HDACs play a pivotal role in T1DM by regulating pancreatic β-cells. However, studies about the roles of individual HDAC members remain limited.T2DM is characterized by insulin resistance and increased hepatic glucose production, accompanied by a progressive decline in pancreatic β-cell function. Recent studies indicate that HDAC inhibitors may have protective effects in T2DM. For instance, Chriett et al.410 demonstrated that NaB improved insulin signaling in an insulin resistance model by upregulating insulin receptor substrate 1 (IRS1). Currently, various HDACs play regulatory roles in insulin resistance and glucose homeostasis. Among them, HDAC4 and HDAC6 have been implicated in regulating insulin sensitivity. HDAC6 plays dual roles in insulin signaling. Adipocyte-specific deletion of HDAC6 led to reduced insulin sensitivity in mice.411 However, elevated HDAC6 expression was shown to suppress IRS1 levels and impair insulin signaling in skeletal muscle.412 For HDAC4, Ozcan et al.413 found that its nuclear exclusion promoted insulin resistance in hepatocytes by reducing DACH1 SUMOylation. HDAC3, HDAC5, and HDAC7 also influence β-cell function in T2DM. Daneshpajooh et al.414 reported that increased HDAC7 in pancreatic islets from patients with T2DM impaired insulin secretion and mitochondrial function, while HDAC7 silencing or inhibition improved β-cell function and insulin secretion. In addition, HDAC3 inhibition was shown to protect β-cells from cytokine-induced inflammation and metabolic injury.415 Conversely, phosphorylation of HDAC5 by GRK5 was found to promote β-cell proliferation, indicating that the HDAC5-GRK5 axis may serve as a potential target to preserve β-cell mass in T2DM.416 Collectively, these findings highlight the critical roles of HDACs in modulating β-cell function and insulin signaling, suggesting that selective HDAC targeting holds promise for therapeutic intervention in T2DM.The findings above demonstrate that HDACs are involved in both T1DM and T2DM by regulating insulin secretion through their effects on β-cell mass and function, as well as by modulating insulin signaling pathways. Notably, targeting HDACs has provided a promising foundation for the development of novel therapeutic strategies. However, further research is needed to elucidate the precise molecular mechanisms of HDACs in diabetes and to identify their specific targets, thereby enabling more targeted and effective treatment approaches.DM complicationsDiabetic kidney disease (DKD)DKD is a serious complication of diabetes, affecting approximately 40% of patients with DM.417 Recent studies have increasingly demonstrated that various HDACs are involved in the pathogenesis of DKD, with most exerting detrimental effects on kidney structure and function.Class II HDACs are among the most extensively studied HDACs in DKD. HDAC4 has been shown to aggravate DKD by inducing podocyte and tubular epithelial cell injury. Wang et al.149 reported that HDAC4 expression was upregulated in kidney biopsies from patients with diabetes, as well as in diabetic animal and cell models. HDAC5 has also been implicated in DKD progression. Its expression was elevated in the renal tubular cells of diabetic mice and HG-treated HK2 cells. Suppressing HDAC5 activity reduced HG-induced EMT in HK2 cells, as evidenced by increased E-cadherin and decreased α-SMA levels, which were linked to downregulation of TGF-β1.418 Regarding HDAC6, Hou et al.419 showed that pharmacological inhibition using CAY10603 (see Table 3 and Fig. 17) attenuated DKD by suppressing NLRP3 inflammasome activation in both tubular cells and macrophages. These findings suggest that class II HDACs could be promising therapeutic targets for DKD.HDAC1 and HDAC2 have also been discovered to aggravate DKD. Dong et al.420 reported that inhibiting HDAC1 could improve renal dysfunction in db/db mice by restoring autophagy in glomerular endothelial cells and mitigating endothelial-to-mesenchymal transition. In addition, the related studies demonstrated that HDAC2 promoted ECM production in tubular epithelial cells421, and inhibiting HDAC2 could protect against renal injury by alleviating renal fibrosis in diabetic mice.421,422,423 Notably, the HDAC inhibitor SAHA has been shown to improve diabetes-induced renal injury,424 highlighting the therapeutic potential of targeting HDACs in DKD.Collectively, current findings suggest that HDACs primarily exert detrimental effects in DKD through disrupting the function of podocytes, tubular epithelial cells, and glomerular endothelial cells, and HDAC inhibition exhibits protective effects in DKD. However, most existing research has been limited to cellular and animal models. Future studies should prioritize clinical trials to validate these findings and facilitate translation into clinical applications.Diabetic cardiomyopathyDCM is a major cardiovascular complication of DM and the leading cause of mortality among patients with diabetes.425 Administration of the HDACi NaB has been reported to improve myocardial function and prevent cardiac remodeling in STZ-induced diabetic mice. The observed protective effects were associated with enhanced angiogenesis, inhibition of apoptosis, and increased acetylation of GLUT1.426 For the role of individual HDACs, HDAC3 plays detrimental roles in DCM, whereas HDAC4 appears to be protective. For example, Xu et al.317 found that HDAC3 activity was significantly elevated in the hearts of diabetic mice, and selective inhibition using RGFP966 effectively prevented cardiac dysfunction and pathological changes. Mechanistically, HDAC3 suppressed the expression of dual specificity phosphatase 5 (DUSP5) by deacetylating H3 at the promoter region of the DUSP5 gene, thereby contributing to DCM development. In contrast, Kronlage et al.427 reported that HDAC4 knockout mice developed heart failure in both type 1 and type 2 diabetic models, indicating a protective function of HDAC4 in DCM. Their study further showed that O-GlcNAcylation of HDAC4 at S642 exerted cardioprotective effects by counteracting pathological Ca²⁺/calmodulin–dependent protein kinase II signaling. However, the roles of other HDACs in DCM remain poorly understood and warrant further investigation.Other DM-associated organ damageHDACs are also involved in a variety of other diabetes-induced organ complications, including diabetic neuropathy (DN),141 diabetic retinopathy (DR),428 neurovascular dysfunction,429 diabetic osteoporosis,430 and diabetic foot ulcers (DFUs).431 For instance, HDAC3 expression and activity were markedly increased in the hippocampus and cortex of db/db mice. Additionally, treatment with the highly selective HDAC3 inhibitor RGFP966 significantly alleviated blood‒brain barrier damage both in vivo and in vitro.429ObesityObesity is defined as abnormal or excessive fat accumulation resulting from dysregulation of energy intake and expenditure, loosely linked to increased risk of numerous diseases.432 However, effective strategies for the prevention and treatment of obesity remain limited. Notably, various HDACs have been identified as key regulators involved in the development and progression of obesity.HDAC4 and HDAC6 have been shown to exert complex effects in obesity. HDAC6, in particular, plays a complicated role. On the one hand, inhibition of HDAC6 has been reported to improve obesity by restoring leptin sensitivity.433,434 Leptin, a hormone secreted by adipose tissue, regulates feeding behavior and energy metabolism by acting on leptin receptors (LepRs), which are predominantly expressed in the central nervous system.435,436 However, a study by Lieber et al.437 revealed that male HDAC6-deficient mice were not protected from weight gain and instead developed exacerbated obesity under microbe-induced conditions. These findings highlight the pivotal yet context-dependent role of HDAC6 in obesity. Further studies are needed to clarify the molecular mechanisms underlying HDAC6’s effects under different pathogenic conditions and to support the development of targeted therapeutics. HDAC4 has also demonstrated diverse effects in obesity-induced insulin resistance, which may depend on its subcellular localization and tissue context. For instance, phosphorylation of HDAC4 by CaMKII was found to block its nuclear translocation, thereby promoting hepatic insulin resistance in obese mice.413 However, Luan et al.438 showed that leptin stimulated the nuclear translocation of HDAC4 in adipose tissue-resident macrophages, leading to the suppression of NF-κB activity and a reduction in systemic insulin resistance associated with obesity.HDAC3, HDAC8, HDAC9, and HDAC11 have been identified as contributors to obesity, primarily through their adverse regulatory effects on metabolic pathways. Dávalos-Salas et al.439 demonstrated that intestine-specific deletion of Hdac3 protected mice from diet-induced obesity. Mechanistically, intestinal HDAC3 acted as a transcriptional corepressor, suppressing genes involved in FA oxidation. Regarding HDAC8, Yang et al.440 reported that oral administration of sulforaphane, an HDAC8 inhibitor, effectively reduced obesity in high-fat diet (HFD)-fed mice. This effect was mediated through enhanced mitochondrial biogenesis in skeletal muscle by the HDAC8–PGC1α axis, highlighting a novel therapeutic approach targeting HDAC8. The decrease in HDAC9 expression in white adipose tissue contributes to the protection of butyrate against diet-induced obesity.441 HDAC11 knockout mice have been reported to be resistant to high-fat diet-induced obesity and metabolic syndrome, suggesting the potential therapeutic benefit of selective HDAC11 inhibitors for the prevention or treatment of obesity and obesity-related diseases.92In contrast, HDAC5 exerts protective effects against obesity, particularly through central regulatory mechanisms. Kabra et al.442 demonstrated that overexpression of hypothalamic HDAC5 enhanced leptin signaling and partially protected against HFD-induced leptin resistance and obesity. This protective effect was mediated through direct interaction with STAT3 and deacetylation at K685, promoting improved leptin action. This result suggests that HDAC5 contributes to antiobesity effects by modulating hypothalamic signaling pathways, offering new insights into the central regulation of energy balance.Overall, current evidence shows that several HDAC members play important roles in the development and regulation of obesity through diverse mechanisms, including regulating leptin signaling, FA metabolism, and gut microbiota composition. Notably, modulating the expression or activity of these HDACs exerts beneficial effects in in vivo obesity models, offering novel therapeutic insights for obesity management. However, the roles of HDAC1, HDAC2, HDAC7, and HDAC10 in obesity remain poorly understood. Further studies are needed to elucidate the specific functions and molecular mechanisms of individual HDAC members, which may facilitate the development of targeted and precise anti-obesity therapies.Other endocrine diseasesHDACs have also been implicated in other endocrine disorders, including Cushing’s syndrome (CS),443 hypothyroidism,444 and Niemann-Pick type C disease.445,446 For instance, Lee et al.443 demonstrated that MS-275 ameliorated hypertension and hyperglycemia in a CS model. Mechanistically, HDAC inhibition increased the acetylation of the glucocorticoid receptor, thereby reducing its transcriptional activity.This section summarizes the roles of HDACs in common endocrine diseases, including DM, DM-associated complications, and obesity. HDAC members exhibit diverse and complex functions in these conditions by modulating key cellular processes such as insulin and leptin signaling, apoptosis, and autophagy. Notably, various HDAC inhibitors have demonstrated protective effects across different disease models, offering a promising foundation for the development of novel therapeutic strategies. Nevertheless, the underlying molecular mechanisms remain to be fully elucidated, and well-designed clinical trials are needed to evaluate the therapeutic potential of HDAC-targeted interventions.HDACs and motor system diseasesThe motor system comprises bones, joints, muscles, tendons, and ligaments, which are essential for movement, structural support, and body protection. Diseases affecting the motor system can impair these components, limiting mobility and daily function. Notably, increasing evidence suggests that HDACs play a critical role in bone and muscle disorders.447 In this section, we summarize the roles and underlying mechanisms of HDACs in various motor system disorders, with a particular focus on osteoarthritis (OA), osteoporosis, Duchenne muscular dystrophy (DMD), and skeletal muscle atrophy-related diseases. The effect of HDACs in these motor system diseases is summarized in (Fig. 14).Fig. 14Full size imageHDACs and motor system diseases. Most HDACs act as detrimental factors in musculoskeletal disorders, including osteoarthritis, osteoporosis, Duchenne muscular dystrophy, and skeletal muscle atrophy. HDAC2 and HDAC6 promote the progression of osteoarthritis, whereas HDAC3 and HDAC4 exhibit protective roles in this condition. HDAC4, HDAC5, and HDAC11 contribute to osteoporosis development. In DMD, HDAC8 has a harmful effect, while HDAC4 is considered protective. HDAC inhibitors such as givinostat and YSR734 have been shown to attenuate disease progression. HDAC1 and HDAC6 facilitate the progression of skeletal muscle atrophy, and HDAC9 has been implicated in CS-induced muscle wasting in a mouse model of COPD. The figure was created with BioRender under an academic license (https://www.biorender.com/)OsteoarthritisOA, an age-related disorder characterized by the progressive degeneration of articular cartilage and chronic joint pain, is a leading cause of physical disability.448 Notably, accumulating studies have shown that HDACs play crucial roles in OA by modulating key pathogenic processes, suggesting that targeting HDACs may offer a potential therapeutic strategy for OA.HDAC3 and HDAC4 have been shown to protect against OA, with HDAC4 being the most extensively studied. HDAC4 has been revealed to alleviate OA through various mechanisms, such as inhibiting hypertrophy, reducing cartilage degeneration, and promoting cartilage repair. For example, Gu et al. found that OA cartilage had reduced HDAC4 expression but increased Runx2, MMP-13, and type X collagen, which are markers of chondrocyte hypertrophy and cartilage damage.449 Furthermore, overexpression of HDAC4 could attenuate articular cartilage damage and delay OA progression.450 These findings suggest that HDAC4 may play a protective role in OA. For HDAC3, Fu et al.228 discovered that intra-articular injection of an HDAC3-expressing adeno-associated virus could delay chondrocyte aging and slow OA initiation and progression in vivo. At the molecular level, HDAC3 inhibits hyperactivated mitophagy by modulating Parkin acetylation.HDAC2 and HDAC6 have been shown to aggravate OA. HDAC2 exacerbates OA by affecting chondrocyte function and cartilage matrix synthesis. For example, Wang et al.451 found that overexpression of HDAC2 accelerated OA by inhibiting chondrocyte proliferation, promoting apoptosis, and enhancing inflammation. Mechanistically, HDAC2 upregulates the expression of serum- and glucocorticoid-inducible kinase-1, a serine/threonine kinase that can regulate inflammation, cell proliferation, and apoptosis. Regarding HDAC6, inhibition with tubastatin A has been shown to protect chondrocyte survival and the joint microenvironment by modulating various cellular processes, including improving mitochondrial function, reducing oxidative stress, and inhibiting ECM degradation.452 Additionally, the HDACi panobinostat (see Table 3 and Fig. 17) has been shown to reduce the severity of histological changes in cartilage, synovium and subchondral bone and improve pain behaviors in a murine OA model, suggesting that targeting HDACs can be a potential target for OA.453Collectively, these results highlight the crucial roles of the HDAC family in OA. However, the clinical use of HDAC modulators for OA treatment is limited by the diverse roles of HDACs in the disease, as outlined above. Therefore, further investigation is essential to elucidate the specific functions of individual HDACs in OA, which will be crucial for developing targeted and effective therapeutic strategies.OsteoporosisOsteoporosis is a common systemic skeletal disorder characterized by progressive bone mass loss and structural deterioration, leading to increased bone fragility and a heightened risk of fractures.454 The pathogenesis of osteoporosis involves the disruption of bone homeostasis, specifically an imbalance between bone formation by osteoblasts and bone resorption by osteoclasts. Emerging evidence suggests that several HDAC members play a role in osteoporosis by modulating the process.HDAC4 is the most extensively studied HDAC member in osteoporosis and has been shown to accelerate disease progression. For instance, Zhang et al.430 demonstrated that inhibition of HDAC4 could ameliorate diabetic osteoporosis by promoting the differentiation of osteoblast precursor cells into osteoblasts through activation of the HIF-1α/VEGFA pathway. Additionally, in prenatal dexamethasone–induced intrauterine hypoglucocorticoid exposure, upregulated HDAC4 mediates osteogenic dysdifferentiation and increases susceptibility to adult osteoporosis.455 Mechanistically, HDAC4 suppressed osteogenic differentiation of bone marrow mesenchymal stem cells by reducing insulin-like growth factor 1 (IGF1) expression through inhibiting H3K27 acetylation in the IGF1 promoter region. IGF1 is a crucial cytokine in fetal development and plays a vital role in maintaining bone mass throughout life. Collectively, these findings indicate that HDAC4 plays a detrimental role in osteoporosis and may represent a promising therapeutic target.HDAC5 and HDAC11 have also been implicated in osteoporosis. For instance, HDAC11 was found to inhibit the expression of 11β-hydroxysteroid dehydrogenase 2 by binding to its promoter region and reducing H3K9 acetylation levels.456,457 This inhibition contributed to the suppressive effects of corticosterone on the osteogenic differentiation of BMSCs, thereby increasing susceptibility to osteoporosis. Moreover, inhibition of HDAC5 by miR-2861 has been shown to exert protective effects against osteoporosis.458 Notably, SAHA inhibits RANKL-induced osteoclast differentiation in a dose-dependent manner, thereby alleviating ovariectomy-induced bone loss, highlighting the translational potential of HDACis in osteoporosis therapy.459In summary, the available evidence demonstrates that HDAC4, HDAC5, and HDAC11 play detrimental roles in osteoporosis by disrupting bone homeostasis. Therefore, targeting these HDACs may represent a promising therapeutic strategy, warranting further investigation.Duchenne muscular dystrophyDMD is an X-linked inherited disorder caused by the absence of functional dystrophin in muscle cells, leading to progressive muscle deterioration and premature death.460 Notably, growing evidence suggests that HDAC inhibition exerts beneficial effects in DMD, offering potential therapeutic insights.461 This section summarizes the effects of various HDAC inhibitors and the roles of specific HDAC members in DMD.Recently, the pan-HDAC inhibitor givinostat (see Table 3 and Fig. 17) has been approved by the FDA for the treatment of DMD in patients aged six and older based on both preclinical and clinical evidence of its efficacy. Among this evidence, a phase III randomized, double-blind clinical trial (NCT02851797) evaluated givinostat versus placebo over 18 months in 179 patients with DMD with a mean age of nine years who were receiving stable steroid treatment. The study met its primary endpoint, demonstrating a slower decline in muscle function, measured by changes in the four-stair climb time, in the givinostat-treated group, highlighting its significant therapeutic potential for DMD.462 Beyond givinostat, Raouf et al.463 identified YSR734 (see Table 3 and Fig. 17), a covalent HDAC inhibitor, as a promising therapeutic candidate for DMD. In C2C12 myoblasts, YSR734 activated muscle-specific biomarkers, including myogenin and Cav3, promoting potent differentiation into myotubes. Additionally, Spreafico et al.464 reported that HDAC8 expression was elevated in both patients with DMD and dystrophic zebrafish. Selective inhibition of HDAC8 with PCI-34051 rescued skeletal muscle defects, similar to the effects of givinostat. Mechanistically, HDAC8 inhibition increased α-tubulin acetylation, suggesting that targeting HDAC8 may be a promising therapeutic strategy for DMD. However, a study by Renzini et al.465 revealed that cytoplasmic HDAC4 plays a role in muscle repair following damage, likely by stabilizing Trim72 mRNA in DMD. These findings suggest that, rather than being inhibited, cytoplasmic HDAC4 functions should be preserved or stimulated in DMD. Therefore, further research is needed to elucidate the specific roles and targets of individual HDAC members and to develop selective inhibitors for precise and effective therapy.Skeletal muscle atrophy-related diseasesSkeletal muscle atrophy, characterized by a reduction in muscle mass and strength, can result from various factors.466 Currently, emerging studies have demonstrated that HDACs contribute to skeletal muscle atrophy associated with various diseases. HDAC9 is implicated in skeletal muscle atrophy associated with cigarette smoke (CS)-induced COPD. Zheng et al. reported that HDAC9 KO mitigated skeletal muscle atrophy and enhanced regeneration in a mouse model of CS-induced COPD. Mechanistically, HDAC9 inhibition improved CS-induced impairments in muscle differentiation and regeneration, potentially by activating the AKT/mTOR pathway and suppressing the P53/P21 pathway.467 In addition, HDAC1 and HDAC6 have been implicated in the pathogenesis of skeletal muscle atrophy. For instance, Ratti et al.468 demonstrated that HDAC6 expression is upregulated by FoxO3 in skeletal muscle atrophy and that HDAC6 inactivation mitigates atrophic processes. Similarly, Beharry et al.469 reported that HDAC1 activates FoxO, leading to muscle fiber atrophy in vivo. FoxO transcription factors have been shown to induce the atrophy-related ubiquitin ligase atrogin-1, which plays a critical role in muscle degradation. These findings underscore the pivotal roles of HDACs in skeletal muscle atrophy and highlight the need for further investigation into their precise mechanisms and potential as therapeutic targets.In summary, emerging evidence suggests that various HDACs play critical roles in multiple motor system diseases. Given their pivotal roles in regulating muscle mass, structure, and function, HDACs represent promising therapeutic targets. However, significant limitations remain in this field. Future research should focus on elucidating the specific functions and therapeutic potential of individual HDACs in each disease, providing a solid foundation for their clinical application.HDACs and urogenital system diseasesThe urogenital system, comprising the urinary and reproductive organs, is fundamental to fluid balance, waste elimination, and reproductive function. Increasing evidence suggests that the activity and expression of the HDAC family are linked to the onset and progression of various urogenital diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), renal fibrosis, oocyte maturation, and spermiogenesis, among others. The roles of HDACs in urogenital system diseases are presented in (Fig. 15).Fig. 15Full size imageHDACs and urogenital system diseases. HDACs and urogenital system diseases. HDACs are widely implicated in promoting the progression of acute kidney injury and chronic kidney disease. Notably, HDAC1 exerts dual roles in acute kidney injury. In the reproductive system, HDACs have been shown to play essential roles in supporting oocyte maturation and spermatogenesis. The figure was created with BioRender under an academic license (https://www.biorender.com/)Acute kidney injury and chronic kidney diseaseAKI refers to a syndrome characterized by a sharp decline or complete loss of kidney function, resulting in impaired glomerular filtration and altered renal tubular concentration and dilution. The HDAC family influences the onset and progression of AKI primarily through autophagy and apoptosis pathways. For instance, HDAC2 inhibition reduces apoptosis in renal tubular epithelial cells by increasing BMP-7 levels.470 In addition, inhibition of HDAC4 can alleviate AKI by suppressing CD4+ T cell apoptosis and promoting autophagy.148 Some studies also suggest that HDAC1 and HDAC2 inhibitors may protect against renal injury by inhibiting ferroptosis in cisplatin-induced AKI.471 Similarly, HDAC3 aberration alleviates AKI-CKD progression by preserving GPX4.160 Furthermore, HDAC1 suppresses inflammatory responses following renal ischemia‒reperfusion injury by promoting chromatin condensation through histone deacetylation and directly interacting with ATF3 to interfere with NF-κB binding at the promoters of pro-inflammatory cytokines such as IL-6.472When AKI progresses for more than three months, renal structural and functional impairments reach a critical threshold, often leading to the development of CKD. Several studies have suggested that the HDAC family may influence the development of CKD and its complications through the modulation of Klotho. For instance, selective inhibition of HDAC3 has been shown to mitigate kidney injury and prevent the loss of Klotho, an anti-aging protein predominantly expressed in the kidneys. Notably, the protective effects of HDAC3 inhibition were significantly diminished when Klotho expression was silenced by siRNA, indicating that aberrant HDAC3 activity and Klotho deficiency are critical contributors to renal damage in chronic kidney disease models.473 Additionally, VPA, another HDAC inhibitor, has been shown to improve CKD severity by reducing proteinuria, podocyte injury, and renal damage474, primarily through promoting autophagy and inactivating the NF-κB/iNOS signaling pathway.475 In summary, HDACs play significant roles in the pathogenesis of AKI and CKD through various mechanisms, and HDAC inhibitors may offer therapeutic potential for mitigating the severity of these conditions.Renal fibrosisRenal fibrosis is a chronic, progressive condition that represents the final stage of CKD. It is characterized by renal tissue injury, inflammation, extracellular matrix deposition, and tubular epithelial–mesenchymal transition. The HDAC family plays a critical role in the progression of renal fibrosis, primarily by modulating the expression of antifibrotic proteins. For example, aberrant HDAC3 activity inhibits the transcription of Klotho and promotes renal fibrosis in mice.476 Moreover, in chronic kidney disease, the expression levels of HDAC2 and HDAC3 are upregulated. Their enhanced regulation of endothelin-1 and deacetylation of NF-κB contributes to the progression of renal fibrosis.48,477 Inhibiting HDAC4 may mitigate renal fibrosis development by suppressing the activation and expression of various profibrotic molecules while enhancing antifibrotic proteins and matrix metalloprotein expression.478 Additionally, HDAC8 activates multiple profibrotic signaling pathways and transcription factors while simultaneously suppressing antifibrotic proteins in murine renal fibrosis.479 Inhibition of HDACs has also been shown to attenuate renal interstitial fibrosis in murine models.480 Consistent with their roles in AKI and CKD, HDACs also contribute to the progression of renal fibrosis, and HDAC inhibitors have demonstrated therapeutic potential in animal models.Genital systemOocytes are fundamental to successful fertility, providing mRNA, proteins, substrates, energy, and other essential factors for early embryonic development. Their proper formation is crucial for conception and embryogenesis, as it is closely linked to the process of meiosis. Studies have confirmed that HDACs influence oocyte formation by regulating meiotic progression. For instance, HDAC3 modulates microtubule stability through the deacetylation of tubulin, which is essential for maintaining proper spindle assembly, accurate chromosome segregation, and orderly meiotic progression during mouse oocyte maturation.481 It has also been proven that HDAC1 and HDAC11 exert positive effects on oocyte maturation.482,483 Sperm, the male germ cells responsible for transmitting genetic material, undergo a complex process of division and differentiation within the seminiferous tubules of the testes before reaching full maturation. HDAC1 interacts with MAGE-A1 to promote spermatogonia maturation and spermatozoa formation.484 Another study found that HDAC3 is specifically expressed during the late meiotic and early haploid stages, where it functions as a key regulator of spermatogenesis through its interaction with SOX30, independent of its deacetylase activity.485 Furthermore, HDACs deacetylate H3K27, reducing chromatin transcriptional activity, preventing premature expression of developmental genes, and safeguarding zygotic genome activation.486 Collectively, these findings indicate that HDACs are deeply involved in germ cell development and function. Animal studies suggest that HDAC inhibition may have detrimental effects on germ cells, highlighting the importance of precise HDAC regulation in reproductive health.In summary, this section discusses the relationship between the HDAC family and the urogenital system. HDAC activity is generally associated with detrimental effects in urinary system diseases, including AKI, CKD, and renal fibrosis, while playing a beneficial role in genital cell function. However, all therapeutic investigations have thus far been limited to cell and animal studies, highlighting the need for further research to assess their clinical applicability.HDAC modulatorsHDAC modulators have emerged as promising therapeutic strategies for diverse pathological conditions. These modulators include both activators and inhibitors, with research predominantly focusing on HDACis. HDACis are commonly classified according to their chemical structure and zinc-binding group (ZBG). Current studies primarily categorize HDACis into four major classes: hydroxamic acids (HAs), benzamides, aliphatic acids, and cyclic peptides. Notably, novel HDACis such as hydrazide-based compounds have garnered increasing attention in recent years. Five HDACis have been approved by the Food and Drug Administration (FDA) to date, primarily for the treatment of cancers and neurological disorders. In addition, several other HDACis are undergoing clinical trials for various indications. Detailed information about relevant HDAC modulators is provided in Tables 2 and 3. The structures of the most relevant HDAC activators and inhibitors are presented in Figs. 16 and 17, respectively. (All references are listed in Supplement Table 1).Fig. 16Full size imageStructures of the most relevant HDAC activators. Chemical structures of the synthetic activators ITSA-1, calcitriol, and theophylline. These activators can engage distinct HDAC isoforms: ITSA-1 can act as HDAC1 activator; calcitriol can target HDAC3; and theophylline predominantly targets HDAC1 and HDAC2. The figure was created with BioRender under an academic license (https://www.biorender.com/)Fig. 17Full size imageStructures of the most relevant HDAC inhibitors. Structures of hydroxamic acids (e.g., vorinostat, panobinostat, belinostat), benzamides (e.g., entinostat, chidamide, mocetinostat), aliphatic acids (valproic acid, sodium butyrate), cyclic peptides (romidepsin, OKI-179), hydrazide-based inhibitors (DS-103, B6, eimbinostat), and others (e.g., SPA3074, compound 59, compound 17). Structures are ordered from left to right according to Table 3. The figure was created with BioRender under an academic license (https://www.biorender.com/)Table 2 Most relevant HDAC activatorsFull size tableTable 3 Most relevant HDAC inhibitorsFull size tableAt present, there are still some challenges regarding HDACis. First, the majority of HDACis are paninhibitors, which leads to off-target effects. Meanwhile, the toxicity of HDACis is another major concern, especially since their use in combination therapies may exacerbate the toxicity of other therapeutic agents. Additionally, HDAC activators have received minimal research attention. Furthermore, most existing research continues to focus predominantly on tumor-related diseases, with relatively little attention to nononcological conditions.Intriguingly, a growing body of research is actively investigating HDACis, with recent advancements expected to enhance their potential for clinical application. These advancements include the development of novel classes of HDACis, combinations with immunotherapy, hybrid molecules, and isoform-selective HDACis, as well as their expanding applications across a vast range of therapeutic fields. First, novel classes of HDACis, such as hydrazide-based HDACis, have emerged as promising therapeutic candidates with distinct advantages over conventional inhibitors. Among the commonly employed ZBGs, HAs and 2-aminobenzamides (a subfamily of benzamides) are predominant. However, the former often exhibits off-target effects due to poor isoform selectivity and affinity for other metalloenzymes, while the latter may cause in vivo toxicity due to the exposed free amine group. Notably, hydrazide-based inhibitors have been discovered to exhibit enhanced potency and isoform selectivity, substantially mitigating off-target interactions. These advantages may be due to their favorable physicochemical properties and structural flexibility, which allow for the incorporation of additional functional groups to address alternative therapeutic targets without compromising HDAC-binding efficiency in most cases. This pharmacological profile could enable the use of lower therapeutic doses, which could minimize systemic toxicity and reduce the range of adverse effects typically associated with HDACis. Conventional combination therapies play a crucial role in disease management, yet the concurrent use of multiple agents often raises concerns about drug–drug interactions and systemic toxicity. Recent studies have focused on integrating multiple pharmacological functions into a single molecular framework to overcome these limitations. When the pharmacophores incorporated into a hybrid inhibit two different targets, the hybrid acts as a dual-function inhibitor. Among them, BET/HDAC hybrid compounds have demonstrated enhanced efficacy and reduced toxicity compared with the coadministration of individual drugs, highlighting their promise as a next-generation therapeutic strategy in HDACi-based treatment. Additionally, the application of hybrid compound strategies has further expanded the therapeutic potential of HDACis, offering the potential to overcome the limitations of conventional combination therapies. Furthermore, the development of increasingly isoform-selective HDACis holds promise for mitigating the adverse effects commonly associated with pan-HDACis. At present, numerous isoform-selective HDACis are under active development; notably, the HDAC6-selective inhibitor ricolinostat (ACY-1215; see Table 3 and Fig. 17) has advanced to phase II clinical trials for multiple myeloma. Isoform-selective HDAC inhibitors are expected to offer a more favorable safety profile. Pan-HDAC inhibitors, which commonly engage multiple human HDAC isoforms simultaneously, have frequently been associated with more severe toxicities. However, most of the currently identified isoform-specific compounds remain in preclinical stages, underscoring the need for further investigation and optimization before clinical translation. Moreover, HDACis have shown significant potential to enhance the efficacy of immunotherapy, particularly in tumor treatment. For instance, in preclinical immune-competent models of refractory or relapsed natural killer/T-cell lymphoma (NKTCL), the combination of anti-PD1 therapy and chidamide has been shown to upregulate T-cell chemokine expression and enhance IFN-γ responses. In addition, SC26, a selective HDAC3 inhibitor, has emerged as a novel epigenetic immunomodulator, representing a promising approach in the development of next-generation cancer immunotherapies. Notably, current research on HDACis is progressively expanding beyond oncology to encompass a broad range of noncancerous diseases, including cardiovascular, respiratory, and digestive disorders, highlighting their therapeutic potential across various diseases.In summary, fully harnessing the therapeutic potential of HDAC modulators, it is imperative to conduct numerous studies under diverse pathological conditions. Clarification and optimization of PK/PD properties, along with efficacy, selectivity, and safety, are essential for advancing these agents toward broader clinical application.ConclusionOver the past two decades, a growing body of research has highlighted the pivotal roles and underlying mechanisms of HDACs in human health and diseases. HDACs participate in various biological processes, including inflammation, metabolism, multiple RCDs, oxidative stress, cell proliferation, cell migration and invasion, and cell senescence. The effect of individual HDAC isoforms on a given process is complex and context dependent, varying according to factors such as the specific target protein, modification site, type of acylation, subcellular localization, and the tissue or organ involved. Given their critical regulatory functions in a wide range of physiological and pathological processes, advancing our understanding of HDACs offers a unique opportunity to develop therapeutic targets in diverse diseases. Currently, HDACs are recognized as vital regulators in various diseases, including tumors and cardiovascular, respiratory, digestive, nervous, endocrine, motor, and urogenital system disorders. Under pathological conditions, particularly in cancer, HDACs are generally associated with deleterious effects. Various HDACis have shown protective and therapeutic benefits in various disease models. Several HDACis have already been approved by the FDA for treating conditions such as cutaneous T-cell lymphoma, multiple myeloma, peripheral T-cell lymphoma, and DMD. These findings provide novel strategies for clinical intervention. Despite these advances, significant challenges remain, such as poor specificity, off-target effects, toxicity, and resistance. Currently available HDAC modulators often lack isoform selectivity, resulting in off-target effects and dose-limiting toxicity, which limits their clinical utility. Investigating the precise mechanisms by which individual HDAC isoforms function under various conditions is essential to address these challenges, given their complex and context-dependent effects. A comprehensive understanding of the roles and molecular mechanisms of specific HDAC isoforms is of significant scientific and clinical value. Moreover, the development of isoform-selective HDAC inhibitors is critical for enhancing therapeutic efficacy while minimizing adverse effects. Furthermore, most current studies are limited to cellular and animal models, and clinical trials validating the therapeutic potential of HDACs remain scarce. Therefore, well-designed clinical investigations are warranted to translate preclinical findings into effective clinical interventions. In this review, we have summarized recent advances in HDAC research to provide a foundation for future studies and highlight the translational potential of HDACs as promising targets for disease intervention.Future directionsDespite significant advances in understanding the biological functions of HDACs, several key areas require further investigation to harness their therapeutic potential.First, it is essential to elucidate the isoform-specific regulatory roles and molecular mechanisms of HDACs in distinct tissues, organs, and systems under various physiological and pathological conditions. These investigations will clarify the context-dependent functions of HDACs and provide a theoretical basis for targeted therapeutic strategies. Moreover, given the coexpression and functional interplay among HDAC family members, clarifying the interactions and regulatory mechanisms between different isoforms is necessary for the design of combination-targeting approaches. Encouragingly, technological advances, such as gene knockout/knockin models, multiomics integration, and machine learning, provide powerful tools for uncovering HDAC-regulated networks and identifying key downstream targets. These studies are expected to yield novel insights into disease pathogenesis and support the development of more effective HDAC-targeted therapies.Second, the development of isoform-selective HDAC modulators with improved efficacy and safety remains a key challenge. Most currently available HDAC inhibitors lack specificity, resulting in off-target effects and toxicity. Future studies should focus on developing highly selective modulators and conducting extensive preclinical and clinical studies to evaluate their therapeutic efficacy and safety. Advancing the clinical translation of HDACis requires systematic studies evaluating their pharmacokinetics, pharmacodynamics, tissue specificity, and half-life. In addition, assessments of potential adverse effects are essential to ensure patient safety. These studies aim to enhance the efficacy and safety of HDAC modulators across different diseases and guide the rational optimization of dosage regimens and therapeutic strategies.Third, combination therapies are of great importance. Combining HDAC modulators with other agents, such as anticancer drugs, immunomodulators, or targeted therapies, should be explored, as this approach is expected to enhance therapeutic outcomes, overcome resistance, and minimize required doses. However, it is essential to evaluate safer combination partners to mitigate toxicity.Moreover, to overcome resistance, several strategies are essential, including developing isoform-selective modulators, combining with other therapeutic agents, and applying advanced drug delivery systems (such as nanoparticles, liposomes, and exosome-based carriers). Additionally, advanced drug delivery systems facilitate targeted and sustained release, thereby enhancing therapeutic precision, minimizing systemic toxicity, and ultimately improving treatment efficacy.Additionally, the potential therapeutic effects of FDA-approved HDACis in treating nononcological conditions warrant further exploration. Moreover, the utility of HDACs as diagnostic and prognostic biomarkers should be assessed in diverse populations through large-scale clinical studies, which would provide more robust evidence. Increasing attention should be given to the various roles of HDACs, including the regulatory functions of other acylations beyond acetylation, scaffolding functions, and involvement in protein‒protein interactions, which may reveal novel biological functions and therapeutic targets.Collectively, these future research directions will contribute to a more comprehensive understanding of HDAC biology and facilitate the development of safer and more effective HDAC-targeted therapies for diverse diseases.Data availabilityData will be made available upon reasonable request from the corresponding author.ReferencesHaberland, M., Montgomery, R. L. & Olson, E. N. The many roles of histone deacetylases in development and physiology: Implications for disease and therapy. Nat. Rev. Genet. 10, 32–42 (2009).Article CAS PubMed PubMed Central Google Scholar Shvedunova, M. & Akhtar, A. Modulation of cellular processes by histone and non-histone protein acetylation. Nat. Rev. Mol. 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We also thank Jia-Xin Xie, Yu-Can Li, and Jia-Yin Wang for their assistance with data verification.Author informationAuthor notesThese authors contributed equally: Ri Wen, Yu-Hang Yang, Tao ZhangAuthors and AffiliationsDepartment of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, ChinaRi Wen, Yu-Hang Yang, Tao Zhang, Sen-Yu Zhang, Xin-Ru Yang, Li-Ying Zhang, Peng-Hui Hao, Yue Zheng, Ni Yang & Tie-Ning ZhangAuthorsRi WenView author publicationsSearch author on:PubMed Google ScholarYu-Hang YangView author publicationsSearch author on:PubMed Google ScholarTao ZhangView author publicationsSearch author on:PubMed Google ScholarSen-Yu ZhangView author publicationsSearch author on:PubMed Google ScholarXin-Ru YangView author publicationsSearch author on:PubMed Google ScholarLi-Ying ZhangView author publicationsSearch author on:PubMed Google ScholarPeng-Hui HaoView author publicationsSearch author on:PubMed Google ScholarYue ZhengView author publicationsSearch author on:PubMed Google ScholarNi YangView author publicationsSearch author on:PubMed Google ScholarTie-Ning ZhangView author publicationsSearch author on:PubMed Google ScholarContributionsN.Y. and T.-N.Z. provided the conceptual idea and design of this study and wrote the manuscript. R.W., Y.-H.Y., T.Z., S.-Y.Z., X.-R.Y., L.-Y.Z., P.-H.H., and Y.Z. performed the literature search and wrote the manuscript. R.W., Y.-H.Y., T.Z., N.Y., and T.-N.Z. made the figures and tables. All authors listed have made a substantial contribution to this work. All authors have read and approved the article. R.W., Y.-H.Y., and T.Z. contributed equally to this work.Corresponding authorsCorrespondence to Ni Yang or Tie-Ning Zhang.Ethics declarationsCompeting interestsThe authors declare no competing interests.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationRights and permissionsOpen Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. 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