{"paper_id":"8090b163-f004-46f9-af9c-2382a8b20621","body_text":"ENDOMETRIOSIS: REVIEW\nReproductive Sciences\nhttps://doi.org/10.1007/s43032-026-02184-7\nShisi Xiong and Junjie Xu contributed equally to this work.\n Shaojie Zhao\nzsjie2005@163.com\n Liping Jiang\nfckjlp1982@163.com\n1 Department of Obstetrics and Gynecology, Wuxi Maternity \nand Child Health Care Hospital, Wuxi 214002, China\n2 Renji Hospital, Shanghai Jiao Tong University School of \nMedicine, Shanghai 200003, China\n3 Wuxi School of Medicine, Jiangnan University,  \nWuxi 214002, China\n4 Wuxi Medical Center of Nanjing Medical University,  \nWuxi 214002, China\nAbstract\nEndometriosis is a complex chronic inflammatory disease with an unclear etiology and limited treatment options, severely \naffecting the reproductive health and quality of life of many women. Histone deacetylases (HDACs), as key epigenetic \nregulatory molecules, play a significant role in the pathogenesis and progression of endometriosis. This article reviews \nthe abnormal expression of HDACs in endometriosis and their molecular mechanisms in driving the disease by regulating \nprocesses such as cell proliferation, apoptosis, inflammation, and epithelial-mesenchymal transition (EMT). It also sum -\nmarizes the therapeutic potential of histone deacetylase inhibitors (HDACis) such as V orinostat, Romidepsin, and Butyr -\nate demonstrated in preclinical studies, and analyzes the main challenges currently faced in clinical translation. Finally, \nthis article discusses the challenges and future research directions for developing novel endometriosis therapies targeting \nHDACs, aiming to provide references for in-depth research and clinical translation in this field.\nKeywords Endometriosis · Histone deacetylase (HDACs) · Histone deacetylase inhibitors (HDACis) · Epigenetics · \nTargeted therapy\nReceived: 9 April 2026 / Accepted: 15 August 2026\n© The Author(s) 2026\nResearch Progress of Histone Deacetylase and Its Inhibitors in \nEndometriosis\nShisi Xiong1,3 · Junjie Xu1,4 · Jingjing Pu2 · Shaojie Zhao1 · Liping Jiang1\nas 30%–50% in infertility patients [ 1]. Currently, the treat-\nment of endometriosis primarily relies on hormonal drugs \nand surgical intervention. However, hormonal therapy is \noften accompanied by a series of side effects and has a high \nrecurrence rate after discontinuation; while surgery can \neffectively remove lesions, it cannot achieve a cure, with a \npostoperative 5-year recurrence rate reaching 40%–50% [2]. \nTherefore, exploring new therapeutic targets and strategies \nand developing safe and effective non-hormonal drugs have \nbecome important directions in endometriosis research.\nIn recent years, epigenetics has gained increasing atten -\ntion in the study of the pathogenesis and treatment of endo-\nmetriosis. Histone acetylation, as an important epigenetic \nmodification, is jointly regulated by histone acetyltrans -\nferases (HATs) and histone deacetylases (HDACs) and is \ninvolved in various biological processes such as cell pro -\nliferation, differentiation, apoptosis, and inflammatory \nresponses [3]. Numerous studies have shown that there are \nabnormalities in the expression and function of HDACs \nin endometriosis [ 4, 5]. This dysregulation participates in \npathological processes such as abnormal proliferation, inva-\nsion, and fibrosis of ectopic endometrial cells by modulating \nkey pathways including estrogen signaling, inflammatory \nresponses, epithelial-mesenchymal transition, and the cell \nEndometriosis is a common benign gynecological disease \ncharacterized by the ectopic presence of viable endometrial-\nlike tissue outside the uterine cavity. Clinically, it mainly \nmanifests as chronic pelvic pain, dysmenorrhea, dyspareu -\nnia, and infertility, severely affecting the quality of life of \nwomen of reproductive age. Epidemiological data show that \nthe prevalence of endometriosis among women of reproduc-\ntive age is approximately 10%–15%, and it can be as high \n\n1 3\nReproductive Sciences\ncycle [ 3, 6]. Histone deacetylase inhibitors (HDACis), \nas a classic class of anti-tumor drugs, can restore histone \nacetylation levels and reactivate silenced tumor suppressor \ngenes. Their potential in endometriosis treatment has gradu-\nally been revealed in recent years. Studies have confirmed \nthat various HDACis exhibit multiple therapeutic effects \nin endometriosis cell and animal models, including inhib -\niting lesion growth, inducing apoptosis, anti-inflammatory \neffects, and analgesia [4, 6, 7].\nHowever, the clinical translation of HDACis still faces \nmany challenges. Traditional pan-HDACis, due to their lack \nof subtype specificity, are often accompanied by off-target \nside effects such as fatigue and thrombocytopenia [ 3]. The \nheterogeneity in the expression of different HDAC subtypes \nin endometriosis lesions also imposes higher requirements \nfor precision therapy. Furthermore, issues such as the poten-\ntial impact of HDACis on female fertility, the safety of long-\nterm medication, and synergistic strategies with existing \ntreatment regimens all require systematic investigation.\nThis article begins with the expression and pathogenic \nmechanisms of HDACs in endometriosis, then summarizes \nthe research progress of both classic and novel HDACis \nfor endometriosis treatment. It also discusses emerging \ncombination therapy strategies, novel drug development, \nand optimization of drug delivery systems, and examines \nthe prospects of biomarker-guided personalized therapy in \nendometriosis management. This review aims to provide \na reference for further research and clinical translation of \nHDACis in endometriosis.\nAbnormal Expression and Function of \nHDACs in Endometriosis\nHDAC Family Expression Profiles and Pathological \nCorrelations\nClassification and Functions of HDACs\nHDACs are a class of enzymes ubiquitously present in \neukaryotic cells that catalyze the deacetylation of histone \nand non-histone substrates, thereby regulating various cel -\nlular biological processes including cell proliferation, apop-\ntosis, immune response, and metabolic homeostasis. Based \non differences in structural homology with yeast, they can \nbe divided into four classes [ 8]. Among them, Classes \nI, II, and IV are zinc-dependent enzymes, while Class III \nare NAD+-dependent enzymes. Class I HDACs include \nHDAC1, 2, 3, and 8, which function by forming complexes \nwith other proteins [9] and are associated with diseases such \nas cancer, inflammation, and infection. Class II HDACs \nare further divided into Class IIa (HDAC4, 5, 7, and 9) and \nClass IIb (HDAC6 and 10) based on their catalytic domains, \nand are characterized by their ability to shuttle between the \nnucleus and cytoplasm [10].Among them, Class IIa HDACs \nexhibit relatively low deacetylase activity towards histones, \nwhereas HDAC6, a Class IIb member, possesses significant \ndeacetylase activity towards non-histone substrates includ -\ning α-tubulin and molecular chaperones, and is involved in \nthe regulation of autophagy and hepatic metabolism [ 11]. \nClass III HDACs consist of the Sirtuins (SIRTs) family \n1–7, which, along with ADP-ribosyltransferases, partici -\npate in regulating various cellular processes [ 8]. HDAC11 \nis the sole member of Class IV HDACs, highly expressed in \norgans such as the brain, heart, and kidneys, and involved \nin multiple pathophysiological processes, closely related to \nmetabolic diseases like obesity and diabetes [12].\nAbnormal Expression of HDACs in Endometriosis\nThe occurrence and development of endometriosis involve \ncomplex epigenetic regulatory mechanisms, among which \nthe abnormal expression of HDACs has received widespread \nattention in recent years. HDACs catalyze the deacetylation \nof histone lysine residues, altering chromatin conformation \nand thereby regulating gene transcription. Studies indicate \nthat multiple HDAC family members exhibit differential \nexpression in endometriosis, and this dysregulation of the \nexpression profile may be involved in pathological pro -\ncesses such as abnormal proliferation and invasion of ecto -\npic endometrial cells (Table 1).\nExpression of Class I HDACs  HDAC1 is one of the most \nextensively studied HDAC subtypes, and there is rela -\ntively consistent evidence for its upregulation in endo -\nmetriosis. Colón-Díaz et al. reported that the mRNA and \nprotein levels of HDAC1 in endometriotic stromal cells \n(Hs832cT) were significantly higher than those in normal \nstromal cells; estradiol combined with progesterone could \ndownregulate HDAC1 expression in normal endometrial \nepithelial cells, but this hormonal regulatory effect was \nlost in Hs832cT cells. However, the HDAC1 mRNA level \nwas lower in homogenates of ectopic tissues compared to \ncontrols; at the protein level, HDAC1 was widely highly \nexpressed in ovarian, skin, and gastrointestinal lesions, \nand its expression was higher in ovarian lesions than in \nperitoneal lesions, suggesting a potential association with \nmalignant transformation potential [ 13]. Another study \nalso showed that HDAC1 mRNA expression was lower \nin ectopic endometrial tissues compared to normal endo -\nmetrium [ 5]. The above differences in mRNA expression \nmay stem from the models used: cell lines reflect intrinsic \ncellular characteristics, whereas tissue samples integrate \nthe multiple influences of the lesion microenvironment. \n\n1 3\nReproductive Sciences\nAdditionally, post-transcriptional regulation and cellular \nheterogeneity within tissues may also contribute to these \ndifferences. Mechanistically, a study based on exosomes \nfrom ovarian endometrioma (OE) patient tissues found that \nlncRNA HOTAIR upregulated HDAC1 protein expression \nby downregulating miR-761; in vivo experiments in nude \nmice confirmed that exosomal HOTAIR could promote \nthe growth of ectopic lesions, providing in vivo functional \nvalidation for the pathogenic role of HDAC1 in endome -\ntriosis [14]. Genetic analysis revealed that HDAC1 single \nnucleotide polymorphisms (SNPs) were significantly asso -\nciated with endometriosis risk in South Indian women, \nsuggesting it may be a genetic susceptibility marker [ 15]. \nIn mouse models, HDAC1 staining intensity progressively \nincreased with lesion progression [ 16]. Zheng et al. fur -\nther found in a TGF-β1-induced epithelial-mesenchymal \ntransition model that HDAC1 expression was upregulated \nin the human endometrial epithelial cell line 11Z, and pri -\nmary stromal cells isolated from OE exhibited significantly \nhigher HDAC1 mRNA and protein levels than normal \ncontrols; immunohistochemical analysis of human lesions \nconfirmed that HDAC1 staining was significantly enhanced \nin deep infiltrating endometriosis (DIE), with expression \nlevels positively correlated with lesion fibrosis [ 4]. Col -\nlectively, these findings indicate that HDAC1 is gener -\nally upregulated in endometriosis, but the inconsistency \nbetween mRNA and protein levels suggests complex post-\ntranscriptional regulation, and the differences in expression \nacross lesion subtypes and cell types should be considered \nin precision therapy.\nThe expression pattern of HDAC2 is more complex. Simi-\nlar to HDAC1, both the mRNA and protein levels of HDAC2 \nin Hs832cT are significantly higher than those in normal  \nstromal cells. In normal stromal cells, estradiol upregulates \nHDAC2 expression, whereas combined treatment with \nestrogen and progesterone downregulates it; however, this \nregulation is lost in Hs832cT. At the human tissue level, \nHDAC2 is highly expressed in skin lesions and eutopic \nendometrial stroma (100% and 82%), whereas the positiv -\nity rates are lower in ovarian and peritoneal lesions. mRNA \nanalysis shows that HDAC2 levels in lesions are lower than \nin eutopic endometrium but higher than in myoma control \nendometrium, indicating expression heterogeneity at the \ntissue level [ 13]. Another study also found that HDAC2 \nmRNA is significantly elevated in the eutopic endometrium \nof endometriosis patients but shows no significant differ -\nence in ectopic endometrium [5]. These results collectively \nindicate that HDAC2 expression exhibits clear model depen-\ndency and tissue heterogeneity. Moreover, Mai et al. found \nthat HDAC2 protein expression in human endometriotic \nlesions is significantly higher than in normal endometrium; \nknockdown of HDAC2 in hEM15A cells can upregulate the \nhepatocyte nuclear factor 4α / AT-rich interactive domain 1 \nA (HNF4A/ARID1A) axis, inhibiting proliferation and inva-\nsion while promoting apoptosis; animal experiments further \nconfirmed that HDAC2 knockdown can reduce lesion size \n[17]. Additionally, in mouse models, HDAC2 staining inten-\nsity gradually decreases with lesion progression [16]. Zheng \net al., through immunohistochemistry of human endometri-\notic lesions, observed that HDAC2 expression in DIE is sig-\nnificantly lower than in OE and is negatively correlated with \nthe degree of lesion fibrosis [ 4]. These pieces of evidence \nsuggest that HDAC2 may exert differential regulatory roles \nat different stages of the disease.\nHDAC3 is downregulated in endometriosis and is associ-\nated with infertility and the severity of lesion fibrosis. Kim \nTable 1 Differential expression and functional roles of HDACs in endometriosis\nClass HDAC Isoform Expression pattern Pathological association Key mechanisms References\nClass I HDAC1 Widely upregulated in \nlesions\nProliferation, invasion, EMT, \nfibrosis\nRegulation of RHOB, p21, and \nassociation with ERα expression\n[6, 13, 32]\nHDAC2 Dynamically altered (high \nin early-stage, low in \nlate-stage)\nDisease progression Regulation of the HNF4A/\nARID1A axis\n[5, 17]\nHDAC3 Downregulated in patients \nwith infertility\nEndometrial receptivity Involvement in decidualization \nand embryo implantation\n[18]\nHDAC8 Progressively upregulated \nwith disease advancement\nFibrosis, pain Regulation of TGF-β signaling [4]\nClass II HDAC6 Significantly upregulated in \nDIE and OE lesions\nRisk of malignant \ntransformation\nα-tubulin deacetylation; associa-\ntion with ARID1A loss\n[19]\nHDAC9 Upregulated in DIE lesions To be validated To be elucidated [20]\nClass III SIRT1 Controversial (mostly \nreported as upregulated)\nInflammation, progesterone \nresistance, infertility\nRegulation of p53, FOXO1, \nBCL6, and NF-κB\n[22, 24, 25]\nSIRT3 Controversial Oxidative stress, mitochon-\ndrial function\nRegulation of SOD2, GDH, and \nSDH\n[28, 29]\nSIRT7 Upregulated Mitochondrial stress, meta-\nbolic reprogramming\nTUFM deficiency promotes \nSIRT7 overexpression\n[31]\nEMT epithelial-mesenchymal transition, ERα estrogen receptor alpha, DIE deep infiltrating endometriosis, OE ovarian endometrioma\n\n1 3\nReproductive Sciences\net al. found that in endometriosis patients with infertility, \nHDAC3 protein in the in situ endometrium was significantly \nlower than in normal controls during the proliferative, early \nsecretory, and mid-secretory phases. In a baboon model \nof endometriosis, HDAC3 expression gradually decreased \nas the disease progressed; in a surgically induced mouse \nmodel, HDAC3 protein in in situ endometrial stromal cells \nwas also significantly lower than in the sham-operated \ngroup. Functionally, mice with uterine-specific deletion of \nHdac3 exhibited implantation failure and defective decidu -\nalization, involving de-repression of collagen genes and \nimpaired progesterone signaling [ 18]. Zheng et al. showed \nthrough immunohistochemical analysis of DIE and OE \nlesions that HDAC3 expression was significantly lower in \nDIE compared to OE and normal controls. Additionally, \nprimary stromal cells from OE also displayed decreased \nHDAC3 mRNA and protein levels. Conversely, HDAC3 \nexpression was upregulated in the TGF-β1-stimulated 11Z \nepithelial cell line, suggesting differences between in vitro \ninduction models and the true in vivo microenvironment \n[4]. In summary, HDAC3 shows a downregulated trend in \nendometriosis, particularly in DIE lesions with higher fibro-\nsis and in patients with infertility.\nHDAC8 is upregulated in endometriotic lesions and is \nclosely associated with the fibrotic process. Zheng et al. first \nfound using a mouse model of endometriosis that HDAC8 \nexpression progressively increased with lesion progression, \nand that stromal HDAC8 levels were strongly positively \ncorrelated with fibrosis markers. Functionally, the HDAC8-\nspecific activator TM-2–51 accelerated lesion growth and \nfibrosis, whereas the inhibitor PCI-34,051 dose-dependently \nsuppressed lesions, alleviated fibrosis, and reduced pain \n[16]. Subsequently, the team provided additional evidence \nat the human tissue and cellular levels: HDAC8 expression \nwas elevated in both OE and DIE, and upregulated in pri -\nmary stromal cells and the 11Z cell line [ 4]. These studies, \nspanning from animal models to human subjects, clearly \nestablish the driving role of HDAC8 in endometriosis-asso-\nciated fibrosis, although more human studies and drug trials \nare required to validate its potential as a therapeutic target.\nExpression of Class II HDACs HDAC6 is upregulated in endo-\nmetriosis and is associated with lesion fibrosis and malig -\nnant transformation. Zheng et al. observed that HDAC6 \nmRNA and protein levels increased with the progression of \nfibrosis in 11Z cells stimulated by TGF-β1. Immunohisto -\nchemistry of human tissues showed that HDAC6 staining \nwas significantly elevated in both the epithelium and stroma \nof DIE lesions and positively correlated with the degree \nof fibrosis, but there was no significant change in OE, and \nHDAC6 expression in primary stromal cells derived from \nOE was also not significantly different [ 4]. Another tissue \nmicroarray analysis including 168 endometriotic lesions \nfrom the ovary, peritoneum, and deep infiltrating endome -\ntriosis confirmed that HDAC6 expression in both the epi -\nthelium and stroma of DIE was significantly higher than in \nother subtypes. In cases with negative ARID1A expression, \nepithelial HDAC6 expression was higher than in controls \nwithout endometriosis, especially in the OE group, while \nstromal expression showed no significant difference [ 19]. \nThese findings indicate that abnormal HDAC6 expression \nis dependent on lesion subtype, cell type, and ARID1A sta-\ntus, and may contribute to the malignant transformation of \nDIE and some OE lesions through the ARID1A deletion \npathway. However, current studies are primarily observa -\ntional and lack functional validation and clinical interven -\ntion evidence, and the differential regulatory mechanisms \nof HDAC6 in the stroma and epithelium remain to be \nelucidated.\nThe role of HDAC9 in endometriosis remains unclear. \nA recent study predicted HDAC9 as a candidate epigenetic \nmarker through bioinformatics analysis (GSE11691) and \nverified its significantly increased mRNA expression in a rat \nendometriosis model using RT-qPCR. Based on the Turku \ndatabase, the study also found that HDAC9 expression is \nlower in the proliferative phase of the endometrium [ 20]. \nHowever, the study had a small sample size and lacked \nprotein and functional validation, which is insufficient to \nconfirm its pathogenic role. Future research should clarify \nits expression profile in human tissues and systematically \ninvestigate its regulatory network and pathogenic mecha -\nnisms through in vitro functional experiments and animal \nmodels.\nExpression of Class III HDACs  Multiple studies have shown \nthat Sirtuin 1 (SIRT1) is abnormally expressed in endo -\nmetriosis and is involved in the progression of the disease. \nTaguchi et al. found that in primary endometriotic stro -\nmal cells derived from OE, SIRT1 activation could inhibit \nTNF α-induced IL-8 release, whereas inhibition of SIRT1 \npromoted IL-8 [ 21], suggesting a direct anti-inflamma -\ntory effect. In the context of eutopic endometrium, both \nhuman tissue and baboon models have shown that SIRT1 \nis upregulated as the disease progresses and is positively \ncorrelated with KRAS. A mouse model with KRAS activa-\ntion confirmed that KRAS can upregulate SIRT1 and sup -\npress progesterone target genes. In the human endometrial \nadenocarcinoma cell line Ishikawa, SIRT1 binds to BCL6 \nto inhibit GLI1 transcription, indicating that the SIRT1/\nBCL6 axis may be involved in progesterone resistance \n[22]. Additionally, in normal female endometrium, SIRT1 \nis only expressed during menstruation, whereas in endo -\nmetriosis patients, SIRT1 is persistently highly expressed \nthroughout the cycle. Mice with uterine-specific Sirt1 \n\n1 3\nReproductive Sciences\noverexpression confirmed that SIRT1 overexpression can \nlead to implantation failure and downregulation of proges -\nterone target genes, thereby promoting the growth of ecto -\npic lesions [ 23]. Other studies combining human tissue \nand Ishikawa cell experiments found that SIRT1 promotes \nEMT by helping epithelial cells escape damage-induced \nsenescence, thus driving disease progression [ 24]. The \nevidence related to eutopic endometrium is relatively con -\nsistent, suggesting that SIRT1 overexpression is involved \nin progesterone resistance and disease progression through \nmultiple mechanisms. However, in ectopic stromal cells \nalso derived from OE, Zhang et al. found that miR-22-3p \ncarried by peritoneal macrophage exosomes targeted \nand inhibited SIRT1, subsequently activating the NF-κB \npathway and promoting cell proliferation, migration, and \ninvasion [ 25]. This differs from the findings of Taguchi \net al., and the discrepancy may stem from differences in \nintervention methods: the former mimicked a persistent \nexogenous downregulation of SIRT1 in the pathological \nmicroenvironment through exosomal miRNA, activat -\ning an NF-κB-driven invasive phenotype, while the latter \ndirectly regulated SIRT1 activity with pharmacological \nactivators or inhibitors, reflecting its underlying anti-\ninflammatory function. Therefore, within the same cells, \nSIRT1 can both maintain anti-inflammatory homeostasis \nand shift to a pro-invasive state under specific upstream \nsignals, demonstrating that its function is clearly depen -\ndent on the mode of regulation.In addition, there is dis -\nagreement regarding the clinical biomarker value of \nSIRT1: studies based on serum ELISA suggest that SIRT1 \nlevels are elevated in patients with advanced endometrio -\nsis [ 26], whereas prospective studies using endometrial \nbiopsies in mixed infertile populations have not found an \nassociation between SIRT1 and diagnosis or pregnancy \noutcomes [ 27]. The discrepancy may originate from dif -\nferences in sample type (circulating blood vs. local tissue) \nand study populations (covering different stages vs. mixed \ninfertility), indicating that strict standardization of detec -\ntion methods and population selection is required when \nconsidering SIRT1 as a biomarker.\nIn OE lesions, the expression level of Sirtuin 3 (SIRT3) \nprotein is significantly lower than that in normal endome -\ntrial tissue. The activities of its downstream target enzymes, \nglutamate dehydrogenase (GDH), succinate dehydrogenase \n(SDH), and manganese superoxide dismutase (MnSOD), \nshow a declining trend in both tissue homogenates and \nmitochondria (though the activity of MnSOD in mitochon -\ndria appears increased). In contrast, there is no significant \ndifference in SIRT3 levels in serum samples. The impair -\nment of mitochondrial energy metabolism and antioxidant \ndefense in ectopic lesions is associated with downregulation \nof SIRT3, suggesting that SIRT3 deficiency may be an \nimportant pathogenic mechanism in endometriosis [ 28]. \nHowever, the findings of Goday et al. contradict this. By \nassessing SIRT3 levels in patients with different types of \nendometriosis-related infertility undergoing in vitro fertil -\nization cycles, they found that in patients with DIE, SIRT3 \nlevels in peripheral blood mononuclear cells were higher \nthan in OE patients, and those with a history of surgery had \neven higher SIRT3 levels. This suggests a possible associa-\ntion between disease severity and SIRT3 upregulation [29]. \nThe aforementioned differences may arise from variations \nin the sample types (local lesion tissue vs. circulating mono-\nnuclear cells) and disease subtypes (OE vs. DIE), reflecting \ndifferent regulatory patterns of SIRT3 in local lesions and \nsystemic immune responses.\nResearch on SIRT7 in endometriosis is currently insuf -\nficient. Clinical studies have found that in patients with \nendometriosis undergoing in vitro fertilization, the expres -\nsion levels of SIRT in hGL are positively correlated with the \ndoses of FSH and LH used [30], suggesting that SIRT7 may \nbe positively regulated by sex hormones, which requires \nfurther functional validation. Regarding the pathogenic \nmechanism, primary ectopic stromal cells derived from \nOE exhibit a metabolic shift from mitochondrial respira -\ntion to glycolysis, with SIRT7 being significantly upregu -\nlated in the ectopic lesions. Functional experiments have \nconfirmed that in primary ectopic stromal cells, overex -\npression of SIRT7 promotes cell proliferation and migra -\ntion, whereas knockdown has the opposite effect; SIRT7 \ndrives metabolic reprogramming by upregulating glycolytic \nenzymes (GBE1, PYGL), downregulating mitochondrial \nenzymes (IDH1, SDHB), and activating the RhoA/ROCK/\nAKT pathway. SIRT7 interacts with the mitochondrial pro-\ntein TUFM, and TUFM deficiency leads to increased SIRT7 \nprotein levels; moreover, the phenotype induced by TUFM \nknockdown can be reversed by SIRT7 knockdown, suggest-\ning that TUFM negatively regulates SIRT7. In a BALB/c \nfemale mouse model of endometriosis, SIRT7 overexpres -\nsion promotes the growth of ectopic lesions, while knock -\ndown inhibits lesion development [31]. In summary, SIRT7 \ndrives metabolic reprogramming and disease progression \nthrough the TUFM/SIRT7 axis, and its clinical translational \nvalue and regulatory relationship with sex hormones require \nfurther validation.\nIn summary, HDACs exhibit differential expression pro-\nfiles in endometriosis, suggesting that distinct HDAC sub -\ntypes may play stage- and context-dependent regulatory \nroles in the pathogenesis of the disease. This expression het-\nerogeneity also provides a theoretical basis for the applica -\ntion of HDACis in endometriosis treatment.  \n\n1 3\nReproductive Sciences\nPathogenic Mechanisms of HDACs in Endometriosis\nAs crucial epigenetic regulatory molecules, HDACs influ -\nence core biological processes such as cell proliferation, dif-\nferentiation, and apoptosis by modulating histone acetylation \nstatus in various diseases. Given the universality of these \nmechanisms, HDACs may participate in multiple pathologi-\ncal aspects of endometriosis in similar ways (Fig. 1). Based \non their functional differences, the related pathogenic mech-\nanisms can be summarized as follows: (1) Immune-inflam -\nmatory regulation: HDACs can promote the transcription of \npro-inflammatory factors such as TNF-α, IL-1β, and IL-6 by \ndeacetylating histones and non-histone proteins, while also \nregulating the activity of T cells and macrophages, leading \nto weakened immune surveillance function and impaired \nclearance of ectopic endometrial cells [ 33]. Among them, \nSIRT1 plays an important role in endometriosis. Zhang et \nal. [25] found that exosomes derived from peritoneal mac -\nrophages can be taken up by ectopic endometrial stromal \ncells. The miR-22-3p enriched in these exosomes promotes \nthe proliferation, migration, and invasion of ectopic endo -\nmetrial stromal cells by targeting and inhibiting SIRT1 \nand activating the NF-κB pathway. Additionally, HDAC1 \ncan activate the STAT3 signaling pathway through the \nexosome-mediated HOTAIR/miR-761 axis, promoting the \nrelease of inflammatory factors and further exacerbating \nthe local inflammatory microenvironment [ 14]. (2) Imbal -\nance between cell proliferation and apoptosis: Studies have \nshown that in fibroblasts and B cells, HDAC1/2 can directly \nbind to the promoter regions of CDK inhibitors such as p21 \nand p57, inhibiting their transcription through deacetylation \nmodifications, thereby promoting the G1/S phase transition \nand inhibiting apoptosis [ 34]. In endometriosis, upregula -\ntion of SIRT1 expression is closely related to downregula -\ntion of p53 expression, leading to an imbalance between \ncell proliferation and apoptosis by inhibiting p53-medi -\nated apoptotic signaling [ 35]. Moreover, the LINC01638/\nHDAC1/p21/p27 axis is involved in the regulation of abnor-\nmal cell proliferation in endometriosis by modulating G1 \nphase arrest in the cell cycle [6]. (3) Enhanced invasion and \nmigration capabilities: HDACs synergistically participate \nin the invasion and migration processes of endometriosis \nthrough different mechanisms. HDAC1 promotes EMT by \ninhibiting RHOB expression, thereby enhancing cell migra-\ntion and invasion [6]. HDAC2 affects cell invasion by regu-\nlating the HNF4A/ARID1A axis [ 17]. Additionally, SIRT1 \nFig. 1 Schematic diagram of the pathogenic mechanisms of HDACs in \nendometriosis Abbreviations: HDAC, histone deacetylase; EMT, epi -\nthelial-mesenchymal transition. HDACs are divided into four classes \n(Class I, Class II, Class III, and Class IV), with Class II further subdi-\nvided into two subclasses: Class IIa and Class IIb. Through deacety -\nlation of histone and non-histone substrates, HDACs regulate chro -\nmatin conformation and protein activity, thereby modulating multiple \ncellular processes. In endometriosis, aberrant HDAC activity drives \nfive interconnected pathological pathways: immune inflammation, \nproliferation/apoptosis imbalance, enhanced invasion/migration/EMT, \nangiogenesis/hypoxia, and hormone dysregulation. These pathways \ncollectively contribute to ectopic lesion growth, chronic pelvic pain, \ninfertility, and recurrence\n \n\n1 3\nReproductive Sciences\nis involved in the regulation of cell migration through the \nFoxO1-mediated autophagy pathway [36]. In DIE, HDAC6 \nexpression is significantly elevated, influencing cytoskel -\netal dynamic remodeling by regulating α-tubulin deacety -\nlation, thereby promoting cell migration [ 19]. HDAC8 is \nalso highly expressed in DIE lesions, and its expression is \nclosely related to the fibrosis process. Mechanistic studies \nsuggest that HDAC8 may participate in EMT and fibro -\nsis processes by regulating the TGF-β signaling pathway, \nthereby promoting lesion invasion and progression [ 4]. (4) \nAngiogenesis and hypoxia response: HDAC1 enhances the \ntube-forming ability of vascular endothelial cells by acti -\nvating the STAT3 pathway, promoting angiogenesis [ 14]. \nFurthermore, under hypoxic conditions, HDACs expres -\nsion increases by binding to HIF-1, downregulates EZH2 \nexpression, and drives the overexpression of genes involved \nin cell adhesion, proliferation, migration, and angiogenesis \n[37]. (5) Steroid hormone synthesis and signal transduc -\ntion: Estrogen plays a central role in the pathogenesis of \nendometriosis. HDACs can regulate the transcription of key \nenzymes in estrogen synthesis, such as aromatase, leading \nto elevated local estrogen levels [38]. Additionally, HDAC1 \nis significantly correlated with estrogen receptor α (ER-α) \nexpression, suggesting its potential involvement in hormone \nsignaling regulation [32]. Notably, in ectopic cells, the regu-\nlatory effect of hormones on HDAC1/2 expression is lost \n[13], indicating that HDACs may participate in disease pro-\ngression through hormone-independent pathways.\nOverview of HDACis and Preclinical Studies \nin the Treatment of Endometriosis\nOverview of HDACis\nHDACis are natural or synthetic small-molecule com -\npounds that can inhibit the activity of HDACs, restoring or \nincreasing histone acetylation levels. Based on their chemi-\ncal structures, they are classified into six types: short-chain \nfatty acids, hydroxamic acids, benzamides, cyclic peptides, \nthiol ketones, and sirtuin inhibitors [9].\n1. Short-chain fatty acids: such as butyrate and valproic \nacid (VPA). Changes in dietary fiber can alter the micro-\nbiota, thereby affecting short-chain fatty acid levels.\n2. Hydroxamic acids: such as V orinostat (SAHA), Tricho-\nstatin A (TSA), Panobinostat, and TH34. Hydroxamic \nacids are important molecules with metal-chelating abil-\nities, helping microorganisms better acquire iron ions \n[39] and possessing anti-tumor potential.\n3. Benzamides: such as Entinostat (MS-275). They play \na significant role in the development of novel CDK \ninhibitors, helping to inhibit the activity of cyclin-depen-\ndent kinases [40].\n4. Cyclic peptides: such as Romidepsin, Trapoxin A, and \nHC Toxin. Cyclic peptides have complex and diverse \nstructures composed of proteinogenic amino acids, \nD-amino acids, and non-proteinogenic amino acids, and \nare considered Class I HDACis [41].\n5. Thiol ketones: such as KD5150 and KD5170. KD5170 \ncan induce apoptosis and inhibit cell proliferation, exhib-\niting broad-spectrum anti-tumor activity both in vitro \nand in vivo [42].\n6. Sirtuin inhibitors: such as nicotinamide, EX-527, sirtinol, \n3-TYP, etc. They primarily help the body resist aging and \nother diseases by reducing the activity of the SIRT fam -\nily and regulating metabolism, antioxidant activity, and \nanti-inflammatory responses [43].\nTheoretical Basis for HDACis in Targeted Therapy for \nEndometriosis\nThe pathogenesis of endometriosis involves multiple fac -\ntors, including estrogen dependence, progesterone resis -\ntance, and chronic inflammation, with abnormal epigenetic \nregulation playing a key role. As important enzymes in \nepigenetic modification, HDACs are closely related to \nthe pathological progression of endometriosis, providing \na theoretical basis for the application of HDACis. First, \nHDACs exhibit abnormal expression in endometriosis \nlesions. Studies have confirmed that HDAC1, HDAC6, \nand HDAC8 are generally upregulated in ectopic lesions \n[4, 13, 19], suggesting their involvement in disease pro -\ngression, while HDAC3 is downregulated in patients with \ninfertility [ 18]. This differential expression provides a \nmolecular basis for targeted intervention with HDACis. \nSecond, HDACs are widely involved in the epigenetic \nregulation of key pathways in endometriosis. They affect \nestrogen synthesis and signaling by regulating aromatase \nand ER-α expression [ 32, 44]. They also mediate the epi -\ngenetic silencing of the progesterone receptor B subtype \n(PR-B), contributing to progesterone resistance [ 45]. Addi-\ntionally, HDAC1 can regulate EMT and promote the tran -\nscription of inflammatory factors, driving lesion invasion \nand maintaining the inflammatory microenvironment [ 6, \n33]. Furthermore, HDACis offer the advantage of “multi-\ntarget” intervention. Due to the reversibility of epigenetic \nmodifications, HDACis can simultaneously regulate mul -\ntiple pathogenic pathways by restoring histone acetylation \nlevels [ 46]. Finally, some HDACis already have a foun -\ndation for clinical translation. Safety data for drugs such \nas VPA and butyrate are available from clinical applica -\ntions [47, 48], laying the groundwork for drug repurposing \nstrategies.\n\n1 3\nReproductive Sciences\nPreclinical Studies of HDACis in the Treatment of \nEndometriosis\nIn recent years, various HDAC inhibitors have been evalu -\nated for their pharmacological effects in cellular and animal \nmodels of endometriosis (Table 2).\nClassical HDACis\nSAHA, as a classical HDACi, demonstrates potential for \ndirect anti-cell activity in endometriosis treatment. Its mech-\nanism of action is closely related to the regulation of intra -\ncellular oxidative stress. The study utilized primary human \nendometrial stromal cells isolated from the in situ endome -\ntrium of patients without endometriosis and from the ecto -\npic endometrium of patients with OE, as well as Ishikawa \ncells, and treated them with 1.25–10 µM SAHA for 48 h. \nThe results showed that SAHA significantly upregulated \nthe mRNA and protein levels of thioredoxin-binding pro -\ntein-2 (TBP-2) in HESCs, reduced the thioredoxin (TRX)/\nTBP-2 ratio, and promoted cell apoptosis. Under oxidative \nstress conditions induced by rHMGB-1 (10 ng/mL, 24 h), \n2.5 µM SAHA similarly upregulated TBP-2 expression and \nenhanced apoptosis. After inhibiting TRX expression with \nsiRNA, SAHA-induced apoptosis was further exacerbated, \nindicating that the effect of SAHA depends on the TRX/\nTBP-2 system [ 7]. Additionally, SAHA also has the func -\ntion of inhibiting HDAC6 activity. Treatment of human \nEAOC cell lines TOV-21G (clear cell carcinoma) and TOV-\n112D (endometrioid carcinoma) with 10 nM SAHA for 4 \nand 8 h showed simultaneous downregulation of HDAC6 \nand GATA3 protein expression and induction of cell apop -\ntosis. In a mouse model of endometriosis-associated ovar -\nian cancer (EAOC), intraperitoneal injection of 50 mg/kg \nvorinostat every 3 days significantly reduced ovarian tumor \nvolume, with the mechanism related to inhibition of M2 \nmacrophage polarization and downregulation of IL-10 lev -\nels [49]. These findings provide an experimental basis for \nthe subsequent preclinical and clinical studies of SAHA.\nRomidepsin, as a specific class I HDAC inhibitor, has \nhad its mechanisms of action in preclinical studies of endo-\nmetriosis explored at two levels. In the human immortalized \nepithelial endometrial cell line 11Z, romidepsin (10–100 \nnM) inhibited HDAC enzymatic activity in a concentration-\ndependent manner (IC50 = 6.5 nM), induced acetylation \nof histones H2A/H2B/H3/H4, upregulated p21, and down -\nregulated cyclin B1/D1, thereby inhibiting cell proliferation \nand activating the intrinsic apoptosis pathway (caspase-9/3 \nactivation and PARP cleavage) [50]. In the human endome-\ntriotic epithelial cell line 12Z, romidepsin (1.5–2.5 nM) was \nused as an HDAC1/2 inhibitor, confirming that LINC01638 \npromotes EMT and cell migration/invasion by inhibiting \nHDAC1 and upregulating RHOB expression; romidepsin \ntreatment could partially reverse RHOB downregulation \ncaused by LINC01638 knockdown, and ChIP assays con -\nfirmed that its mechanism is related to H3K27ac levels at the \nRHOB promoter [6]. In summary, romidepsin exhibits anti-\nproliferative, pro-apoptotic, and EMT-inhibitory effects in \ncell models, but research remains limited to in vitro studies, \nlacking validation in animal models, and its in vivo effects \non ectopic lesion growth, fibrosis, and pain have not been \nassessed. Further pharmacodynamic studies are required for \nclinical translation.\nAs a classic hydroxamic acid class HDAC inhibitor, \nTSA demonstrates multi-target potential in the treatment of \nendometriosis. In in vivo studies, Lu et al. confirmed using \na C57BL/6 mouse autotransplantation model that TSA (0.5 \nmg/kg/day, subcutaneous injection for 4 weeks) significantly \nreduced lesion area (by 54.3%) and alleviated hyperalgesia, \nwhile also decreasing the expression of TRPV1, PKCε, and \nPGP9.5 [51]. However, this study only used a single dose \nand did not evaluate the effects on fibrosis or fertility. At \nthe cellular level, Wu et al. found that TSA (0.1–100 µM) \nexhibited a strong and sustained anti-proliferative effect on \nimmortalized YHES stromal cells, which was superior to \nCDB-2914 and NAC, with the mechanism associated with \nupregulation of PR-B and AR [52]. Subsequently, the same \ngroup demonstrated in YHES cells that TSA could inhibit \nIL-1β-induced COX-2 expression [53], and further revealed \nin 11Z/22B endometriotic cell lines that TSA (0.1–1 µM) \nsuppressed constitutive NF-κB activation and TNF-α-\ninduced p65 nuclear translocation, with endometriotic cells \nbeing more than ten times more sensitive than normal cells \n[54]. Seo et al. further showed using primary stromal cells \nderived from ovarian endometriomas that TSA (250–1000 \nng/mL) could promote apoptosis through the induction of \nNAG-1 expression [ 55]. In summary, TSA exerts thera -\npeutic potential through multiple mechanisms including \nanti-proliferation, anti-inflammation, pro-apoptosis, and \nanalgesic effects. Future studies should systematically assess \nits impact on different lesion subtypes, stages, and fibrosis, \noptimize dosing regimens, and conduct combined in vivo \nand in vitro validation to facilitate clinical translation.\nNatural Product and Metabolite-Derived HDACis\nThe role of the gut microbiota metabolite butyrate in endo -\nmetriosis has been gradually elucidated step by step, from \ndysbiosis and metabolite supplementation to molecular \nmechanisms. Alghetaa and colleagues, using a mouse model \nof endometriosis, found that endometriosis could lead to \na reduction in the abundance of butyrate-producing gut \nmicrobiota and a decrease in colonic butyrate levels, accom-\npanied by peritoneal inflammation and immune-metabolic \n\n1 3\nReproductive Sciences\nAgent (Class) Research model Dosage/administration Key findings References\nSAHA \n(hydroxamate)\nPrimary human HESC \n(normal and OE-derived \nectopic); Ishikawa cell \nline\nCells: 1.25–10 µM, 48 h Induces apoptosis; upregulates TBP-2, reduces TRX/\nTBP-2 ratio; dependent on TRX/TBP-2 system.\n[7]\nEAOC transgenic mouse \nmodel (TOV-21G, \nTOV-112D-derived)\nAnimal: 50 mg/kg, i.p., \nevery 3 days\nSuppresses tumor growth; downregulates HDAC6 and \nGATA3, inhibits M2 macrophage polarization, reduces \nIL-10 levels.\n[49]\nRomidepsin \n(cyclic peptide)\nHuman immortalized \nepithelial endometrial \ncell line 11Z\n10–100 nM, 24–144 h Suppresses proliferation, induces apoptosis; inhibits \nHDAC activity (IC₅₀=6.5 nM), induces histone acetyla-\ntion, upregulates p21, downregulates cyclin B1/D1, \nactivates caspase-9/3 and PARP cleavage.\n[50]\nHuman endometriotic \nepithelial cell line 12Z\n1.5–2.5 nM, 24 h (com-\nbined with LINC01638 \nsiRNA knockdown)\nPartially reverses RHOB downregulation induced by \nLINC01638 knockdown; inhibits EMT and migration/\ninvasion; upregulates RHOB by reducing RHOB pro-\nmoter deacetylation via HDAC1/2 inhibition.\n[6]\nTSA \n(hydroxamate)\nC57BL/6 mouse, \nintraperitoneal autolo-\ngous uterine fragment \nimplantation\n0.5 mg/kg/d, s.c., 4 weeks Reduces lesion area (↓54.3%); prolongs hot plate latency \n(ameliorates hyperalgesia); reduces serum TNFα (trend); \ninhibits HDAC activity, reduces TRPV1 (eutopic endo-\nmetrium), PKCε (ectopic lesions), and PGP9.5 (vagina) \nexpression.\n[51]\nImmortalized human \nendometrial stromal cell \nline YHES\n0.1–100 µM, 48 h (some \nexperiments observed up \nto 4 weeks)\nInhibits proliferation in a concentration-dependent man-\nner (90% inhibition at 100 µM); sustained effect (no \nrecovery at 4 weeks); upregulates PR-A, PR-B, AR, and \nFasL expression.\n[52]\nYHES Pretreatment with 1–100 \nµM for 1 h, then IL-1β \n(0.1–1 ng/mL) stimulation \nfor 4 h (mRNA) or 16 h \n(protein)\nInhibits IL-1β-induced COX-2 mRNA and protein \nexpression in a concentration-dependent manner; possibly \nthrough PPARγ activation, NF-κB inhibition, or coactiva-\ntor competition.\n[53]\nYHES, 11Z, 22B \n(stromal-like)\n0.1–10 µM, 48 h (YHES: \n10 µM; 11Z/22B: 0.1–1 \nµM)\nInhibits cell proliferation; inhibits constitutive and TNF-\nα-induced NF-κB activation; inhibits IκBα phosphoryla-\ntion, p65 phosphorylation, and nuclear translocation.\n[54]\nPrimary human EESC \n(OE-derived)\n250–1000 ng/mL (≈ \n0.83–3.3 µM), 48 h\nReduces cell viability in a concentration-dependent man-\nner, induces apoptosis; upregulates NAG-1 mRNA and \nprotein; NAG-1 siRNA reverses apoptosis.\n[55]\nButyrate \n(SCFA)\nBALB/c mouse, ovari-\nectomy + intraperitoneal \nendometrial fragment \ninjection (OVX + END \nmodel)\nNo intervention (observa-\ntion only)\nButyrate-producing gut microbiota abundance and \ncolonic butyrate levels reduced in endometriosis mice, \naccompanied by peritoneal inflammation and immuno-\nmetabolic reprogramming.\n[56]\nC57BL/6 mouse \n(antibiotic-depleted or \nnormal); iHEEC/Luc, \nprimary HEnSCs\nAnimal: 300 mM in \ndrinking water, 21 days; \nCells: 2 mM\nReduces lesion volume and weight, decreases prolif-\neration (Ki-67⁺) and macrophage infiltration (F4/80⁺); \nactivates GPR43/GPR109A; inhibits HDAC activity \n(increases H3 acetylation); upregulates RAP1GAP to \ninactivate pro-proliferative RAP1.\n[57]\nEndometriosis patients \n(n = 11) and controls \n(n = 4) serum/feces; \nmicrobiota-depleted \nmice; primary eESCs\nAnimal: 300 mM in \ndrinking water; Cells: 10 \nmM\nSerum butyrate levels decreased and negatively corre-\nlated with rAFS stage; butyrate supplementation reduces \nlesion size in MD mice; inhibits eESC viability; activates \nFFAR2/PPAR-γ/PINK1/Parkin axis, inhibits mitophagy, \nenhances ferroptosis sensitivity.\n[58]\nValproic acid \n(SCFA)\nSD rat, autologous uter-\nine fragment intraperito-\nneal transplantation\nLow dose: 100 mg/kg/d \noral; High dose: 200 mg/\nkg/d oral; P4: 1 mg/kg/d \ni.m.; Combination: high-\ndose VPA + P4. All for 4 \nweeks.\nAll treatments reduce lesion volume (↓51.2%–62.3%); \nprolong hot plate and tail-flick latency (ameliorate hyper-\nalgesia); increase body weight.\n[59]\nPrimary human NESC \nand endometriosis-\nderived ESC\n8 mM, 24 h Inhibits cell survival and proliferation, induces apoptosis; \ndownregulates CYP19 mRNA and protein; increases \nglobal H3/H4 acetylation, reduces CYP19 promoter H3/\nH4 acetylation.\n[44]\nTable 2 Preclinical evidence of HDAC inhibitors in endometriosis\n\n1 3\nReproductive Sciences\nreprogramming [ 56]. Chadchan and colleagues, through \nfecal microbiota transplantation, confirmed that the feces \nfrom endometriosis mice promoted lesion growth, while \nthose from normal mice inhibited lesions; mechanistically, \nbutyrate suppressed endometrial cell proliferation and \nmouse lesion growth by concurrently activating GPR43/\nGPR109A, inhibiting HDAC activity, and upregulating \nRAP1GAP to inactivate RAP1 [ 57]. Gou and colleagues \nsupplemented the mechanism with ferroptosis studies at \nhuman, animal, and primary cell levels: endometriosis \npatients had reduced serum butyrate levels negatively cor -\nrelated with disease staging; in germ-free mice, butyrate \nsupplementation reduced lesion size; in primary ectopic \nstromal cells, butyrate inhibited mitophagy and enhanced \nferroptosis sensitivity through the FFAR2/PPAR-γ/PINK1/\nParkin axis [ 58].Although the aforementioned studies \nreveal the therapeutic potential of butyrate from different \nperspectives, significant limitations still exist in the current \nevidence. To date, no rigorously designed randomized con-\ntrolled trials have verified the clinical efficacy and safety \nof butyrate in patients with endometriosis, and its pharma -\ncokinetic characteristics in humans (optimal administration \nroute, effective plasma concentration, tissue distribution) \nremain unclear. In addition, butyrate has an extremely short \nhalf-life, and its levels are influenced by diet, antibiotics, \nand individual differences in gut microbiota composition. \nHow to achieve standardized supplementation remains an \nunresolved issue. Therefore, whether butyrate can become \nan effective therapeutic approach for endometriosis still \nrequires verification through rigorously designed human \nclinical trials and systematic pharmacokinetic-pharmacody-\nnamic evaluations.\nVPA is a common antiepileptic drug, and studies have \nshown that it also has therapeutic potential in endometrio -\nsis. In rat models, daily oral administration of 100 mg/kg \nor 200 mg/kg (for 4 consecutive weeks) dose-dependently \nreduced ectopic lesions, alleviated hyperalgesia, and exhib-\nited disease-specific effects [59]. Mechanistically, VPA can \nact through multiple pathways. In primary endometriotic \nstromal cells, treatment with 8 mM for 24 h inhibited his -\ntone acetylation in the CYP19 promoter region, thereby \ndownregulating aromatase, reducing estrogen synthesis, \ninhibiting proliferation, and inducing apoptosis [ 44]; in \nimmortalized YHES stromal cells, treatment with 3 mM for \n16 h induced G0/G1 cell cycle arrest and upregulated p21 \n[60]; in human tissues and primary cells, treatment with 8 \nmM for 72 h increased acetylation of the C/EBPα promoter \nregion, upregulating the expression of this tumor suppressor \ngene, with forced expression of C/EBPα inhibiting prolif -\neration and inducing apoptosis, while knockdown promoted \nproliferation and resisted apoptosis [ 61]. In summary, VPA \nexerts multiple effects including HDAC inhibition, anti-\nestrogen activity, and activation of tumor suppressor genes, \nbut it lacks human safety and pharmacokinetic data, and fur-\nther optimization of dosing regimens and clinical validation \nare still required.\nAgent (Class) Research model Dosage/administration Key findings References\nYHES 3 mM, 16 h Induces G0/G1 cell cycle arrest; upregulates p21 protein \nexpression.\n[60]\nOvarian endome-\ntrioma cyst stromal cells \n(ECSCs) and normal \nendometrial stromal cells \n(NESCs); endometriotic \nand normal endometrial \ntissues\nCells: 8 mM, 72 h Upregulates C/EBPα expression; increases H3/H4 \nacetylation at the C/EBPα promoter; C/EBPα regulates \ndownstream PPARγ, p53, caspases.\n[61]\nPCI-34,051 \n(selective \nHDAC8 \ninhibitor)\n11Z (TGF-β1-stimulated, \n72 h); primary EESC\nNo intervention (expres-\nsion only)\nHDAC8 mRNA and protein upregulated in TGF-β1-\nstimulated 11Z cells and EESC.\n[4]\nHuman tissues: OE (n \n= 38), DIE (n = 20), \ncontrol endometrium (n \n= 24)\nIHC detection HDAC8 staining significantly enhanced in OE and DIE \nlesions; elevated in both epithelium and stroma of DIE \n(stroma > epithelium), positively correlated with fibrosis.\n[4]\nBALB/c mouse, sub-\nstance P-induced DIE \nmodel\n20 mg/kg/d, i.p., starting \n4 weeks after induction, \nfor 2 weeks\nLesion weight reduced by 63.6%; prolonged hot plate \nlatency; reduced fibrosis; E-cadherin↑, α-SMA↓, des-\nmin↓, Sm-MHC↓.\n[4]\nSAHA suberoylanilide hydroxamic acid, TSA trichostatin A, VPA valproic acid, SCFA short-chain fatty acid, EESC ectopic endometrial stro -\nmal cells, HESC human endometrial stromal cells, NESC normal endometrial stromal cells, OE ovarian endometrioma, DIE deep infiltrating \nendometriosis, EAOC endometriosis-associated ovarian cancer, rAFS revised American Fertility Society, i.p. intraperitoneal, s.c. subcutaneous, \ni.m. intramuscular\nTable 2 (continued) \n\n1 3\nReproductive Sciences\nNovel Selective HDAC8 Inhibitors \nSelective HDAC8 inhibitors show promising potential in \nthe treatment of endometriosis. In a DIE mouse model, the \nHDAC8 inhibitor PCI-34,051 (20 mg/kg/day intraperitoneal \ninjection for 2 weeks) significantly reduced lesion volume \nand fibrosis, with lesion weight decreasing by nearly two-\nthirds, a marked reduction in fibrotic tissue formation, and \npain relief. Mechanistic studies suggest that this effect may be \nrelated to the regulation of key signaling pathways involved \nin fibrosis and inflammation, such as TGF-β, restoring nor-\nmal cell function by inhibiting HDAC8 and improving the \nlocal tissue microenvironment of the lesions [4]. Compared \nto conventional pan-HDAC inhibitors, HDAC8 inhibitors \nhave higher subtype selectivity, theoretically reducing the \nrisk of off-target effects, and initial safety assessments show \nminimal impact on the function of other HDAC subtypes \n[62]. Recent advances in medicinal chemistry have devel -\noped various highly selective HDAC8 inhibitors, including \nnovel hydrazide-based compounds, allowing precise regula-\ntion by specifically targeting HDAC8 [ 63]. These studies \nindicate that selective HDAC8 inhibitors demonstrate effi -\ncacy and safety advantages in preclinical models, but their \neffectiveness and safety in endometriosis patients still need \nto be verified through systematic clinical research. This is \nespecially important for women of reproductive age with \nfertility needs, as the long-term effects on ovarian function, \nendometrial receptivity, and embryo development are still \nunclear. Additionally, current evidence mainly comes from \na single animal model, with no comparative data across dif-\nferent models or species, and the long-term dosing regimen \n(dose, frequency, duration) of PCI-34,051 has not been sys-\ntematically optimized. Therefore, whether HDAC8 inhibi -\ntors can truly transition from animals to humans for clinical \nuse still requires careful evaluation through more preclinical \nstudies and clinical trials.\nSafety and Fertility Considerations of HDACis\nHDACis have multiple drugs approved or in clinical trials \nfor diseases such as tumors, and their safety profiles have \nbeen relatively well established [ 64, 65]. Clinical stud -\nies show that the main adverse effects of HDACis include \nmyelosuppression (thrombocytopenia, leukopenia), gastro -\nintestinal reactions (nausea, vomiting, diarrhea), fatigue, \nand cardiotoxicity (QT interval prolongation) [ 66]. The \nspectrum of adverse events varies among different drugs. \nReported adverse events for SAHA include thrombosis, \nQT interval prolongation, and potentially fatal ventricular \ntachycardia [67]; belinostat commonly causes gastrointes -\ntinal symptoms such as nausea and vomiting [ 68]; throm-\nbocytopenia has been reported with SAHA, panobinostat, \nand romidepsin, which may be related to dual inhibition of \nHDAC1 and HDAC2 [69, 70].\nIn addition to the systemic adverse reactions mentioned \nabove, the reproductive safety of HDACis has also been a \nmajor concern, as the HDACs they target play key regula -\ntory roles in reproductive processes such as gametogenesis, \nfollicular development, embryo implantation, and endome -\ntrial receptivity [71–75]. Current research indicates that the \neffects of different HDACis on reproductive function vary \nsignificantly. In a rat fertility study, SAHA was administered \nat three doses: 15, 50, and 150 mg/kg/day. The 150 mg/kg/\nday dose did not affect mating or fertility in either sex; how-\never, it increased the post-implantation loss rate and the \nnumber of corpus luteums in female rats, while no repro -\nductive toxicity was observed in male rats [ 76]; TSA pro-\ntects the male reproductive system and ovarian tissue from \ndamage in models of radiation or cigarette smoke exposure \n[77, 78]. Regarding embryonic development, Nervi et al. \nfound that TSA treatment transiently accelerated embryonic \ngrowth in mice and increased the number of somites, but no \nmaternal toxicity, embryonic developmental disturbances, \nor teratogenic effects were observed, suggesting that TSA \nmay have relatively good embryonic safety in rodents [79]; \nhowever, further studies by Peng et al. found that the effects \nof TSA on embryonic development are highly dependent \non treatment concentration, duration, and embryo origin, \nwith in vivo fertilized embryos being the most sensitive \nto TSA; blastocyst formation rates and live birth rates can \ndecrease significantly with increasing TSA concentration \nand treatment duration [ 80], suggesting that the effects of \nTSA on embryos vary under different experimental con -\nditions; butyrate can improve ovarian function in a PCOS \nmodel [81], yet embryonic exposure to butyrate or VPA can \ninhibit primordial germ cell differentiation and lead to insuf-\nficient spermatogenesis in mice [82], suggesting that it has a \nfundamental impact on germ cell development. VPA, as an \nHDAC inhibitor, is widely used in the treatment of epilepsy, \nbipolar disorder, and cancer [83]. However, its clinical use is \nlimited by a well-established teratogenic risk—pregnancy-\nrelated exposure is associated with a congenital malforma -\ntion rate of approximately 10%, primarily involving neural \ntube defects, cardiac abnormalities, and craniofacial malfor-\nmations, and this risk is dose-dependent [84].\nIn summary, although HDAC inhibitors have dem -\nonstrated clinical value in cancer treatment, no HDAC \ninhibitor has yet been approved for the clinical treatment \nof endometriosis. Although basic research has preliminar -\nily revealed the involvement of HDAC family members in \nthe pathological process of endometriosis, and some HDAC \ninhibitors have demonstrated the potential to reduce the vol-\nume of endometriotic lesions in mouse models, issues such \nas the long-term safety of these drugs, their potential impact \n\n1 3\nReproductive Sciences\non fertility in women of childbearing age, and the identifica-\ntion of patient groups most likely to benefit from this class \nof drugs remain unresolved. Therefore, before expanding \nthe use of HDACi to benign gynecological conditions such \nas endometriosis, there is an urgent need for systematic and \nin-depth research addressing the aforementioned issues.  \nSynergistic Effects and Challenges of HDACis \nCombined with Other Treatment Strategies\nPotential for Combination Therapy\nHDACis demonstrate potential for combination with \nexisting therapies in endometriosis treatment. Regarding \nhormone combination therapy, HDACs are involved in \nregulating estrogen receptor signaling pathways [ 32], and \nHDACis may enhance the efficacy of traditional hormonal \ndrugs or overcome resistance by remodeling the activity of \nhormone receptor co-regulators [ 3]. Additionally, SAHA \ncan induce endometrial cell apoptosis by regulating the \nTRX and TBP-2 system, a mechanism independent of but \npotentially synergistic with hormonal pathways, providing \na molecular basis for combination therapy [7]. Progesterone \nresistance, common in endometriosis, is partly attributed to \nthe epigenetic silencing of PR-B, and HDACis may partici-\npate in restoring PR-B expression by affecting histone mod-\nifications, thereby enhancing progesterone efficacy [ 45]. \nSecondly, regarding combination with anti-inflammatory \nand anti-angiogenic drugs, endometriosis is essentially a \nchronic inflammatory disease with abundant inflammatory \nmediators and abnormal angiogenesis in the lesion micro -\nenvironment [85]. The role of HDACis in regulating inflam-\nmation and angiogenesis makes them ideal candidates for \ncombination therapy. Butyrate, as a short-chain fatty acid \nand HDAC inhibitor, can regulate gene expression, immune \nresponses, and inflammation by inhibiting immune dysreg -\nulation and reducing lesion proliferation [ 48]. Combining \nit with non-steroidal anti-inflammatory drugs (NSAIDs) \nmay more effectively control pain and lesion progres -\nsion by inhibiting prostaglandin synthesis and modulating \ninflammation-related epigenetics. Regarding angiogen -\nesis, exosomal long non-coding RNA HOTAIR promotes \nendometriosis progression and angiogenesis through the \nmiR-761/HDAC1 axis and activates the STAT3-mediated \ninflammatory pathway [ 14]. HDACis targeting this path -\nway combined with anti-vascular endothelial growth factor \n(VEGF) drugs may simultaneously block pro-angiogenic \nsignals and epigenetic regulation, thereby more effectively \ninhibiting the establishment and growth of ectopic lesions. \nPreclinical studies also support the feasibility of combina -\ntion strategies. For example, in an endometriosis-associated \novarian cancer model, vorinostat inhibited M2 macrophage \npolarization through the ARID1A/HDAC6/IL-10 signaling \npathway, demonstrating the potential of combining immune \nmodulation with epigenetic regulation [49].\nChallenges and Limitations\nDespite the promising prospects of HDACis in endometrio-\nsis treatment, their clinical translation faces multiple chal -\nlenges and limitations. Tissue selectivity and side effects \nare currently primary issues. Most HDACis lack tissue \nspecificity, and systemic administration can easily cause \nside effects such as fatigue and thrombocytopenia, limit -\ning long-term use [ 3]. Developing lesion-targeted delivery \nsystems, such as nanocarrier- or exosome-based platforms, \nis key to improving efficacy and reducing systemic toxic -\nity. Studies have found that exosomes can serve as carriers \nfor epigenetic regulators like lncRNA HOTAIR, playing \nan important role in intercellular communication in endo -\nmetriosis and providing ideas for designing targeted deliv -\nery tools [ 14]. Additionally, natural HDACis like butyrate \nhave limited clinical application due to their short half-life, \nprompting research into analogs or probiotics to maintain \nstable levels [ 48]. Secondly, disease heterogeneity and \ndrug resistance are another major obstacle. Endometriosis \nis highly heterogeneous, and HDAC subtype expression \nprofiles may vary significantly among different lesion types \n[4]. For example, studies found that HDAC8 expression \nis significantly elevated in endometriosis lesions, while \nHDAC1 and HDAC6 are elevated in DIE lesions, and \nHDAC2 and HDAC3 are decreased [ 4]. This differential \nexpression suggests the need for specific HDACis based on \npatient molecular subtypes rather than a “one-size-fits-all” \napproach. Simultaneously, long-term use of HDACis may \ninduce acquired resistance, possibly involving compensa -\ntory signaling pathway activation or reprogramming of the \nepigenetic landscape, requiring further study [ 86]. Finally, \nclinical translation barriers are particularly prominent. The \nvast majority of research on HDACis in endometriosis \nremains at the cellular and animal model stages, lacking \nlarge-scale, prospective clinical data to verify their efficacy \nand safety [3]. A core unresolved issue is the unclear long-\nterm impact of HDACis on female fertility, ovarian func -\ntion, and pregnancy. For example, deacetylases like SIRT1 \nmay play a role in embryo implantation and endometrial \nreceptivity, and the potential reproductive toxicity of their \ninhibitors requires careful evaluation [ 87]. Additionally, \nendometriosis is often associated with infertility, and treat -\nment itself should not impair future fertility potential. \nTherefore, future clinical studies need to strictly evaluate \nthese parameters and explore strategies like local admin -\nistration (e.g., intrauterine delivery) to reduce systemic \n\n1 3\nReproductive Sciences\neffects on the reproductive system. Although the reversibil-\nity of epigenetic modifications makes them attractive thera-\npeutic targets, transitioning from basic research to clinical \npractice still requires overcoming many difficulties [ 88].\nFuture Research Directions and Prospects\nDevelopment of Novel HDACis and Drug Delivery \nSystems\nGiven that non-selective or pan-HDACis often cause \nadverse reactions due to off-target effects in clinical applica-\ntions [89, 90], developing highly selective subtype-specific \ninhibitors has become a key strategy to improve efficacy \nand reduce toxicity. In endometriosis, subtypes such as \nHDAC8, HDAC1, and HDAC6 are highly promising selec-\ntive inhibition targets due to their abnormal expression in \nlesions. Studies confirm that in OE and DE lesions, HDAC8 \nimmunostaining is significantly elevated, and its expression \nis closely related to the fibrosis process; in animal models, \nspecific inhibition of HDAC8 significantly reduces lesion \nweight, decreases fibrosis, and prolongs hot plate latency, \nproviding strong evidence for HDAC8 as a therapeutic \ntarget [4, 16]. Additionally, HDAC1 and HDAC6 are also \nsignificantly elevated in DIE lesions [ 4]. Among them, \nHDAC6 expression is associated with ARID1A status, \nupregulated in ARID1A-negative ovarian endometriosis, \nsuggesting its involvement in specific disease subtypes or \nmalignant transformation processes [ 19]. Therefore, devel-\noping highly selective inhibitors targeting key subtypes like \nHDAC8, HDAC1, and HDAC6 is expected to provide pre -\ncise treatment options for endometriosis patients with dif -\nferent molecular characteristics. Currently, methods such as \nstructure-based virtual screening and pharmacophore mod -\nels have successfully discovered selective inhibitors with \nnanomolar affinity for HDAC1, HDAC3, and HDAC6 [ 91, \n92], providing a methodological foundation for designing \nhighly selective compounds targeting endometriosis-related \nsubtypes. Simultaneously, optimizing drug delivery sys -\ntems is equally crucial for the clinical application of HDAC \ninhibitors. Targeted delivery carriers like nanoparticles can \nimprove drug solubility and bioavailability, achieve targeted \naccumulation and sustained release at lesion sites, thereby \nenhancing efficacy while reducing adverse reactions caused \nby systemic exposure. In terms of reproductive safety \nassessment, lesion-targeted delivery systems are expected \nto reduce the potential risks of HDAC inhibitors to ovar -\nian function, oocyte quality, and embryonic development \nby minimizing systemic exposure. In the future, combining \nin-depth research on HDAC expression profiles in endo -\nmetriosis lesions, systematically conducting preclinical \npharmacodynamic and safety evaluations of highly selec -\ntive inhibitors targeting subtypes like HDAC8, HDAC1, \nand HDAC6, and integrating advanced drug delivery strate-\ngies will promote the entry of safer and more effective epi -\ngenetic-targeted therapies into clinical practice.\nEpigenetic Combination Therapy and Multi-Omics \nIntegrated Analysis\nExploring the combination of HDACis with other epigenetic \ndrugs holds promise for synergistic effects, more effectively \nreversing abnormal gene expression programs in endometri-\nosis. Existing research indicates that endometriosis involve \nvarious epigenetic regulatory abnormalities, including DNA \nmethylation, histone modifications, and non-coding RNAs \n[93]. The combined application of HDACis and DNA meth-\nyltransferase inhibitors (DNMTi) has demonstrated syner -\ngistic anti-tumor effects in other diseases; this strategy also \nhas potential in endometriosis, as it can simultaneously \ntarget different epigenetic layers to more effectively reac -\ntivate silenced cancer suppressor genes or correct abnor -\nmal transcriptional programs [ 94]. Developing HDAC \nhybrid inhibitors with dual or multi-targeting capabilities is \nanother noteworthy direction. These molecules combine the \nHDAC-inhibiting pharmacophore with pharmacophores of \nother anticancer targets (such as receptor tyrosine kinases, \ntopoisomerases, etc.), enabling simultaneous inhibition of \nmultiple pathogenic pathways at the single-molecule level, \nwhich helps overcome issues like limited efficacy of single \nagents, drug resistance, and off-target toxicity [95, 96]. For \nexample, studies have designed dual-target inhibitors simul-\ntaneously targeting HDAC and vascular endothelial growth \nfactor receptor (VEGFR), showing good anti-proliferative \nand anti-angiogenic activity in various cancer cell lines \n[97]. Given the close association of endometriosis with \ninflammation, angiogenesis, and fibrosis, similar dual-target \nstrategies may provide more comprehensive therapeutic \ninterventions for this disease. To lay the foundation for pre-\ncision therapy, it is crucial to use multi-omics technologies \nsuch as single-cell sequencing and spatial transcriptomics \nto map cell type-specific profiles of HDAC expression in \nendometriosis lesions. Traditional studies based on tissue \nhomogenates mask the heterogeneity among different cell \ntypes (e.g., epithelial cells, stromal cells, immune cells [ 4]. \nMulti-omics analysis at single-cell resolution can precisely \nidentify which cell subpopulations specifically overexpress \nHDAC8, HDAC1, or HDAC6, and how these abnormal \nexpressions are associated with specific cellular states (e.g., \nproliferation, epithelial-mesenchymal transition, fibrosis) \n[98]. For instance, functional experiments have found that \nthe long non-coding RNA LINC01638 promotes prolifera -\ntion and epithelial-mesenchymal transition in endometrial \n\n1 3\nReproductive Sciences\nectopic epithelial cells by inhibiting HDAC1 [ 6].Multi-\nomics integrated analysis helps systematically reveal the \nspecificity of such HDAC-mediated regulatory networks \nin different cell types, thereby identifying cell populations \nmost sensitive to HDACis and providing a basis for bio -\nmarker-based patient stratification, ultimately advancing \npersonalized epigenetic therapy tailored to specific molecu-\nlar subtypes and cellular environments in endometriosis.\nBiomarker-Based Personalized Therapy\nResearching biomarkers that reflect HDAC activity or sen -\nsitivity to HDACis is crucial for achieving personalized \ntherapy in endometriosis. Such markers can be derived \nfrom blood or endometrial tissue and used to guide patient \nstratification and efficacy prediction. Potential candidate \nbiomarkers include histone acetylation levels, where the \nacetylation status of histone H3 is a direct downstream \nindicator of HDAC activity, reflecting drug targeting effects \n[99]. In endometriosis, detecting acetylation levels at spe -\ncific histone modification sites (e.g., H3K9ac, H3K27ac) in \nlesions or circulating cells helps identify patient subgroups \nwith abnormally elevated HDAC activity, thereby predict -\ning their response to HDAC inhibitors [ 100]. Additionally, \nnon-coding RNAs (ncRNAs) in circulating exosomes are \npromising. As important carriers of intercellular commu -\nnication, exosomes carry miRNAs, lncRNAs, etc., which \ncan reflect the epigenetic state of source cells. Studies \nhave confirmed that ncRNAs are involved in endometrio -\nsis pathogenesis [ 93]; analyzing ncRNA profiles related \nto the HDAC pathway in patient plasma exosomes may \nyield non-invasive, dynamic markers for efficacy monitor -\ning. Meanwhile, identifying markers associated with resis -\ntance to HDACis is equally important. Research in other \ntumor fields shows that transcription factors like BCL6 can \nrecruit HDACs to inhibit drug-induced histone acetylation, \nleading to resistance [ 101]. Whether similar mechanisms \nexist in endometriosis warrants further exploration. For \nexample, HDAC8 is known to be significantly elevated \nin endometriosis lesions and associated with disease pro -\ngression [ 4, 16]; whether its expression level can serve \nas a predictive marker for efficacy requires validation in \nprospective clinical studies. In the future, systematically \nvalidating the predictive value of these biomarkers can be \nachieved by correlating HDAC subtype expression levels, \nhistone acetylation markers, or circulating ncRNA signa -\ntures with patient clinical outcomes (e.g., pain relief, lesion \nreduction, recurrence time). Biomarker-based patient strat -\nification will help identify endometriosis populations most \nlikely to benefit from HDAC-targeted therapy, promoting \nthe application of precision medicine in the management \nof this disease.\nConclusion\nHDACs, as important epigenetic regulatory molecules, play \na key role in the pathogenesis and progression of endometri-\nosis. This article reviews the abnormal expression profiles of \nHDACs in endometriosis and their pathogenic mechanisms, \nsummarizes preclinical research progress on HDACis in \nendometriosis treatment, and discusses future directions \nsuch as combination therapy strategies, novel drug develop-\nment, and personalized therapy. At the expression and func-\ntional level, endometriosis exhibits differential expression \nof HDAC family members: HDAC1, HDAC6, and HDAC8 \nare generally upregulated in lesions and associated with \ndisease progression, fibrosis, and malignant transforma -\ntion risk; HDAC2 expression shows dynamic changes with \ndisease stages; while HDAC3 is downregulated in patients \nwith concurrent infertility, potentially affecting endome -\ntrial receptivity. These subtype-specific expression patterns \nsuggest that different HDACs play distinct roles in various \npathological processes of endometriosis, providing a theo -\nretical basis for developing subtype-selective inhibitors. \nIn terms of pathogenic mechanisms, HDACs synergisti -\ncally promote the occurrence and development of endome -\ntriosis by regulating multiple pathways, including immune \ninflammation, cell proliferation and apoptosis, invasion \nand migration, angiogenesis, and hormone signal trans -\nduction. In therapeutic research, classical HDACis such as \nSAHA, romidepsin, and TSA have demonstrated multiple \ntherapeutic effects in vitro and in animal models, includ -\ning inhibiting proliferation, inducing apoptosis, anti-inflam-\nmatory, and analgesic effects. Naturally derived HDACis \nlike butyrate and VPA, due to their endogenous or already \nmarketed drug properties, combine good safety with clini -\ncal translation potential. Novel selective HDAC8 inhibitors \nshow unique advantages in reducing fibrosis and alleviat -\ning pain, highlighting the value of subtype-targeted therapy. \nHowever, the clinical translation of HDACis still faces \nmany challenges. Off-target effects of non-selective inhibi-\ntors, efficacy variations due to disease heterogeneity, and \npotential impacts on fertility are all urgent issues to address. \nFuture research should focus on the following directions: \nfirst, developing highly selective inhibitors and optimizing \ntargeted delivery systems based on HDAC subtype expres -\nsion profiles in endometriosis lesions; second, exploring \nsynergistic strategies of HDACis with hormone therapy, \nanti-inflammatory drugs, etc., to form multi-target combina-\ntion treatment plans; third, using multi-omics technologies \nsuch as single-cell sequencing and spatial transcriptomics \nto map cell type-specific profiles of HDAC regulatory net -\nworks; fourth, discovering biomarkers like histone acetyla -\ntion levels and circulating exosomal non-coding RNAs to \nadvance patient stratification and personalized therapy. In \n\n1 3\nReproductive Sciences\nsummary, HDACis, as key epigenetic regulatory factors in \nendometriosis pathogenesis, have become highly promis -\ning therapeutic targets. Although the translation from basic \nresearch to clinical application still faces challenges, with \nthe development of subtype-selective inhibitors, optimiza -\ntion of combination therapy strategies, and the deepening of \nprecision medicine concepts, HDACis are expected to open \nnew avenues for non-hormonal treatment of endometriosis, \nproviding patients with safer and more effective therapeutic \noptions.\nAcknowledgements The authors would like to thank the collective \nefforts of all team members.\nAuthor Contribution Conceptualization: Shaojie Zhao, Liping Jiang; \nMethodology: Shisi Xiong, Junjie Xu, Jingjing Pu;Investigation: all \nauthors;Writing – original draft: Shisi Xiong, Junjie Xu;Writing – re -\nview & editing: Shaojie Zhao, Liping Jiang, Jingjing Pu;Visualization: \nShisi Xiong;Supervision: Shaojie Zhao, Liping Jiang;Funding acquisi-\ntion: Shaojie Zhao, Liping Jiang.\nFunding This study was Supported by Medical Key Strategic Project \nof Wuxi Health Commission and Elite Talent Program of Wuxi Mater-\nnal and Child Health Hospital (LY2023004).\nData Availability This study did not generate new data. All findings \nsummarized in this manuscript come from articles cited in the refer -\nence list.\nDeclarations\nEthics Approval Not applicable. This manuscript is a review article \nand does not involve human participants or animals.\nCompeting Interests The authors declare no competing interests.\nConsent for Publication  All authors consent to publication of this \nmanuscript.\nConsent to Participate Not applicable.\nHuman and Animal Rights This manuscript is a narrative review based \nexclusively on previously published studies. It does not involve hu -\nman participants, animals, patient data, or any new experimental pro -\ncedures; therefore, Institutional Review Board (IRB) approval was not \nrequired.\nOpen Access   This article is licensed under a Creative Commons \nAttribution 4.0 International License, which permits use, sharing, \nadaptation, distribution and reproduction in any medium or format, \nas long as you give appropriate credit to the original author(s) and the \nsource, provide a link to the Creative Commons licence, and indicate \nif changes were made. The images or other third party material in this \narticle are included in the article’s Creative Commons licence, unless \nindicated otherwise in a credit line to the material. If material is not \nincluded in the article’s Creative Commons licence and your intended \nuse is not permitted by statutory regulation or exceeds the permitted \nuse, you will need to obtain permission directly from the copyright \nholder. 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Biochem Pharmacol. 2024;227:116466. \nhttps:   //d oi. or g/10 . 10 1 6/j. bcp.2024.116466.\nPublisher’s Note Springer Nature remains neutral with regard to juris-\ndictional claims in published maps and institutional affiliations.","source_license":"CC0","license_restricted":false}