Research Progress of Histone Deacetylase and Its Inhibitors in Endometriosis

Endometriosis is a complex chronic inflammatory disease with an unclear etiology and limited treatment options, severely affecting the reproductive health and quality of life of many women. Histone deacetylases (HDACs), as key epigenetic regulatory molecules, play a significant role in the pathogenesis and progression of endometriosis. This article reviews the abnormal expression of HDACs in endometriosis and their molecular mechanisms in driving the disease by regulating processes such as cell proliferation, apoptosis, inflammation, and epithelial-mesenchymal transition (EMT). It also sum - marizes the therapeutic potential of histone deacetylase inhibitors (HDACis) such as V orinostat, Romidepsin, and Butyr - ate demonstrated in preclinical studies, and analyzes the main challenges currently faced in clinical translation. Finally, this article discusses the challenges and future research directions for developing novel endometriosis therapies targeting HDACs, aiming to provide references for in-depth research and clinical translation in this field.

Endometriosis · Histone deacetylase (HDACs) · Histone deacetylase inhibitors (HDACis) · Epigenetics · Targeted therapy Received: 9 April 2026 / Accepted: 15 August 2026 © The Author(s) 2026 Research Progress of Histone Deacetylase and Its Inhibitors in Endometriosis Shisi Xiong1,3 · Junjie Xu1,4 · Jingjing Pu2 · Shaojie Zhao1 · Liping Jiang1 as 30%–50% in infertility patients [ 1]. Currently, the treat- ment of endometriosis primarily relies on hormonal drugs and surgical intervention. However, hormonal therapy is often accompanied by a series of side effects and has a high recurrence rate after discontinuation; while surgery can effectively remove lesions, it cannot achieve a cure, with a postoperative 5-year recurrence rate reaching 40%–50% [2]. Therefore, exploring new therapeutic targets and strategies and developing safe and effective non-hormonal drugs have become important directions in endometriosis research. In recent years, epigenetics has gained increasing atten - tion in the study of the pathogenesis and treatment of endo- metriosis. Histone acetylation, as an important epigenetic modification, is jointly regulated by histone acetyltrans - ferases (HATs) and histone deacetylases (HDACs) and is involved in various biological processes such as cell pro - liferation, differentiation, apoptosis, and inflammatory responses [3]. Numerous studies have shown that there are abnormalities in the expression and function of HDACs in endometriosis [ 4, 5]. This dysregulation participates in pathological processes such as abnormal proliferation, inva- sion, and fibrosis of ectopic endometrial cells by modulating key pathways including estrogen signaling, inflammatory responses, epithelial-mesenchymal transition, and the cell Endometriosis is a common benign gynecological disease characterized by the ectopic presence of viable endometrial- like tissue outside the uterine cavity. Clinically, it mainly manifests as chronic pelvic pain, dysmenorrhea, dyspareu - nia, and infertility, severely affecting the quality of life of women of reproductive age. Epidemiological data show that the prevalence of endometriosis among women of reproduc- tive age is approximately 10%–15%, and it can be as high 1 3 Reproductive Sciences cycle [ 3, 6]. Histone deacetylase inhibitors (HDACis), as a classic class of anti-tumor drugs, can restore histone acetylation levels and reactivate silenced tumor suppressor genes. Their potential in endometriosis treatment has gradu- ally been revealed in recent years. Studies have confirmed that various HDACis exhibit multiple therapeutic effects in endometriosis cell and animal models, including inhib - iting lesion growth, inducing apoptosis, anti-inflammatory effects, and analgesia [4, 6, 7]. However, the clinical translation of HDACis still faces many challenges. Traditional pan-HDACis, due to their lack of subtype specificity, are often accompanied by off-target side effects such as fatigue and thrombocytopenia [ 3]. The heterogeneity in the expression of different HDAC subtypes in endometriosis lesions also imposes higher requirements for precision therapy. Furthermore, issues such as the poten- tial impact of HDACis on female fertility, the safety of long- term medication, and synergistic strategies with existing treatment regimens all require systematic investigation. This article begins with the expression and pathogenic mechanisms of HDACs in endometriosis, then summarizes the research progress of both classic and novel HDACis for endometriosis treatment. It also discusses emerging combination therapy strategies, novel drug development, and optimization of drug delivery systems, and examines the prospects of biomarker-guided personalized therapy in endometriosis management. This review aims to provide a reference for further research and clinical translation of HDACis in endometriosis. Abnormal Expression and Function of HDACs in Endometriosis HDAC Family Expression Profiles and Pathological Correlations Classification and Functions of HDACs HDACs are a class of enzymes ubiquitously present in eukaryotic cells that catalyze the deacetylation of histone and non-histone substrates, thereby regulating various cel - lular biological processes including cell proliferation, apop- tosis, immune response, and metabolic homeostasis. Based on differences in structural homology with yeast, they can be divided into four classes [ 8]. Among them, Classes I, II, and IV are zinc-dependent enzymes, while Class III are NAD+-dependent enzymes. Class I HDACs include HDAC1, 2, 3, and 8, which function by forming complexes with other proteins [9] and are associated with diseases such as cancer, inflammation, and infection. Class II HDACs are further divided into Class IIa (HDAC4, 5, 7, and 9) and Class IIb (HDAC6 and 10) based on their catalytic domains, and are characterized by their ability to shuttle between the nucleus and cytoplasm [10].Among them, Class IIa HDACs exhibit relatively low deacetylase activity towards histones, whereas HDAC6, a Class IIb member, possesses significant deacetylase activity towards non-histone substrates includ - ing α-tubulin and molecular chaperones, and is involved in the regulation of autophagy and hepatic metabolism [ 11]. Class III HDACs consist of the Sirtuins (SIRTs) family 1–7, which, along with ADP-ribosyltransferases, partici - pate in regulating various cellular processes [ 8]. HDAC11 is the sole member of Class IV HDACs, highly expressed in organs such as the brain, heart, and kidneys, and involved in multiple pathophysiological processes, closely related to metabolic diseases like obesity and diabetes [12]. Abnormal Expression of HDACs in Endometriosis The occurrence and development of endometriosis involve complex epigenetic regulatory mechanisms, among which the abnormal expression of HDACs has received widespread attention in recent years. HDACs catalyze the deacetylation of histone lysine residues, altering chromatin conformation and thereby regulating gene transcription. Studies indicate that multiple HDAC family members exhibit differential expression in endometriosis, and this dysregulation of the expression profile may be involved in pathological pro - cesses such as abnormal proliferation and invasion of ecto - pic endometrial cells (Table 1). Expression of Class I HDACs HDAC1 is one of the most extensively studied HDAC subtypes, and there is rela - tively consistent evidence for its upregulation in endo - metriosis. Colón-Díaz et al. reported that the mRNA and protein levels of HDAC1 in endometriotic stromal cells (Hs832cT) were significantly higher than those in normal stromal cells; estradiol combined with progesterone could downregulate HDAC1 expression in normal endometrial epithelial cells, but this hormonal regulatory effect was lost in Hs832cT cells. However, the HDAC1 mRNA level was lower in homogenates of ectopic tissues compared to controls; at the protein level, HDAC1 was widely highly expressed in ovarian, skin, and gastrointestinal lesions, and its expression was higher in ovarian lesions than in peritoneal lesions, suggesting a potential association with malignant transformation potential [ 13]. Another study also showed that HDAC1 mRNA expression was lower in ectopic endometrial tissues compared to normal endo - metrium [ 5]. The above differences in mRNA expression may stem from the models used: cell lines reflect intrinsic cellular characteristics, whereas tissue samples integrate the multiple influences of the lesion microenvironment. 1 3 Reproductive Sciences Additionally, post-transcriptional regulation and cellular heterogeneity within tissues may also contribute to these differences. Mechanistically, a study based on exosomes from ovarian endometrioma (OE) patient tissues found that lncRNA HOTAIR upregulated HDAC1 protein expression by downregulating miR-761; in vivo experiments in nude mice confirmed that exosomal HOTAIR could promote the growth of ectopic lesions, providing in vivo functional validation for the pathogenic role of HDAC1 in endome - triosis [14]. Genetic analysis revealed that HDAC1 single nucleotide polymorphisms (SNPs) were significantly asso - ciated with endometriosis risk in South Indian women, suggesting it may be a genetic susceptibility marker [ 15]. In mouse models, HDAC1 staining intensity progressively increased with lesion progression [ 16]. Zheng et al. fur - ther found in a TGF-β1-induced epithelial-mesenchymal transition model that HDAC1 expression was upregulated in the human endometrial epithelial cell line 11Z, and pri - mary stromal cells isolated from OE exhibited significantly higher HDAC1 mRNA and protein levels than normal controls; immunohistochemical analysis of human lesions confirmed that HDAC1 staining was significantly enhanced in deep infiltrating endometriosis (DIE), with expression levels positively correlated with lesion fibrosis [ 4]. Col - lectively, these findings indicate that HDAC1 is gener - ally upregulated in endometriosis, but the inconsistency between mRNA and protein levels suggests complex post- transcriptional regulation, and the differences in expression across lesion subtypes and cell types should be considered in precision therapy. The expression pattern of HDAC2 is more complex. Simi- lar to HDAC1, both the mRNA and protein levels of HDAC2 in Hs832cT are significantly higher than those in normal stromal cells. In normal stromal cells, estradiol upregulates HDAC2 expression, whereas combined treatment with estrogen and progesterone downregulates it; however, this regulation is lost in Hs832cT. At the human tissue level, HDAC2 is highly expressed in skin lesions and eutopic endometrial stroma (100% and 82%), whereas the positiv - ity rates are lower in ovarian and peritoneal lesions. mRNA analysis shows that HDAC2 levels in lesions are lower than in eutopic endometrium but higher than in myoma control endometrium, indicating expression heterogeneity at the tissue level [ 13]. Another study also found that HDAC2 mRNA is significantly elevated in the eutopic endometrium of endometriosis patients but shows no significant differ - ence in ectopic endometrium [5]. These results collectively indicate that HDAC2 expression exhibits clear model depen- dency and tissue heterogeneity. Moreover, Mai et al. found that HDAC2 protein expression in human endometriotic lesions is significantly higher than in normal endometrium; knockdown of HDAC2 in hEM15A cells can upregulate the hepatocyte nuclear factor 4α / AT-rich interactive domain 1 A (HNF4A/ARID1A) axis, inhibiting proliferation and inva- sion while promoting apoptosis; animal experiments further confirmed that HDAC2 knockdown can reduce lesion size [17]. Additionally, in mouse models, HDAC2 staining inten- sity gradually decreases with lesion progression [16]. Zheng et al., through immunohistochemistry of human endometri- otic lesions, observed that HDAC2 expression in DIE is sig- nificantly lower than in OE and is negatively correlated with the degree of lesion fibrosis [ 4]. These pieces of evidence suggest that HDAC2 may exert differential regulatory roles at different stages of the disease. HDAC3 is downregulated in endometriosis and is associ- ated with infertility and the severity of lesion fibrosis. Kim Table 1 Differential expression and functional roles of HDACs in endometriosis Class HDAC Isoform Expression pattern Pathological association Key mechanisms References Class I HDAC1 Widely upregulated in lesions Proliferation, invasion, EMT, fibrosis Regulation of RHOB, p21, and association with ERα expression [6, 13, 32] HDAC2 Dynamically altered (high in early-stage, low in late-stage) Disease progression Regulation of the HNF4A/ ARID1A axis [5, 17] HDAC3 Downregulated in patients with infertility Endometrial receptivity Involvement in decidualization and embryo implantation [18] HDAC8 Progressively upregulated with disease advancement Fibrosis, pain Regulation of TGF-β signaling [4] Class II HDAC6 Significantly upregulated in DIE and OE lesions Risk of malignant transformation α-tubulin deacetylation; associa- tion with ARID1A loss [19] HDAC9 Upregulated in DIE lesions To be validated To be elucidated [20] Class III SIRT1 Controversial (mostly reported as upregulated) Inflammation, progesterone resistance, infertility Regulation of p53, FOXO1, BCL6, and NF-κB [22, 24, 25] SIRT3 Controversial Oxidative stress, mitochon- drial function Regulation of SOD2, GDH, and SDH [28, 29] SIRT7 Upregulated Mitochondrial stress, meta- bolic reprogramming TUFM deficiency promotes SIRT7 overexpression [31] EMT epithelial-mesenchymal transition, ERα estrogen receptor alpha, DIE deep infiltrating endometriosis, OE ovarian endometrioma 1 3 Reproductive Sciences et al. found that in endometriosis patients with infertility, HDAC3 protein in the in situ endometrium was significantly lower than in normal controls during the proliferative, early secretory, and mid-secretory phases. In a baboon model of endometriosis, HDAC3 expression gradually decreased as the disease progressed; in a surgically induced mouse model, HDAC3 protein in in situ endometrial stromal cells was also significantly lower than in the sham-operated group. Functionally, mice with uterine-specific deletion of Hdac3 exhibited implantation failure and defective decidu - alization, involving de-repression of collagen genes and impaired progesterone signaling [ 18]. Zheng et al. showed through immunohistochemical analysis of DIE and OE lesions that HDAC3 expression was significantly lower in DIE compared to OE and normal controls. Additionally, primary stromal cells from OE also displayed decreased HDAC3 mRNA and protein levels. Conversely, HDAC3 expression was upregulated in the TGF-β1-stimulated 11Z epithelial cell line, suggesting differences between in vitro induction models and the true in vivo microenvironment [4]. In summary, HDAC3 shows a downregulated trend in endometriosis, particularly in DIE lesions with higher fibro- sis and in patients with infertility. HDAC8 is upregulated in endometriotic lesions and is closely associated with the fibrotic process. Zheng et al. first found using a mouse model of endometriosis that HDAC8 expression progressively increased with lesion progression, and that stromal HDAC8 levels were strongly positively correlated with fibrosis markers. Functionally, the HDAC8- specific activator TM-2–51 accelerated lesion growth and fibrosis, whereas the inhibitor PCI-34,051 dose-dependently suppressed lesions, alleviated fibrosis, and reduced pain [16]. Subsequently, the team provided additional evidence at the human tissue and cellular levels: HDAC8 expression was elevated in both OE and DIE, and upregulated in pri - mary stromal cells and the 11Z cell line [ 4]. These studies, spanning from animal models to human subjects, clearly establish the driving role of HDAC8 in endometriosis-asso- ciated fibrosis, although more human studies and drug trials are required to validate its potential as a therapeutic target. Expression of Class II HDACs HDAC6 is upregulated in endo- metriosis and is associated with lesion fibrosis and malig - nant transformation. Zheng et al. observed that HDAC6 mRNA and protein levels increased with the progression of fibrosis in 11Z cells stimulated by TGF-β1. Immunohisto - chemistry of human tissues showed that HDAC6 staining was significantly elevated in both the epithelium and stroma of DIE lesions and positively correlated with the degree of fibrosis, but there was no significant change in OE, and HDAC6 expression in primary stromal cells derived from OE was also not significantly different [ 4]. Another tissue microarray analysis including 168 endometriotic lesions from the ovary, peritoneum, and deep infiltrating endome - triosis confirmed that HDAC6 expression in both the epi - thelium and stroma of DIE was significantly higher than in other subtypes. In cases with negative ARID1A expression, epithelial HDAC6 expression was higher than in controls without endometriosis, especially in the OE group, while stromal expression showed no significant difference [ 19]. These findings indicate that abnormal HDAC6 expression is dependent on lesion subtype, cell type, and ARID1A sta- tus, and may contribute to the malignant transformation of DIE and some OE lesions through the ARID1A deletion pathway. However, current studies are primarily observa - tional and lack functional validation and clinical interven - tion evidence, and the differential regulatory mechanisms of HDAC6 in the stroma and epithelium remain to be elucidated. The role of HDAC9 in endometriosis remains unclear. A recent study predicted HDAC9 as a candidate epigenetic marker through bioinformatics analysis (GSE11691) and verified its significantly increased mRNA expression in a rat endometriosis model using RT-qPCR. Based on the Turku database, the study also found that HDAC9 expression is lower in the proliferative phase of the endometrium [ 20]. However, the study had a small sample size and lacked protein and functional validation, which is insufficient to confirm its pathogenic role. Future research should clarify its expression profile in human tissues and systematically investigate its regulatory network and pathogenic mecha - nisms through in vitro functional experiments and animal models. Expression of Class III HDACs Multiple studies have shown that Sirtuin 1 (SIRT1) is abnormally expressed in endo - metriosis and is involved in the progression of the disease. Taguchi et al. found that in primary endometriotic stro - mal cells derived from OE, SIRT1 activation could inhibit TNF α-induced IL-8 release, whereas inhibition of SIRT1 promoted IL-8 [ 21], suggesting a direct anti-inflamma - tory effect. In the context of eutopic endometrium, both human tissue and baboon models have shown that SIRT1 is upregulated as the disease progresses and is positively correlated with KRAS. A mouse model with KRAS activa- tion confirmed that KRAS can upregulate SIRT1 and sup - press progesterone target genes. In the human endometrial adenocarcinoma cell line Ishikawa, SIRT1 binds to BCL6 to inhibit GLI1 transcription, indicating that the SIRT1/ BCL6 axis may be involved in progesterone resistance [22]. Additionally, in normal female endometrium, SIRT1 is only expressed during menstruation, whereas in endo - metriosis patients, SIRT1 is persistently highly expressed throughout the cycle. Mice with uterine-specific Sirt1 1 3 Reproductive Sciences overexpression confirmed that SIRT1 overexpression can lead to implantation failure and downregulation of proges - terone target genes, thereby promoting the growth of ecto - pic lesions [ 23]. Other studies combining human tissue and Ishikawa cell experiments found that SIRT1 promotes EMT by helping epithelial cells escape damage-induced senescence, thus driving disease progression [ 24]. The evidence related to eutopic endometrium is relatively con - sistent, suggesting that SIRT1 overexpression is involved in progesterone resistance and disease progression through multiple mechanisms. However, in ectopic stromal cells also derived from OE, Zhang et al. found that miR-22-3p carried by peritoneal macrophage exosomes targeted and inhibited SIRT1, subsequently activating the NF-κB pathway and promoting cell proliferation, migration, and invasion [ 25]. This differs from the findings of Taguchi et al., and the discrepancy may stem from differences in intervention methods: the former mimicked a persistent exogenous downregulation of SIRT1 in the pathological microenvironment through exosomal miRNA, activat - ing an NF-κB-driven invasive phenotype, while the latter directly regulated SIRT1 activity with pharmacological activators or inhibitors, reflecting its underlying anti- inflammatory function. Therefore, within the same cells, SIRT1 can both maintain anti-inflammatory homeostasis and shift to a pro-invasive state under specific upstream signals, demonstrating that its function is clearly depen - dent on the mode of regulation.In addition, there is dis - agreement regarding the clinical biomarker value of SIRT1: studies based on serum ELISA suggest that SIRT1 levels are elevated in patients with advanced endometrio - sis [ 26], whereas prospective studies using endometrial biopsies in mixed infertile populations have not found an association between SIRT1 and diagnosis or pregnancy outcomes [ 27]. The discrepancy may originate from dif - ferences in sample type (circulating blood vs. local tissue) and study populations (covering different stages vs. mixed infertility), indicating that strict standardization of detec - tion methods and population selection is required when considering SIRT1 as a biomarker. In OE lesions, the expression level of Sirtuin 3 (SIRT3) protein is significantly lower than that in normal endome - trial tissue. The activities of its downstream target enzymes, glutamate dehydrogenase (GDH), succinate dehydrogenase (SDH), and manganese superoxide dismutase (MnSOD), show a declining trend in both tissue homogenates and mitochondria (though the activity of MnSOD in mitochon - dria appears increased). In contrast, there is no significant difference in SIRT3 levels in serum samples. The impair - ment of mitochondrial energy metabolism and antioxidant defense in ectopic lesions is associated with downregulation of SIRT3, suggesting that SIRT3 deficiency may be an important pathogenic mechanism in endometriosis [ 28]. However, the findings of Goday et al. contradict this. By assessing SIRT3 levels in patients with different types of endometriosis-related infertility undergoing in vitro fertil - ization cycles, they found that in patients with DIE, SIRT3 levels in peripheral blood mononuclear cells were higher than in OE patients, and those with a history of surgery had even higher SIRT3 levels. This suggests a possible associa- tion between disease severity and SIRT3 upregulation [29]. The aforementioned differences may arise from variations in the sample types (local lesion tissue vs. circulating mono- nuclear cells) and disease subtypes (OE vs. DIE), reflecting different regulatory patterns of SIRT3 in local lesions and systemic immune responses. Research on SIRT7 in endometriosis is currently insuf - ficient. Clinical studies have found that in patients with endometriosis undergoing in vitro fertilization, the expres - sion levels of SIRT in hGL are positively correlated with the doses of FSH and LH used [30], suggesting that SIRT7 may be positively regulated by sex hormones, which requires further functional validation. Regarding the pathogenic mechanism, primary ectopic stromal cells derived from OE exhibit a metabolic shift from mitochondrial respira - tion to glycolysis, with SIRT7 being significantly upregu - lated in the ectopic lesions. Functional experiments have confirmed that in primary ectopic stromal cells, overex - pression of SIRT7 promotes cell proliferation and migra - tion, whereas knockdown has the opposite effect; SIRT7 drives metabolic reprogramming by upregulating glycolytic enzymes (GBE1, PYGL), downregulating mitochondrial enzymes (IDH1, SDHB), and activating the RhoA/ROCK/ AKT pathway. SIRT7 interacts with the mitochondrial pro- tein TUFM, and TUFM deficiency leads to increased SIRT7 protein levels; moreover, the phenotype induced by TUFM knockdown can be reversed by SIRT7 knockdown, suggest- ing that TUFM negatively regulates SIRT7. In a BALB/c female mouse model of endometriosis, SIRT7 overexpres - sion promotes the growth of ectopic lesions, while knock - down inhibits lesion development [31]. In summary, SIRT7 drives metabolic reprogramming and disease progression through the TUFM/SIRT7 axis, and its clinical translational value and regulatory relationship with sex hormones require further validation. In summary, HDACs exhibit differential expression pro- files in endometriosis, suggesting that distinct HDAC sub - types may play stage- and context-dependent regulatory roles in the pathogenesis of the disease. This expression het- erogeneity also provides a theoretical basis for the applica - tion of HDACis in endometriosis treatment. 1 3 Reproductive Sciences Pathogenic Mechanisms of HDACs in Endometriosis As crucial epigenetic regulatory molecules, HDACs influ - ence core biological processes such as cell proliferation, dif- ferentiation, and apoptosis by modulating histone acetylation status in various diseases. Given the universality of these mechanisms, HDACs may participate in multiple pathologi- cal aspects of endometriosis in similar ways (Fig. 1). Based on their functional differences, the related pathogenic mech- anisms can be summarized as follows: (1) Immune-inflam - matory regulation: HDACs can promote the transcription of pro-inflammatory factors such as TNF-α, IL-1β, and IL-6 by deacetylating histones and non-histone proteins, while also regulating the activity of T cells and macrophages, leading to weakened immune surveillance function and impaired clearance of ectopic endometrial cells [ 33]. Among them, SIRT1 plays an important role in endometriosis. Zhang et al. [25] found that exosomes derived from peritoneal mac - rophages can be taken up by ectopic endometrial stromal cells. The miR-22-3p enriched in these exosomes promotes the proliferation, migration, and invasion of ectopic endo - metrial stromal cells by targeting and inhibiting SIRT1 and activating the NF-κB pathway. Additionally, HDAC1 can activate the STAT3 signaling pathway through the exosome-mediated HOTAIR/miR-761 axis, promoting the release of inflammatory factors and further exacerbating the local inflammatory microenvironment [ 14]. (2) Imbal - ance between cell proliferation and apoptosis: Studies have shown that in fibroblasts and B cells, HDAC1/2 can directly bind to the promoter regions of CDK inhibitors such as p21 and p57, inhibiting their transcription through deacetylation modifications, thereby promoting the G1/S phase transition and inhibiting apoptosis [ 34]. In endometriosis, upregula - tion of SIRT1 expression is closely related to downregula - tion of p53 expression, leading to an imbalance between cell proliferation and apoptosis by inhibiting p53-medi - ated apoptotic signaling [ 35]. Moreover, the LINC01638/ HDAC1/p21/p27 axis is involved in the regulation of abnor- mal cell proliferation in endometriosis by modulating G1 phase arrest in the cell cycle [6]. (3) Enhanced invasion and migration capabilities: HDACs synergistically participate in the invasion and migration processes of endometriosis through different mechanisms. HDAC1 promotes EMT by inhibiting RHOB expression, thereby enhancing cell migra- tion and invasion [6]. HDAC2 affects cell invasion by regu- lating the HNF4A/ARID1A axis [ 17]. Additionally, SIRT1 Fig. 1 Schematic diagram of the pathogenic mechanisms of HDACs in endometriosis Abbreviations: HDAC, histone deacetylase; EMT, epi - thelial-mesenchymal transition. HDACs are divided into four classes (Class I, Class II, Class III, and Class IV), with Class II further subdi- vided into two subclasses: Class IIa and Class IIb. Through deacety - lation of histone and non-histone substrates, HDACs regulate chro - matin conformation and protein activity, thereby modulating multiple cellular processes. In endometriosis, aberrant HDAC activity drives five interconnected pathological pathways: immune inflammation, proliferation/apoptosis imbalance, enhanced invasion/migration/EMT, angiogenesis/hypoxia, and hormone dysregulation. These pathways collectively contribute to ectopic lesion growth, chronic pelvic pain, infertility, and recurrence 1 3 Reproductive Sciences is involved in the regulation of cell migration through the FoxO1-mediated autophagy pathway [36]. In DIE, HDAC6 expression is significantly elevated, influencing cytoskel - etal dynamic remodeling by regulating α-tubulin deacety - lation, thereby promoting cell migration [ 19]. HDAC8 is also highly expressed in DIE lesions, and its expression is closely related to the fibrosis process. Mechanistic studies suggest that HDAC8 may participate in EMT and fibro - sis processes by regulating the TGF-β signaling pathway, thereby promoting lesion invasion and progression [ 4]. (4) Angiogenesis and hypoxia response: HDAC1 enhances the tube-forming ability of vascular endothelial cells by acti - vating the STAT3 pathway, promoting angiogenesis [ 14]. Furthermore, under hypoxic conditions, HDACs expres - sion increases by binding to HIF-1, downregulates EZH2 expression, and drives the overexpression of genes involved in cell adhesion, proliferation, migration, and angiogenesis [37]. (5) Steroid hormone synthesis and signal transduc - tion: Estrogen plays a central role in the pathogenesis of endometriosis. HDACs can regulate the transcription of key enzymes in estrogen synthesis, such as aromatase, leading to elevated local estrogen levels [38]. Additionally, HDAC1 is significantly correlated with estrogen receptor α (ER-α) expression, suggesting its potential involvement in hormone signaling regulation [32]. Notably, in ectopic cells, the regu- latory effect of hormones on HDAC1/2 expression is lost [13], indicating that HDACs may participate in disease pro- gression through hormone-independent pathways. Overview of HDACis and Preclinical Studies in the Treatment of Endometriosis Overview of HDACis HDACis are natural or synthetic small-molecule com - pounds that can inhibit the activity of HDACs, restoring or increasing histone acetylation levels. Based on their chemi- cal structures, they are classified into six types: short-chain fatty acids, hydroxamic acids, benzamides, cyclic peptides, thiol ketones, and sirtuin inhibitors [9]. 1. Short-chain fatty acids: such as butyrate and valproic acid (VPA). Changes in dietary fiber can alter the micro- biota, thereby affecting short-chain fatty acid levels. 2. Hydroxamic acids: such as V orinostat (SAHA), Tricho- statin A (TSA), Panobinostat, and TH34. Hydroxamic acids are important molecules with metal-chelating abil- ities, helping microorganisms better acquire iron ions [39] and possessing anti-tumor potential. 3. Benzamides: such as Entinostat (MS-275). They play a significant role in the development of novel CDK inhibitors, helping to inhibit the activity of cyclin-depen- dent kinases [40]. 4. Cyclic peptides: such as Romidepsin, Trapoxin A, and HC Toxin. Cyclic peptides have complex and diverse structures composed of proteinogenic amino acids, D-amino acids, and non-proteinogenic amino acids, and are considered Class I HDACis [41]. 5. Thiol ketones: such as KD5150 and KD5170. KD5170 can induce apoptosis and inhibit cell proliferation, exhib- iting broad-spectrum anti-tumor activity both in vitro and in vivo [42]. 6. Sirtuin inhibitors: such as nicotinamide, EX-527, sirtinol, 3-TYP, etc. They primarily help the body resist aging and other diseases by reducing the activity of the SIRT fam - ily and regulating metabolism, antioxidant activity, and anti-inflammatory responses [43]. Theoretical Basis for HDACis in Targeted Therapy for Endometriosis The pathogenesis of endometriosis involves multiple fac - tors, including estrogen dependence, progesterone resis - tance, and chronic inflammation, with abnormal epigenetic regulation playing a key role. As important enzymes in epigenetic modification, HDACs are closely related to the pathological progression of endometriosis, providing a theoretical basis for the application of HDACis. First, HDACs exhibit abnormal expression in endometriosis lesions. Studies have confirmed that HDAC1, HDAC6, and HDAC8 are generally upregulated in ectopic lesions [4, 13, 19], suggesting their involvement in disease pro - gression, while HDAC3 is downregulated in patients with infertility [ 18]. This differential expression provides a molecular basis for targeted intervention with HDACis. Second, HDACs are widely involved in the epigenetic regulation of key pathways in endometriosis. They affect estrogen synthesis and signaling by regulating aromatase and ER-α expression [ 32, 44]. They also mediate the epi - genetic silencing of the progesterone receptor B subtype (PR-B), contributing to progesterone resistance [ 45]. Addi- tionally, HDAC1 can regulate EMT and promote the tran - scription of inflammatory factors, driving lesion invasion and maintaining the inflammatory microenvironment [ 6, 33]. Furthermore, HDACis offer the advantage of “multi- target” intervention. Due to the reversibility of epigenetic modifications, HDACis can simultaneously regulate mul - tiple pathogenic pathways by restoring histone acetylation levels [ 46]. Finally, some HDACis already have a foun - dation for clinical translation. Safety data for drugs such as VPA and butyrate are available from clinical applica - tions [47, 48], laying the groundwork for drug repurposing strategies. 1 3 Reproductive Sciences Preclinical Studies of HDACis in the Treatment of Endometriosis In recent years, various HDAC inhibitors have been evalu - ated for their pharmacological effects in cellular and animal models of endometriosis (Table 2). Classical HDACis SAHA, as a classical HDACi, demonstrates potential for direct anti-cell activity in endometriosis treatment. Its mech- anism of action is closely related to the regulation of intra - cellular oxidative stress. The study utilized primary human endometrial stromal cells isolated from the in situ endome - trium of patients without endometriosis and from the ecto - pic endometrium of patients with OE, as well as Ishikawa cells, and treated them with 1.25–10 µM SAHA for 48 h. The results showed that SAHA significantly upregulated the mRNA and protein levels of thioredoxin-binding pro - tein-2 (TBP-2) in HESCs, reduced the thioredoxin (TRX)/ TBP-2 ratio, and promoted cell apoptosis. Under oxidative stress conditions induced by rHMGB-1 (10 ng/mL, 24 h), 2.5 µM SAHA similarly upregulated TBP-2 expression and enhanced apoptosis. After inhibiting TRX expression with siRNA, SAHA-induced apoptosis was further exacerbated, indicating that the effect of SAHA depends on the TRX/ TBP-2 system [ 7]. Additionally, SAHA also has the func - tion of inhibiting HDAC6 activity. Treatment of human EAOC cell lines TOV-21G (clear cell carcinoma) and TOV- 112D (endometrioid carcinoma) with 10 nM SAHA for 4 and 8 h showed simultaneous downregulation of HDAC6 and GATA3 protein expression and induction of cell apop - tosis. In a mouse model of endometriosis-associated ovar - ian cancer (EAOC), intraperitoneal injection of 50 mg/kg vorinostat every 3 days significantly reduced ovarian tumor volume, with the mechanism related to inhibition of M2 macrophage polarization and downregulation of IL-10 lev - els [49]. These findings provide an experimental basis for the subsequent preclinical and clinical studies of SAHA. Romidepsin, as a specific class I HDAC inhibitor, has had its mechanisms of action in preclinical studies of endo- metriosis explored at two levels. In the human immortalized epithelial endometrial cell line 11Z, romidepsin (10–100 nM) inhibited HDAC enzymatic activity in a concentration- dependent manner (IC50 = 6.5 nM), induced acetylation of histones H2A/H2B/H3/H4, upregulated p21, and down - regulated cyclin B1/D1, thereby inhibiting cell proliferation and activating the intrinsic apoptosis pathway (caspase-9/3 activation and PARP cleavage) [50]. In the human endome- triotic epithelial cell line 12Z, romidepsin (1.5–2.5 nM) was used as an HDAC1/2 inhibitor, confirming that LINC01638 promotes EMT and cell migration/invasion by inhibiting HDAC1 and upregulating RHOB expression; romidepsin treatment could partially reverse RHOB downregulation caused by LINC01638 knockdown, and ChIP assays con - firmed that its mechanism is related to H3K27ac levels at the RHOB promoter [6]. In summary, romidepsin exhibits anti- proliferative, pro-apoptotic, and EMT-inhibitory effects in cell models, but research remains limited to in vitro studies, lacking validation in animal models, and its in vivo effects on ectopic lesion growth, fibrosis, and pain have not been assessed. Further pharmacodynamic studies are required for clinical translation. As a classic hydroxamic acid class HDAC inhibitor, TSA demonstrates multi-target potential in the treatment of endometriosis. In in vivo studies, Lu et al. confirmed using a C57BL/6 mouse autotransplantation model that TSA (0.5 mg/kg/day, subcutaneous injection for 4 weeks) significantly reduced lesion area (by 54.3%) and alleviated hyperalgesia, while also decreasing the expression of TRPV1, PKCε, and PGP9.5 [51]. However, this study only used a single dose and did not evaluate the effects on fibrosis or fertility. At the cellular level, Wu et al. found that TSA (0.1–100 µM) exhibited a strong and sustained anti-proliferative effect on immortalized YHES stromal cells, which was superior to CDB-2914 and NAC, with the mechanism associated with upregulation of PR-B and AR [52]. Subsequently, the same group demonstrated in YHES cells that TSA could inhibit IL-1β-induced COX-2 expression [53], and further revealed in 11Z/22B endometriotic cell lines that TSA (0.1–1 µM) suppressed constitutive NF-κB activation and TNF-α- induced p65 nuclear translocation, with endometriotic cells being more than ten times more sensitive than normal cells [54]. Seo et al. further showed using primary stromal cells derived from ovarian endometriomas that TSA (250–1000 ng/mL) could promote apoptosis through the induction of NAG-1 expression [ 55]. In summary, TSA exerts thera - peutic potential through multiple mechanisms including anti-proliferation, anti-inflammation, pro-apoptosis, and analgesic effects. Future studies should systematically assess its impact on different lesion subtypes, stages, and fibrosis, optimize dosing regimens, and conduct combined in vivo and in vitro validation to facilitate clinical translation. Natural Product and Metabolite-Derived HDACis The role of the gut microbiota metabolite butyrate in endo - metriosis has been gradually elucidated step by step, from dysbiosis and metabolite supplementation to molecular mechanisms. Alghetaa and colleagues, using a mouse model of endometriosis, found that endometriosis could lead to a reduction in the abundance of butyrate-producing gut microbiota and a decrease in colonic butyrate levels, accom- panied by peritoneal inflammation and immune-metabolic 1 3 Reproductive Sciences Agent (Class) Research model Dosage/administration Key findings References SAHA (hydroxamate) Primary human HESC (normal and OE-derived ectopic); Ishikawa cell line Cells: 1.25–10 µM, 48 h Induces apoptosis; upregulates TBP-2, reduces TRX/ TBP-2 ratio; dependent on TRX/TBP-2 system. [7] EAOC transgenic mouse model (TOV-21G, TOV-112D-derived) Animal: 50 mg/kg, i.p., every 3 days Suppresses tumor growth; downregulates HDAC6 and GATA3, inhibits M2 macrophage polarization, reduces IL-10 levels. [49] Romidepsin (cyclic peptide) Human immortalized epithelial endometrial cell line 11Z 10–100 nM, 24–144 h Suppresses proliferation, induces apoptosis; inhibits HDAC activity (IC₅₀=6.5 nM), induces histone acetyla- tion, upregulates p21, downregulates cyclin B1/D1, activates caspase-9/3 and PARP cleavage. [50] Human endometriotic epithelial cell line 12Z 1.5–2.5 nM, 24 h (com- bined with LINC01638 siRNA knockdown) Partially reverses RHOB downregulation induced by LINC01638 knockdown; inhibits EMT and migration/ invasion; upregulates RHOB by reducing RHOB pro- moter deacetylation via HDAC1/2 inhibition. [6] TSA (hydroxamate) C57BL/6 mouse, intraperitoneal autolo- gous uterine fragment implantation 0.5 mg/kg/d, s.c., 4 weeks Reduces lesion area (↓54.3%); prolongs hot plate latency (ameliorates hyperalgesia); reduces serum TNFα (trend); inhibits HDAC activity, reduces TRPV1 (eutopic endo- metrium), PKCε (ectopic lesions), and PGP9.5 (vagina) expression. [51] Immortalized human endometrial stromal cell line YHES 0.1–100 µM, 48 h (some experiments observed up to 4 weeks) Inhibits proliferation in a concentration-dependent man- ner (90% inhibition at 100 µM); sustained effect (no recovery at 4 weeks); upregulates PR-A, PR-B, AR, and FasL expression. [52] YHES Pretreatment with 1–100 µM for 1 h, then IL-1β (0.1–1 ng/mL) stimulation for 4 h (mRNA) or 16 h (protein) Inhibits IL-1β-induced COX-2 mRNA and protein expression in a concentration-dependent manner; possibly through PPARγ activation, NF-κB inhibition, or coactiva- tor competition. [53] YHES, 11Z, 22B (stromal-like) 0.1–10 µM, 48 h (YHES: 10 µM; 11Z/22B: 0.1–1 µM) Inhibits cell proliferation; inhibits constitutive and TNF- α-induced NF-κB activation; inhibits IκBα phosphoryla- tion, p65 phosphorylation, and nuclear translocation. [54] Primary human EESC (OE-derived) 250–1000 ng/mL (≈ 0.83–3.3 µM), 48 h Reduces cell viability in a concentration-dependent man- ner, induces apoptosis; upregulates NAG-1 mRNA and protein; NAG-1 siRNA reverses apoptosis. [55] Butyrate (SCFA) BALB/c mouse, ovari- ectomy + intraperitoneal endometrial fragment injection (OVX + END model) No intervention (observa- tion only) Butyrate-producing gut microbiota abundance and colonic butyrate levels reduced in endometriosis mice, accompanied by peritoneal inflammation and immuno- metabolic reprogramming. [56] C57BL/6 mouse (antibiotic-depleted or normal); iHEEC/Luc, primary HEnSCs Animal: 300 mM in drinking water, 21 days; Cells: 2 mM Reduces lesion volume and weight, decreases prolif- eration (Ki-67⁺) and macrophage infiltration (F4/80⁺); activates GPR43/GPR109A; inhibits HDAC activity (increases H3 acetylation); upregulates RAP1GAP to inactivate pro-proliferative RAP1. [57] Endometriosis patients (n = 11) and controls (n = 4) serum/feces; microbiota-depleted mice; primary eESCs Animal: 300 mM in drinking water; Cells: 10 mM Serum butyrate levels decreased and negatively corre- lated with rAFS stage; butyrate supplementation reduces lesion size in MD mice; inhibits eESC viability; activates FFAR2/PPAR-γ/PINK1/Parkin axis, inhibits mitophagy, enhances ferroptosis sensitivity. [58] Valproic acid (SCFA) SD rat, autologous uter- ine fragment intraperito- neal transplantation Low dose: 100 mg/kg/d oral; High dose: 200 mg/ kg/d oral; P4: 1 mg/kg/d i.m.; Combination: high- dose VPA + P4. All for 4 weeks. All treatments reduce lesion volume (↓51.2%–62.3%); prolong hot plate and tail-flick latency (ameliorate hyper- algesia); increase body weight. [59] Primary human NESC and endometriosis- derived ESC 8 mM, 24 h Inhibits cell survival and proliferation, induces apoptosis; downregulates CYP19 mRNA and protein; increases global H3/H4 acetylation, reduces CYP19 promoter H3/ H4 acetylation. [44] Table 2 Preclinical evidence of HDAC inhibitors in endometriosis 1 3 Reproductive Sciences reprogramming [ 56]. Chadchan and colleagues, through fecal microbiota transplantation, confirmed that the feces from endometriosis mice promoted lesion growth, while those from normal mice inhibited lesions; mechanistically, butyrate suppressed endometrial cell proliferation and mouse lesion growth by concurrently activating GPR43/ GPR109A, inhibiting HDAC activity, and upregulating RAP1GAP to inactivate RAP1 [ 57]. Gou and colleagues supplemented the mechanism with ferroptosis studies at human, animal, and primary cell levels: endometriosis patients had reduced serum butyrate levels negatively cor - related with disease staging; in germ-free mice, butyrate supplementation reduced lesion size; in primary ectopic stromal cells, butyrate inhibited mitophagy and enhanced ferroptosis sensitivity through the FFAR2/PPAR-γ/PINK1/ Parkin axis [ 58].Although the aforementioned studies reveal the therapeutic potential of butyrate from different perspectives, significant limitations still exist in the current evidence. To date, no rigorously designed randomized con- trolled trials have verified the clinical efficacy and safety of butyrate in patients with endometriosis, and its pharma - cokinetic characteristics in humans (optimal administration route, effective plasma concentration, tissue distribution) remain unclear. In addition, butyrate has an extremely short half-life, and its levels are influenced by diet, antibiotics, and individual differences in gut microbiota composition. How to achieve standardized supplementation remains an unresolved issue. Therefore, whether butyrate can become an effective therapeutic approach for endometriosis still requires verification through rigorously designed human clinical trials and systematic pharmacokinetic-pharmacody- namic evaluations. VPA is a common antiepileptic drug, and studies have shown that it also has therapeutic potential in endometrio - sis. In rat models, daily oral administration of 100 mg/kg or 200 mg/kg (for 4 consecutive weeks) dose-dependently reduced ectopic lesions, alleviated hyperalgesia, and exhib- ited disease-specific effects [59]. Mechanistically, VPA can act through multiple pathways. In primary endometriotic stromal cells, treatment with 8 mM for 24 h inhibited his - tone acetylation in the CYP19 promoter region, thereby downregulating aromatase, reducing estrogen synthesis, inhibiting proliferation, and inducing apoptosis [ 44]; in immortalized YHES stromal cells, treatment with 3 mM for 16 h induced G0/G1 cell cycle arrest and upregulated p21 [60]; in human tissues and primary cells, treatment with 8 mM for 72 h increased acetylation of the C/EBPα promoter region, upregulating the expression of this tumor suppressor gene, with forced expression of C/EBPα inhibiting prolif - eration and inducing apoptosis, while knockdown promoted proliferation and resisted apoptosis [ 61]. In summary, VPA exerts multiple effects including HDAC inhibition, anti- estrogen activity, and activation of tumor suppressor genes, but it lacks human safety and pharmacokinetic data, and fur- ther optimization of dosing regimens and clinical validation are still required. Agent (Class) Research model Dosage/administration Key findings References YHES 3 mM, 16 h Induces G0/G1 cell cycle arrest; upregulates p21 protein expression. [60] Ovarian endome- trioma cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs); endometriotic and normal endometrial tissues Cells: 8 mM, 72 h Upregulates C/EBPα expression; increases H3/H4 acetylation at the C/EBPα promoter; C/EBPα regulates downstream PPARγ, p53, caspases. [61] PCI-34,051 (selective HDAC8 inhibitor) 11Z (TGF-β1-stimulated, 72 h); primary EESC No intervention (expres- sion only) HDAC8 mRNA and protein upregulated in TGF-β1- stimulated 11Z cells and EESC. [4] Human tissues: OE (n = 38), DIE (n = 20), control endometrium (n = 24) IHC detection HDAC8 staining significantly enhanced in OE and DIE lesions; elevated in both epithelium and stroma of DIE (stroma > epithelium), positively correlated with fibrosis. [4] BALB/c mouse, sub- stance P-induced DIE model 20 mg/kg/d, i.p., starting 4 weeks after induction, for 2 weeks Lesion weight reduced by 63.6%; prolonged hot plate latency; reduced fibrosis; E-cadherin↑, α-SMA↓, des- min↓, Sm-MHC↓. [4] SAHA suberoylanilide hydroxamic acid, TSA trichostatin A, VPA valproic acid, SCFA short-chain fatty acid, EESC ectopic endometrial stro - mal cells, HESC human endometrial stromal cells, NESC normal endometrial stromal cells, OE ovarian endometrioma, DIE deep infiltrating endometriosis, EAOC endometriosis-associated ovarian cancer, rAFS revised American Fertility Society, i.p. intraperitoneal, s.c. subcutaneous, i.m. intramuscular Table 2 (continued) 1 3 Reproductive Sciences Novel Selective HDAC8 Inhibitors Selective HDAC8 inhibitors show promising potential in the treatment of endometriosis. In a DIE mouse model, the HDAC8 inhibitor PCI-34,051 (20 mg/kg/day intraperitoneal injection for 2 weeks) significantly reduced lesion volume and fibrosis, with lesion weight decreasing by nearly two- thirds, a marked reduction in fibrotic tissue formation, and pain relief. Mechanistic studies suggest that this effect may be related to the regulation of key signaling pathways involved in fibrosis and inflammation, such as TGF-β, restoring nor- mal cell function by inhibiting HDAC8 and improving the local tissue microenvironment of the lesions [4]. Compared to conventional pan-HDAC inhibitors, HDAC8 inhibitors have higher subtype selectivity, theoretically reducing the risk of off-target effects, and initial safety assessments show minimal impact on the function of other HDAC subtypes [62]. Recent advances in medicinal chemistry have devel - oped various highly selective HDAC8 inhibitors, including novel hydrazide-based compounds, allowing precise regula- tion by specifically targeting HDAC8 [ 63]. These studies indicate that selective HDAC8 inhibitors demonstrate effi - cacy and safety advantages in preclinical models, but their effectiveness and safety in endometriosis patients still need to be verified through systematic clinical research. This is especially important for women of reproductive age with fertility needs, as the long-term effects on ovarian function, endometrial receptivity, and embryo development are still unclear. Additionally, current evidence mainly comes from a single animal model, with no comparative data across dif- ferent models or species, and the long-term dosing regimen (dose, frequency, duration) of PCI-34,051 has not been sys- tematically optimized. Therefore, whether HDAC8 inhibi - tors can truly transition from animals to humans for clinical use still requires careful evaluation through more preclinical studies and clinical trials. Safety and Fertility Considerations of HDACis HDACis have multiple drugs approved or in clinical trials for diseases such as tumors, and their safety profiles have been relatively well established [ 64, 65]. Clinical stud - ies show that the main adverse effects of HDACis include myelosuppression (thrombocytopenia, leukopenia), gastro - intestinal reactions (nausea, vomiting, diarrhea), fatigue, and cardiotoxicity (QT interval prolongation) [ 66]. The spectrum of adverse events varies among different drugs. Reported adverse events for SAHA include thrombosis, QT interval prolongation, and potentially fatal ventricular tachycardia [67]; belinostat commonly causes gastrointes - tinal symptoms such as nausea and vomiting [ 68]; throm- bocytopenia has been reported with SAHA, panobinostat, and romidepsin, which may be related to dual inhibition of HDAC1 and HDAC2 [69, 70]. In addition to the systemic adverse reactions mentioned above, the reproductive safety of HDACis has also been a major concern, as the HDACs they target play key regula - tory roles in reproductive processes such as gametogenesis, follicular development, embryo implantation, and endome - trial receptivity [71–75]. Current research indicates that the effects of different HDACis on reproductive function vary significantly. In a rat fertility study, SAHA was administered at three doses: 15, 50, and 150 mg/kg/day. The 150 mg/kg/ day dose did not affect mating or fertility in either sex; how- ever, it increased the post-implantation loss rate and the number of corpus luteums in female rats, while no repro - ductive toxicity was observed in male rats [ 76]; TSA pro- tects the male reproductive system and ovarian tissue from damage in models of radiation or cigarette smoke exposure [77, 78]. Regarding embryonic development, Nervi et al. found that TSA treatment transiently accelerated embryonic growth in mice and increased the number of somites, but no maternal toxicity, embryonic developmental disturbances, or teratogenic effects were observed, suggesting that TSA may have relatively good embryonic safety in rodents [79]; however, further studies by Peng et al. found that the effects of TSA on embryonic development are highly dependent on treatment concentration, duration, and embryo origin, with in vivo fertilized embryos being the most sensitive to TSA; blastocyst formation rates and live birth rates can decrease significantly with increasing TSA concentration and treatment duration [ 80], suggesting that the effects of TSA on embryos vary under different experimental con - ditions; butyrate can improve ovarian function in a PCOS model [81], yet embryonic exposure to butyrate or VPA can inhibit primordial germ cell differentiation and lead to insuf- ficient spermatogenesis in mice [82], suggesting that it has a fundamental impact on germ cell development. VPA, as an HDAC inhibitor, is widely used in the treatment of epilepsy, bipolar disorder, and cancer [83]. However, its clinical use is limited by a well-established teratogenic risk—pregnancy- related exposure is associated with a congenital malforma - tion rate of approximately 10%, primarily involving neural tube defects, cardiac abnormalities, and craniofacial malfor- mations, and this risk is dose-dependent [84]. In summary, although HDAC inhibitors have dem - onstrated clinical value in cancer treatment, no HDAC inhibitor has yet been approved for the clinical treatment of endometriosis. Although basic research has preliminar - ily revealed the involvement of HDAC family members in the pathological process of endometriosis, and some HDAC inhibitors have demonstrated the potential to reduce the vol- ume of endometriotic lesions in mouse models, issues such as the long-term safety of these drugs, their potential impact 1 3 Reproductive Sciences on fertility in women of childbearing age, and the identifica- tion of patient groups most likely to benefit from this class of drugs remain unresolved. Therefore, before expanding the use of HDACi to benign gynecological conditions such as endometriosis, there is an urgent need for systematic and in-depth research addressing the aforementioned issues. Synergistic Effects and Challenges of HDACis Combined with Other Treatment Strategies Potential for Combination Therapy HDACis demonstrate potential for combination with existing therapies in endometriosis treatment. Regarding hormone combination therapy, HDACs are involved in regulating estrogen receptor signaling pathways [ 32], and HDACis may enhance the efficacy of traditional hormonal drugs or overcome resistance by remodeling the activity of hormone receptor co-regulators [ 3]. Additionally, SAHA can induce endometrial cell apoptosis by regulating the TRX and TBP-2 system, a mechanism independent of but potentially synergistic with hormonal pathways, providing a molecular basis for combination therapy [7]. Progesterone resistance, common in endometriosis, is partly attributed to the epigenetic silencing of PR-B, and HDACis may partici- pate in restoring PR-B expression by affecting histone mod- ifications, thereby enhancing progesterone efficacy [ 45]. Secondly, regarding combination with anti-inflammatory and anti-angiogenic drugs, endometriosis is essentially a chronic inflammatory disease with abundant inflammatory mediators and abnormal angiogenesis in the lesion micro - environment [85]. The role of HDACis in regulating inflam- mation and angiogenesis makes them ideal candidates for combination therapy. Butyrate, as a short-chain fatty acid and HDAC inhibitor, can regulate gene expression, immune responses, and inflammation by inhibiting immune dysreg - ulation and reducing lesion proliferation [ 48]. Combining it with non-steroidal anti-inflammatory drugs (NSAIDs) may more effectively control pain and lesion progres - sion by inhibiting prostaglandin synthesis and modulating inflammation-related epigenetics. Regarding angiogen - esis, exosomal long non-coding RNA HOTAIR promotes endometriosis progression and angiogenesis through the miR-761/HDAC1 axis and activates the STAT3-mediated inflammatory pathway [ 14]. HDACis targeting this path - way combined with anti-vascular endothelial growth factor (VEGF) drugs may simultaneously block pro-angiogenic signals and epigenetic regulation, thereby more effectively inhibiting the establishment and growth of ectopic lesions. Preclinical studies also support the feasibility of combina - tion strategies. For example, in an endometriosis-associated ovarian cancer model, vorinostat inhibited M2 macrophage polarization through the ARID1A/HDAC6/IL-10 signaling pathway, demonstrating the potential of combining immune modulation with epigenetic regulation [49]. Challenges and Limitations Despite the promising prospects of HDACis in endometrio- sis treatment, their clinical translation faces multiple chal - lenges and limitations. Tissue selectivity and side effects are currently primary issues. Most HDACis lack tissue specificity, and systemic administration can easily cause side effects such as fatigue and thrombocytopenia, limit - ing long-term use [ 3]. Developing lesion-targeted delivery systems, such as nanocarrier- or exosome-based platforms, is key to improving efficacy and reducing systemic toxic - ity. Studies have found that exosomes can serve as carriers for epigenetic regulators like lncRNA HOTAIR, playing an important role in intercellular communication in endo - metriosis and providing ideas for designing targeted deliv - ery tools [ 14]. Additionally, natural HDACis like butyrate have limited clinical application due to their short half-life, prompting research into analogs or probiotics to maintain stable levels [ 48]. Secondly, disease heterogeneity and drug resistance are another major obstacle. Endometriosis is highly heterogeneous, and HDAC subtype expression profiles may vary significantly among different lesion types [4]. For example, studies found that HDAC8 expression is significantly elevated in endometriosis lesions, while HDAC1 and HDAC6 are elevated in DIE lesions, and HDAC2 and HDAC3 are decreased [ 4]. This differential expression suggests the need for specific HDACis based on patient molecular subtypes rather than a “one-size-fits-all” approach. Simultaneously, long-term use of HDACis may induce acquired resistance, possibly involving compensa - tory signaling pathway activation or reprogramming of the epigenetic landscape, requiring further study [ 86]. Finally, clinical translation barriers are particularly prominent. The vast majority of research on HDACis in endometriosis remains at the cellular and animal model stages, lacking large-scale, prospective clinical data to verify their efficacy and safety [3]. A core unresolved issue is the unclear long- term impact of HDACis on female fertility, ovarian func - tion, and pregnancy. For example, deacetylases like SIRT1 may play a role in embryo implantation and endometrial receptivity, and the potential reproductive toxicity of their inhibitors requires careful evaluation [ 87]. Additionally, endometriosis is often associated with infertility, and treat - ment itself should not impair future fertility potential. Therefore, future clinical studies need to strictly evaluate these parameters and explore strategies like local admin - istration (e.g., intrauterine delivery) to reduce systemic 1 3 Reproductive Sciences effects on the reproductive system. Although the reversibil- ity of epigenetic modifications makes them attractive thera- peutic targets, transitioning from basic research to clinical practice still requires overcoming many difficulties [ 88]. Future Research Directions and Prospects Development of Novel HDACis and Drug Delivery Systems Given that non-selective or pan-HDACis often cause adverse reactions due to off-target effects in clinical applica- tions [89, 90], developing highly selective subtype-specific inhibitors has become a key strategy to improve efficacy and reduce toxicity. In endometriosis, subtypes such as HDAC8, HDAC1, and HDAC6 are highly promising selec- tive inhibition targets due to their abnormal expression in lesions. Studies confirm that in OE and DE lesions, HDAC8 immunostaining is significantly elevated, and its expression is closely related to the fibrosis process; in animal models, specific inhibition of HDAC8 significantly reduces lesion weight, decreases fibrosis, and prolongs hot plate latency, providing strong evidence for HDAC8 as a therapeutic target [4, 16]. Additionally, HDAC1 and HDAC6 are also significantly elevated in DIE lesions [ 4]. Among them, HDAC6 expression is associated with ARID1A status, upregulated in ARID1A-negative ovarian endometriosis, suggesting its involvement in specific disease subtypes or malignant transformation processes [ 19]. Therefore, devel- oping highly selective inhibitors targeting key subtypes like HDAC8, HDAC1, and HDAC6 is expected to provide pre - cise treatment options for endometriosis patients with dif - ferent molecular characteristics. Currently, methods such as structure-based virtual screening and pharmacophore mod - els have successfully discovered selective inhibitors with nanomolar affinity for HDAC1, HDAC3, and HDAC6 [ 91, 92], providing a methodological foundation for designing highly selective compounds targeting endometriosis-related subtypes. Simultaneously, optimizing drug delivery sys - tems is equally crucial for the clinical application of HDAC inhibitors. Targeted delivery carriers like nanoparticles can improve drug solubility and bioavailability, achieve targeted accumulation and sustained release at lesion sites, thereby enhancing efficacy while reducing adverse reactions caused by systemic exposure. In terms of reproductive safety assessment, lesion-targeted delivery systems are expected to reduce the potential risks of HDAC inhibitors to ovar - ian function, oocyte quality, and embryonic development by minimizing systemic exposure. In the future, combining in-depth research on HDAC expression profiles in endo - metriosis lesions, systematically conducting preclinical pharmacodynamic and safety evaluations of highly selec - tive inhibitors targeting subtypes like HDAC8, HDAC1, and HDAC6, and integrating advanced drug delivery strate- gies will promote the entry of safer and more effective epi - genetic-targeted therapies into clinical practice. Epigenetic Combination Therapy and Multi-Omics Integrated Analysis Exploring the combination of HDACis with other epigenetic drugs holds promise for synergistic effects, more effectively reversing abnormal gene expression programs in endometri- osis. Existing research indicates that endometriosis involve various epigenetic regulatory abnormalities, including DNA methylation, histone modifications, and non-coding RNAs [93]. The combined application of HDACis and DNA meth- yltransferase inhibitors (DNMTi) has demonstrated syner - gistic anti-tumor effects in other diseases; this strategy also has potential in endometriosis, as it can simultaneously target different epigenetic layers to more effectively reac - tivate silenced cancer suppressor genes or correct abnor - mal transcriptional programs [ 94]. Developing HDAC hybrid inhibitors with dual or multi-targeting capabilities is another noteworthy direction. These molecules combine the HDAC-inhibiting pharmacophore with pharmacophores of other anticancer targets (such as receptor tyrosine kinases, topoisomerases, etc.), enabling simultaneous inhibition of multiple pathogenic pathways at the single-molecule level, which helps overcome issues like limited efficacy of single agents, drug resistance, and off-target toxicity [95, 96]. For example, studies have designed dual-target inhibitors simul- taneously targeting HDAC and vascular endothelial growth factor receptor (VEGFR), showing good anti-proliferative and anti-angiogenic activity in various cancer cell lines [97]. Given the close association of endometriosis with inflammation, angiogenesis, and fibrosis, similar dual-target strategies may provide more comprehensive therapeutic interventions for this disease. To lay the foundation for pre- cision therapy, it is crucial to use multi-omics technologies such as single-cell sequencing and spatial transcriptomics to map cell type-specific profiles of HDAC expression in endometriosis lesions. Traditional studies based on tissue homogenates mask the heterogeneity among different cell types (e.g., epithelial cells, stromal cells, immune cells [ 4]. Multi-omics analysis at single-cell resolution can precisely identify which cell subpopulations specifically overexpress HDAC8, HDAC1, or HDAC6, and how these abnormal expressions are associated with specific cellular states (e.g., proliferation, epithelial-mesenchymal transition, fibrosis) [98]. For instance, functional experiments have found that the long non-coding RNA LINC01638 promotes prolifera - tion and epithelial-mesenchymal transition in endometrial 1 3 Reproductive Sciences ectopic epithelial cells by inhibiting HDAC1 [ 6].Multi- omics integrated analysis helps systematically reveal the specificity of such HDAC-mediated regulatory networks in different cell types, thereby identifying cell populations most sensitive to HDACis and providing a basis for bio - marker-based patient stratification, ultimately advancing personalized epigenetic therapy tailored to specific molecu- lar subtypes and cellular environments in endometriosis. Biomarker-Based Personalized Therapy Researching biomarkers that reflect HDAC activity or sen - sitivity to HDACis is crucial for achieving personalized therapy in endometriosis. Such markers can be derived from blood or endometrial tissue and used to guide patient stratification and efficacy prediction. Potential candidate biomarkers include histone acetylation levels, where the acetylation status of histone H3 is a direct downstream indicator of HDAC activity, reflecting drug targeting effects [99]. In endometriosis, detecting acetylation levels at spe - cific histone modification sites (e.g., H3K9ac, H3K27ac) in lesions or circulating cells helps identify patient subgroups with abnormally elevated HDAC activity, thereby predict - ing their response to HDAC inhibitors [ 100]. Additionally, non-coding RNAs (ncRNAs) in circulating exosomes are promising. As important carriers of intercellular commu - nication, exosomes carry miRNAs, lncRNAs, etc., which can reflect the epigenetic state of source cells. Studies have confirmed that ncRNAs are involved in endometrio - sis pathogenesis [ 93]; analyzing ncRNA profiles related to the HDAC pathway in patient plasma exosomes may yield non-invasive, dynamic markers for efficacy monitor - ing. Meanwhile, identifying markers associated with resis - tance to HDACis is equally important. Research in other tumor fields shows that transcription factors like BCL6 can recruit HDACs to inhibit drug-induced histone acetylation, leading to resistance [ 101]. Whether similar mechanisms exist in endometriosis warrants further exploration. For example, HDAC8 is known to be significantly elevated in endometriosis lesions and associated with disease pro - gression [ 4, 16]; whether its expression level can serve as a predictive marker for efficacy requires validation in prospective clinical studies. In the future, systematically validating the predictive value of these biomarkers can be achieved by correlating HDAC subtype expression levels, histone acetylation markers, or circulating ncRNA signa - tures with patient clinical outcomes (e.g., pain relief, lesion reduction, recurrence time). Biomarker-based patient strat - ification will help identify endometriosis populations most likely to benefit from HDAC-targeted therapy, promoting the application of precision medicine in the management of this disease.

HDACs, as important epigenetic regulatory molecules, play a key role in the pathogenesis and progression of endometri- osis. This article reviews the abnormal expression profiles of HDACs in endometriosis and their pathogenic mechanisms, summarizes preclinical research progress on HDACis in endometriosis treatment, and discusses future directions such as combination therapy strategies, novel drug develop- ment, and personalized therapy. At the expression and func- tional level, endometriosis exhibits differential expression of HDAC family members: HDAC1, HDAC6, and HDAC8 are generally upregulated in lesions and associated with disease progression, fibrosis, and malignant transforma - tion risk; HDAC2 expression shows dynamic changes with disease stages; while HDAC3 is downregulated in patients with concurrent infertility, potentially affecting endome - trial receptivity. These subtype-specific expression patterns suggest that different HDACs play distinct roles in various pathological processes of endometriosis, providing a theo - retical basis for developing subtype-selective inhibitors. In terms of pathogenic mechanisms, HDACs synergisti - cally promote the occurrence and development of endome - triosis by regulating multiple pathways, including immune inflammation, cell proliferation and apoptosis, invasion and migration, angiogenesis, and hormone signal trans - duction. In therapeutic research, classical HDACis such as SAHA, romidepsin, and TSA have demonstrated multiple therapeutic effects in vitro and in animal models, includ - ing inhibiting proliferation, inducing apoptosis, anti-inflam- matory, and analgesic effects. Naturally derived HDACis like butyrate and VPA, due to their endogenous or already marketed drug properties, combine good safety with clini - cal translation potential. Novel selective HDAC8 inhibitors show unique advantages in reducing fibrosis and alleviat - ing pain, highlighting the value of subtype-targeted therapy. However, the clinical translation of HDACis still faces many challenges. Off-target effects of non-selective inhibi- tors, efficacy variations due to disease heterogeneity, and potential impacts on fertility are all urgent issues to address. Future research should focus on the following directions: first, developing highly selective inhibitors and optimizing targeted delivery systems based on HDAC subtype expres - sion profiles in endometriosis lesions; second, exploring synergistic strategies of HDACis with hormone therapy, anti-inflammatory drugs, etc., to form multi-target combina- tion treatment plans; third, using multi-omics technologies such as single-cell sequencing and spatial transcriptomics to map cell type-specific profiles of HDAC regulatory net - works; fourth, discovering biomarkers like histone acetyla - tion levels and circulating exosomal non-coding RNAs to advance patient stratification and personalized therapy. In 1 3 Reproductive Sciences summary, HDACis, as key epigenetic regulatory factors in endometriosis pathogenesis, have become highly promis - ing therapeutic targets. Although the translation from basic research to clinical application still faces challenges, with the development of subtype-selective inhibitors, optimiza - tion of combination therapy strategies, and the deepening of precision medicine concepts, HDACis are expected to open new avenues for non-hormonal treatment of endometriosis, providing patients with safer and more effective therapeutic options.

The authors would like to thank the collective efforts of all team members. Author Contribution Conceptualization: Shaojie Zhao, Liping Jiang; Methodology: Shisi Xiong, Junjie Xu, Jingjing Pu;Investigation: all authors;Writing – original draft: Shisi Xiong, Junjie Xu;Writing – re - view & editing: Shaojie Zhao, Liping Jiang, Jingjing Pu;Visualization: Shisi Xiong;Supervision: Shaojie Zhao, Liping Jiang;Funding acquisi- tion: Shaojie Zhao, Liping Jiang. Funding This study was Supported by Medical Key Strategic Project of Wuxi Health Commission and Elite Talent Program of Wuxi Mater- nal and Child Health Hospital (LY2023004). Data Availability This study did not generate new data. All findings summarized in this manuscript come from articles cited in the refer - ence list. Declarations Ethics Approval Not applicable. This manuscript is a review article and does not involve human participants or animals. Competing Interests The authors declare no competing interests. Consent for Publication All authors consent to publication of this manuscript. Consent to Participate Not applicable. Human and Animal Rights This manuscript is a narrative review based exclusively on previously published studies. It does not involve hu - man participants, animals, patient data, or any new experimental pro - cedures; therefore, Institutional Review Board (IRB) approval was not required. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, 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 changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit h t t p : / / c r e a t i v e c o m m o n s . o r g / l i c e n s e s / b y / 4 . 0 / .

1. Maggiore ULR, Chiappa V , Ceccaroni M, et al. Epidemiology of infertility in women with endometriosis. Best Pract Res Clin Obstet Gynaecol. 2024;92:102454. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . b p o b g y n . 2 0 2 3 . 1 0 2 4 5 4 . 2. Gu X, Zhou H, Miao M, et al. Therapeutic potential of natural resources against endometriosis: current advances and future per- spectives Drug Des Devel Ther. 2024;18:3667–96. h t t p s : / / d o i . o r g / 1 0 . 2 1 4 7 / d d d t . S 4 6 4 9 1 0 . 3. Psilopatis I, Vrettou K, Fleckenstein FN, et al. The impact of his- tone modifications in endometriosis highlights new therapeutic opportunities. Cells. 2023;12(9). h t t p s : / / d o i . o r g / 1 0 . 3 3 9 0 / c e l l s 1 2 0 9 1 2 2 7 . 4. Zheng H, Liu X, Guo SW. Aberrant expression of histone deacet- ylase 8 in endometriosis and its potential as a therapeutic target. Reprod Med Biol. 2023;22(1):e12531. h t t p s : / / d o i . o r g / 1 0 . 1 0 0 2 / r m b 2 . 1 2 5 3 1 . 5. Xiaomeng X, Ming Z, Jiezhi M, et al. Aberrant histone acetyla - tion and methylation levels in woman with endometriosis. Arch Gynecol Obstet. 2013;287(3):487–94. h t t p s : / / d o i . o r g / 1 0 . 1 0 0 7 / s 0 0 4 0 4 - 0 1 2 - 2 5 9 1 - 0 . 6. Yotova I, Proestling K, Pauler FM, et al. LINC01638 promotes epithelial-to-mesenchymal transition in endometriosis epithelial cells by up-regulating RHOB via HDAC1 suppression. Reprod Biomed Online. 2025;51(3):104942. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . r b m o . 2 0 2 5 . 1 0 4 9 4 2 . 7. Kim HI, Seo SK, Chon SJ, et al. Changes in the expression of TBP-2 in response to histone deacetylase inhibitor treatment in human endometrial cells. Int J Mol Sci. 2021;22(3). h t t p s : / / d o i . o r g / 1 0 . 3 3 9 0 / i j m s 2 2 0 3 1 4 2 7 . 8. Seto E, Yoshida M. Erasers of histone acetylation: the his - tone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014;6(4):a018713. h t t p s : / / d o i . o r g / 1 0 . 1 1 0 1 / c s h p e r s p e c t . a 0 1 8 7 1 3 . 9. Pu J, Liu T, Wang X, et al. Exploring the role of histone deacety- lase and histone deacetylase inhibitors in the context of multiple myeloma: mechanisms, therapeutic implications, and future per - spectives. Experimental Hematol Oncol. 2024;13(1). h t t p s : / / d o i . o r g / 1 0 . 1 1 8 6 / s 4 0 1 6 4 - 0 2 4 - 0 0 5 0 7 - 5 . 10. Lahm A, Paolini C, Pallaoro M, et al. Unraveling the hidden cat- alytic activity of vertebrate class IIa histone deacetylases. Proc Natl Acad Sci U S A. 2007;104(44):17335–40. h t t p s : / / d o i . o r g / 1 0 . 1 0 7 3 / p n a s . 0 7 0 6 4 8 7 1 0 4 . 11. Park SY , Kim JS. A short guide to histone deacetylases includ - ing recent progress on class II enzymes. Exp Mol Med. 2020;52(2):204–12. https:/ /doi.or g/10.10 38/s1 2276-020-0382-4. 12. Chen H, Xie C, Chen Q, et al. HDAC11, an emerging therapeu - tic target for metabolic disorders. Front Endocrinol (Lausanne). 2022;13:989305. https:/ /doi.or g/10.33 89/fe ndo.2022.989305. 13. Colón-Díaz M, Báez-Vega P, García M, et al. HDAC1 and HDAC2 are differentially expressed in endometriosis. Reprod Sci. 2012;19(5):483–92. https:/ /doi.or g/10.11 77/19 33719111432870. 14. Zhang L, Yu Z, Qu Q, et al. Exosomal lncRNA HOTAIR pro - motes the progression and angiogenesis of endometriosis via the miR-761/HDAC1 axis and activation of STAT3-mediated inflam- mation. Int J Nanomed. 2022;17:1155–70. h t t p s : / / d o i . o r g / 1 0 . 2 1 4 7 / i j n . S 3 5 4 3 1 4 . 15. Veena KV , Siddamalla S, Deenadayal M, et al. Histone deacety- lase 1, Sirtuin 1, and Sirtuin 3 single-nucleotide polymorphisms and the risk of endometriosis in South Indian women. J Obstet Gynaecol. 2022;42(7):3230–5. h t t p s : / / d o i . o r g / 1 0 . 1 0 8 0 / 0 1 4 4 3 6 1 5 . 2 0 2 2 . 2 1 0 9 9 5 5 . 16. Zheng H, Liu X, Guo SW. Corroborating evidence for aberrant expression of histone deacetylase 8 in endometriosis. Reprod Med Biol. 2023;22(1):e12527. https:/ /doi.or g/10.10 02/rm b2.12527. 1 3 Reproductive Sciences 17. Mai H, Liao Y , Luo S, et al. Histone deacetylase HDAC2 silenc- ing prevents endometriosis by activating the HNF4A/ARID1A axis. J Cell Mol Med. 2021;25(21):9972–82. h t t p s : / / d o i . o r g / 1 0 . 1 1 1 1 / j c m m . 1 6 8 3 5 . 18. Kim TH, Yoo J-Y , Choi K-C, et al. Loss of hdac3 results in non- receptive endometrium and female infertility. Sci Transl Med. 2019. 19. Zingg J, Kalaitzopoulos DR, Karol AA, et al. Expression patterns of HDAC6 in correlation to ARID1A status in different subtypes of endometriosis: a retrospective tissue microarray analysis. Eur J Obstet Gynecol Reprod Biol. 2024;302:73–80. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . e j o g r b . 2 0 2 4 . 0 8 . 0 4 4 . 20. Du J, Lv Z, Zheng X, et al. Study on biomarkers associated with epigenetic factors in endometriosis combining transcriptome with experimental validation. PeerJ. 2026;14:e20703. h t t p s : / / d o i . o r g / 1 0 . 7 7 1 7 / p e e r j . 2 0 7 0 3 . 21. Taguchi A, Wada-Hiraike O, Kawana K, et al. Resveratrol sup - presses inflammatory responses in endometrial stromal cells derived from endometriosis: a possible role of the sirtuin 1 path - way. J Obstet Gynaecol Res. 2014;40(3):770–8. h t t p s : / / d o i . o r g / 1 0 . 1 1 1 1 / j o g . 1 2 2 5 2 . 22. Yoo JY , Kim TH, Fazleabas AT, et al. KRAS activation and over-expression of SIRT1/BCL6 contributes to the pathogen - esis of endometriosis and progesterone resistance. Sci Rep. 2017;7(1):6765. https:/ /doi.or g/10.10 38/s4 1598-017-04577-w. 23. Kim TH, Young SL, Sasaki T, et al. Role of SIRT1 and proges - terone resistance in normal and abnormal endometrium. J Clin Endocrinol Metab. 2022;107(3):788–800. h t t p s : / / d o i . o r g / 1 0 . 1 2 1 0 / c l i n e m / d g a b 7 5 3 . 24. Wang M, Wu Y , He Y , et al. SIRT1 upregulation promotes epi- thelial-mesenchymal transition by inducing senescence escape in endometriosis. Sci Rep. 2022;12(1):12302. h t t p s : / / d o i . o r g / 1 0 . 1 0 3 8 / s 4 1 5 9 8 - 0 2 2 - 1 6 6 2 9 - x . 25. Zhang L, Li HH, Yuan M, et al. Exosomal miR-22-3p derived from peritoneal macrophages enhances proliferation, migration, and invasion of ectopic endometrial stromal cells through regula- tion of the SIRT1/NF-κB signaling pathway. Eur Rev Med Phar- macol Sci. 2020;24(2):571–80. h t t p s : / / d o i . o r g / 1 0 . 2 6 3 5 5 / e u r r e v _ 2 0 2 0 0 1 _ 2 0 0 3 3 . 26. Sansone AM, Hisrich BV , Young RB, et al. Evaluation of BCL6 and SIRT1 as non-invasive diagnostic markers of endometriosis. Curr Issues Mol Biol. 2021;43(3):1350–60. h t t p s : / / d o i . o r g / 1 0 . 3 3 9 0 / c i m b 4 3 0 3 0 0 9 6 . 27. Strug M, Aghajanova L, Khan M, et al. Prospective evaluation of mid-luteal endometrial BCL6/SIRT and correlation with out - comes of euploid frozen embryo transfer: a prospective cohort study. J Assist Reprod Genet. 2025;42(8):2665–74. h t t p s : / / d o i . o r g / 1 0 . 1 0 0 7 / s 1 0 8 1 5 - 0 2 5 - 0 3 5 5 8 - 7 . 28. Kaleler İ, Acikgoz AS, Gezer A, et al. A potential role of Sirtuin3 and its target enzyme activities in patients with ovarian endome - trioma. Gynecol Endocrinol. 2021;37(11):1035–40. h t t p s : / / d o i . o r g / 1 0 . 1 0 8 0 / 0 9 5 1 3 5 9 0 . 2 0 2 1 . 1 9 7 5 6 7 4 . 29. Goday A, Valls-Roca L, Méndez M, et al. Exploring oxidative stress in different endometriosis phenoptypes: insights from ovar- ian and systemic perspectives by the study of SIRT3. Int J Mol Sci. 2025;26(18). https:/ /doi.or g/10.33 90/ij ms26189110. 30. González-Fernández R, Martín-Ramírez R, Rotoli D, et al. Gran- ulosa-lutein cell sirtuin gene expression profiles differ between normal donors and infertile women. Int J Mol Sci. 2019;21(1). https:/ /doi.or g/10.33 90/ij ms21010295. 31. Zhang H, Chen J, Yang M, et al. SIRT7 drives energy metabolic shifts in endometriosis via interaction with TUFM and Rhoa/ Rock/Akt pathway activation. Cell Mol Life Sci. 2025;82(1):381. https:/ /doi.or g/10.10 07/s0 0018-025-05886-4. 32. Samartzis EP, Noske A, Samartzis N, et al. The expres - sion of histone deacetylase 1, but not other class I histone deacetylases, is significantly increased in endometriosis. Reprod Sci. 2013;20(12):1416–22. https:/ /doi.or g/10.11 77/19 33719113488450. 33. Zhang SY , Zhang LY , Wen R, et al. Histone deacetylases and their inhibitors in inflammatory diseases. Biomed Pharmacother. 2024;179:117295. https:/ /doi.or g/10.10 16/j. biopha.2024.117295. 34. Yamaguchi T, Cubizolles F, Zhang Y , et al. Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression. Genes Dev. 2010;24(5):455–69. https:/ /doi.or g/10.11 01/ga d.552310. 35. Rezk NA, Lashin MB, Sabbah NA. MiRNA 34-a regulate SIRT-1 and Foxo-1 expression in endometriosis. Noncoding RNA Res. 2021;6(1):35–41. https:/ /doi.or g/10.10 16/j. ncrna.2021.02.002. 36. Li Y , An M, Fu X, et al. Bushen Wenyang Huayu Decoction inhibits autophagy by regulating the SIRT1-FoXO-1 pathway in endometriosis rats. J Ethnopharmacol. 2023;308:116277. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . j e p . 2 0 2 3 . 1 1 6 2 7 7 . 37. Li WN, Wu MH, Tsai S-J. The role of hypoxia in the devel - opment and progression of endometriosis. Reproduction. 2021;161(1):F19–31. https:/ /doi.or g/10.15 30/re p-20-0267. 38. Manna PR, Molehin D, Ahmed AU. Dysregulation of aromatase in breast, endometrial, and ovarian cancers: an overview of thera- peutic strategies. Prog Mol Biol Transl Sci. 2016;144:487–537. https:/ /doi.or g/10.10 16/bs .pmbts.2016.10.002. 39. Al Shaer D, Al Musaimi O, De La Torre BG, et al. Hydroxamate siderophores: natural occurrence, chemical synthesis, iron bind - ing affinity and use as Trojan horses against pathogens. Eur J Med Chem. 2020;208:112791. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . e j m e c h . 2 0 2 0 . 1 1 2 7 9 1 . 40. Dubey R, Makhija R, Sharma A, et al. Unveiling the promise of pyrimidine-modified CDK inhibitors in cancer treatment. Bioorg Chem. 2024;149:107508. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . b i o o r g . 2 0 2 4 . 1 0 7 5 0 8 . 41. Lanzi C, Favini E, Dal Bo L, et al. Upregulation of ERK-EGR1- heparanase axis by HDAC inhibitors provides targets for ratio - nal therapeutic intervention in synovial sarcoma. J Exp Clin Cancer Res. 2021;40(1):381. h t t p s : / / d o i . o r g / 1 0 . 1 1 8 6 / s 1 3 0 4 6 - 0 2 1 - 0 2 1 5 0 - y . 42. Hassig CA, Symons KT, Guo X, et al. KD5170, a novel mercap- toketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther. 2008;7(5):1054–65. h t t p s : / / d o i . o r g / 1 0 . 1 1 5 8 / 1 5 3 5 - 7 1 6 3 . M c t - 0 7 - 2 3 4 7 . 43. Mishra D, Mohapatra L, Tripathi AS, et al. The influential respon- sibility of sirtuins in senescence and associated diseases: a review. J Biochem Mol Toxicol. 2024;38(9):e23812. h t t p s : / / d o i . o r g / 1 0 . 1 0 0 2 / j b t . 2 3 8 1 2 . 44. Chen Y , Cai S, Wang J, et al. Valproic acid-induced histone acetylation suppresses CYP19 gene expression and inhibits the growth and survival of endometrial stromal cells. Int J Mol Med. 2015;36(3):725–32. https:/ /doi.or g/10.38 92/ij mm.2015.2263. 45. Dutta S, Lee J, Banu SK, et al. Dual inhibition of AKT and ERK1/2 pathways restores the expression of progesterone Recep- tor-B in endometriotic lesions through epigenetic mechanisms. Mol Cell Endocrinol. 2024;592:112290. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . m c e . 2 0 2 4 . 1 1 2 2 9 0 . 46. Kawano Y , Nasu K, Li H, et al. Application of the histone deacetylase inhibitors for the treatment of endometriosis: histone modifications as pathogenesis and novel therapeutic target. Hum Reprod. 2011;26(9):2486–98. h t t p s : / / d o i . o r g / 1 0 . 1 0 9 3 / h u m r e p / d e r 2 0 3 . 47. Liu X, Guo SW. A pilot study on the off-label use of valproic acid to treat adenomyosis. Fertil Steril. 2008;89(1):246–50. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . f e r t n s t e r t . 2 0 0 6 . 1 1 . 0 0 9 . 48. Kim N, Yang C. Butyrate as a potential modulator in gynecologi- cal disease progression. Nutrients. 2024;16(23). h t t p s : / / d o i . o r g / 1 0 . 3 3 9 0 / n u 1 6 2 3 4 1 9 6 . 1 3 Reproductive Sciences 49. Hsieh TH, Hsu CY , Wu CW, et al. V orinostat decrease M2 macro- phage polarization through ARID1A(6488delG)/HDAC6/IL-10 signaling pathway in endometriosis-associated ovarian carci - noma. Biomed Pharmacother. 2023;161:114500. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . b i o p h a . 2 0 2 3 . 1 1 4 5 0 0 . 50. Imesch P, Fink D, Fedier A. Romidepsin reduces histone deacety- lase activity, induces acetylation of histones, inhibits proliferation, and activates apoptosis in immortalized epithelial endometriotic cells. Fertil Steril. 2010;94(7):2838–42. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . f e r t n s t e r t . 2 0 1 0 . 0 4 . 0 5 2 . 51. Lu Y , Nie J, Liu X, et al. Trichostatin A, a histone deacety - lase inhibitor, reduces lesion growth and hyperalgesia in experimentally induced endometriosis in mice. Hum Reprod. 2010;25(4):1014–25. https:/ /doi.or g/10.10 93/hu mrep/dep472. 52. Wu Y , Guo SW. Inhibition of proliferation of endometrial stromal cells by trichostatin A, RU486, CDB-2914, N-acetylcysteine, and ICI 182780. Gynecol Obstet Invest. 2006;62(4):193–205. h t t p s : / / d o i . o r g / 1 0 . 1 1 5 9 / 0 0 0 0 9 3 9 7 5 . 53. Wu Y , Guo SW. Suppression of IL-1beta-induced COX-2 expres- sion by trichostatin A (TSA) in human endometrial stromal cells. Eur J Obstet Gynecol Reprod Biol. 2007;135(1):88–93. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . e j o g r b . 2 0 0 6 . 0 7 . 0 3 4 . 54. Wu Y , Starzinski-Powitz A, Guo SW. Constitutive and tumor necrosis factor-alpha-stimulated activation of nuclear factor-kap- paB in immortalized endometriotic cells and their suppression by trichostatin A. Gynecol Obstet Invest. 2010;70(1):23–33. h t t p s : / / d o i . o r g / 1 0 . 1 1 5 9 / 0 0 0 2 7 9 3 2 4 . 55. Seo SK, Lee JH, Chon SJ, et al. Trichostatin A induces NAG-1 expression and apoptosis in human endometriotic stromal cells. Reprod Sci. 2018;25(9):1349–56. h t t p s : / / d o i . o r g / 1 0 . 1 1 7 7 / 1 9 3 3 7 1 9 1 1 7 7 4 1 3 7 2 . 56. Alghetaa H, Mohammed A, Singh NP, et al. Estrobolome dys - regulation is associated with altered immunometabolism in a mouse model of endometriosis. Front Endocrinol (Lausanne). 2023;14:1261781. https:/ /doi.or g/10.33 89/fe ndo.2023.1261781. 57. Chadchan SB, Popli P, Ambati CR, et al. Gut microbiota-derived short-chain fatty acids protect against the progression of endome- triosis. Life Sci Alliance. 2021;4(12). h t t p s : / / d o i . o r g / 1 0 . 2 6 5 0 8 / l s a . 2 0 2 1 0 1 2 2 4 . 58. Gou Y , Ding J, Wang H, et al. Gut microbiota derived butyrate enhances ferroptosis sensitivity in endometriosis through FFAR2/ PPAR-γ/PINK1/Parkin mediated mitophagy. Free Radic Biol Med. 2025;238:640–52. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . f r e e r a d b i o m e d . 2 0 2 5 . 0 7 . 0 1 9 . 59. Liu M, Liu X, Zhang Y , et al. Valproic acid and progestin inhibit lesion growth and reduce hyperalgesia in experimentally induced endometriosis in rats. Reprod Sci. 2012;19(4):360–73. h t t p s : / / d o i . o r g / 1 0 . 1 1 7 7 / 1 9 3 3 7 1 9 1 1 1 4 2 4 4 5 3 . 60. Wu Y , Guo SW. Histone deacetylase inhibitors trichostatin A and valproic acid induce cell cycle arrest and p21 expression in immortalized human endometrial stromal cells. Eur J Obstet Gynecol Reprod Biol. 2008;137(2):198–203. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . e j o g r b . 2 0 0 7 . 0 2 . 0 1 4 . 61. Kawano Y , Nasu K, Hijiya N, et al. CCAAT/enhancer-binding protein α is epigenetically silenced by histone deacetylation in endometriosis and promotes the pathogenesis of endometriosis. J Clin Endocrinol Metab. 2013;98(9):E1474–82. h t t p s : / / d o i . o r g / 1 0 . 1 2 1 0 / j c . 2 0 1 3 - 1 6 0 8 . 62. Alrouji M, Venkatesan K, Alshammari MS, et al. Repur - posed drugs as histone deacetylase 8 inhibitors: implications in cancer and neuropathological conditions. Front Pharmacol. 2024;15:1488585. https:/ /doi.or g/10.33 89/fp har.2024.1488585. 63. Lowe BD, Fletcher S. Recent progress in synthetic strategies to develop potent, HDAC8-selective, small-molecule inhibitors. Bioorg Med Chem Lett. 2025;128:130312. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . b m c l . 2 0 2 5 . 1 3 0 3 1 2 . 64. Dai W, Qiao X, Fang Y , et al. Epigenetics-targeted drugs: current paradigms and future challenges. Signal Transduct Target Ther. 2024;9(1):332. https:/ /doi.or g/10.10 38/s4 1392-024-02039-0. 65. Hosseini MS, Sanaat Z, Akbarzadeh MA, et al. Histone deacety - lase inhibitors for leukemia treatment: current status and future directions. Eur J Med Res. 2024;29(1):514. h t t p s : / / d o i . o r g / 1 0 . 1 1 8 6 / s 4 0 0 0 1 - 0 2 4 - 0 2 1 0 8 - 8 . 66. Begum R, Parsons JL, Jones AM. Adverse drug reaction profiles of histone deacetylase inhibitors. Sci Rep. 2025;15(1):35880. https:/ /doi.or g/10.10 38/s4 1598-025-19717-w. 67. Lynch DR Jr., Washam JB, Newby LK. QT interval prolongation and torsades de pointes in a patient undergoing treatment with vorinostat: a case report and review of the literature. Cardiol J. 2012;19(4):434–8. 68. Foss F, Advani R, Duvic M, et al. A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br J Haematol. 2015;168(6):811–9. https:/ /doi.or g/10.11 11/bj h.13222. 69. Garcia-Manero G, Sekeres MA, Egyed M, et al. A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts. Leukemia. 2017;31(12):2799–806. https:/ /doi.or g/10.10 38/le u.2017.159. 70. Coiffier B, Pro B, Prince HM, et al. Romidepsin for the treat - ment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol Oncol. 2014;7:11. https:/ /doi.or g/10.11 86/17 56-8722-7-11. 71. Bunkar N, Pathak N, Lohiya NK, et al. Epigenetics: a key paradigm in reproductive health. Clin Exp Reprod Med. 2016;43(2):59–81. https:/ /doi.or g/10.56 53/ce rm.2016.43.2.59. 72. Zhao HC, Ding T, Ren Y , et al. Role of Sirt3 in mitochondrial biogenesis and developmental competence of human in vitro matured oocytes. Hum Reprod. 2016;31(3):607–22. h t t p s : / / d o i . o r g / 1 0 . 1 0 9 3 / h u m r e p / d e v 3 4 5 . 73. Wang P, Zhao C, Zhou H, et al. Dysregulation of histone deacety- lases inhibits trophoblast growth during early placental development partially through TFEB-dependent autophagy-lysosomal pathway. Int J Mol Sci. 2023;24(15). h t t p s : / / d o i . o r g / 1 0 . 3 3 9 0 / i j m s 2 4 1 5 1 1 8 9 9 . 74. Žukauskaitė D, Vitkevičienė A, Žlibinaitė A, et al. Histone H4 hyperacetylation but not DNA methylation regulates the expres - sion of decidualization-associated genes during induced human endometrial stromal cells decidualization. Int J Biochem Cell Biol. 2023;156:106362. https:/ /doi.or g/10.10 16/j. biocel.2023.106362. 75. Caniçais C, Sobral D, Vasconcelos S, et al. Transcriptomic analy- sis and epigenetic regulators in human oocytes at different stages of oocyte meiotic maturation. Dev Biol. 2025;519:55–64. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . y d b i o . 2 0 2 4 . 1 2 . 0 0 4 . 76. Wise LD, Spence S, Saldutti LP, et al. Assessment of female and male fertility in Sprague-Dawley rats administered vorinostat, a histone deacetylase inhibitor. Birth Defects Res B Dev Reprod Toxicol. 2008;83(1):19–26. https:/ /doi.or g/10.10 02/bd rb.20139. 77. Haritwal T, Kalra N, Agrawala PK. Mitigation of radiation injury to reproductive system of male mice by Trichostatin A. Mutat Res Genet Toxicol Environ Mutagen. 2022;881:503522. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . m r g e n t o x . 2 0 2 2 . 5 0 3 5 2 2 . 78. Li F, Ding J, Cong Y , et al. Trichostatin A alleviated ovarian tis- sue damage caused by cigarette smoke exposure. Reprod Toxicol. 2020;93:89–98. https:/ /doi.or g/10.10 16/j. reprotox.2020.01.006. 79. Nervi C, Borello U, Fazi F, et al. Inhibition of histone deacety - lase activity by trichostatin A modulates gene expression during mouse embryogenesis without apparent toxicity. Cancer Res. 2001;61(4):1247–9. 80. Peng C, Lv Z, Hai T, et al. Differential effects of trichostatin A on mouse embryogenesis and development. Reproduction. 2021;162(1):83–94. https:/ /doi.or g/10.15 30/re p-21-0020. 81. Liu K, He X, Huang J, et al. Short-chain fatty acid-butyric acid ameliorates granulosa cells inflammation through regulating 1 3 Reproductive Sciences METTL3-mediated N6-methyladenosine modification of FOSL2 in polycystic ovarian syndrome. Clin Epigenetics. 2023;15(1):86. https:/ /doi.or g/10.11 86/s1 3148-023-01487-9. 82. Li L, Gao J, Yi D, et al. A primordial germ cell-like-cell platform enables CRISPRi screen for epigenetic fertility modifiers. EMBO Rep. 2025;26(23):6044–78. h t t p s : / / d o i . o r g / 1 0 . 1 0 3 8 / s 4 4 3 1 9 - 0 2 5 - 0 0 6 3 3 - z . 83. Trocha A, Piotrowska DG, Markowicz-Piasecka M. Valproic acid as a therapeutic scaffold: advances in structural modification and drug design. Eur J Med Chem. 2026;302(Pt 2):118334. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . e j m e c h . 2 0 2 5 . 1 1 8 3 3 4 . 84. Ornoy A, Echefu B, Becker M. Valproic acid in pregnancy revisited: neurobehavioral, biochemical and molecular changes affecting the embryo and fetus in humans and in animals: a narrative review. Int J Mol Sci. 2023;25(1). h t t p s : / / d o i . o r g / 1 0 . 3 3 9 0 / i j m s 2 5 0 1 0 3 9 0 . 85. Simancas-Racines D, Jiménez-Flores E, Montalvan M, et al. Endometriosis as a systemic and complex disease: toward pheno- type-based classification and personalized therapy. Int J Mol Sci. 2026;27(2). https:/ /doi.or g/10.33 90/ij ms27020908. 86. Sadłocha M, Toczek J, Major K, et al. Endometriosis: molecular pathophysiology and recent treatment strategies-comprehensive literature review. Pharmaceuticals (Basel). 2024;17(7). h t t p s : / / d o i . o r g / 1 0 . 3 3 9 0 / p h 1 7 0 7 0 8 2 7 . 87. Lessey BA, Dong A, Deaton JL, et al. Inflammatory changes after medical suppression of suspected endometriosis for implantation failure: preliminary results. Int J Mol Sci. 2024;25(13). h t t p s : / / d o i . o r g / 1 0 . 3 3 9 0 / i j m s 2 5 1 3 6 8 5 2 . 88. Akano OP, Amos VO, Fawole IO, et al. Epigenetics’ responsi - bility in endometriosis: a comprehensive assessment. J Steroid Biochem Mol Biol. 2025;253:106814. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . j s b m b . 2 0 2 5 . 1 0 6 8 1 4 . 89. Luo Y , Li H. Structure-based inhibitor discovery of Class I his - tone deacetylases (HDACs). Int J Mol Sci. 2020;21(22). h t t p s : / / d o i . o r g / 1 0 . 3 3 9 0 / i j m s 2 1 2 2 8 8 2 8 90. Kashyap K, Kakkar R. Exploring structural requirements of iso - form selective histone deacetylase inhibitors: a comparative in silico study. J Biomol Struct Dyn. 2021;39(2):502–17. h t t p s : / / d o i . o r g / 1 0 . 1 0 8 0 / 0 7 3 9 1 1 0 2 . 2 0 1 9 . 1 7 1 1 1 9 1 . 91. Peng Z, Zhao Q, Tian X, et al. Discovery of potent and iso - form-selective histone deacetylase inhibitors using structure- based virtual screening and biological evaluation. Mol Inf. 2022;41(9):e2100295. https:/ /doi.or g/10.10 02/mi nf.202100295. 92. Wang Z, Zhao L, Zhang B, et al. Discovery of novel polysub - stituted N-alkyl acridone analogues as histone deacetylase iso - form-selective inhibitors for cancer therapy. J Enzyme Inhib Med Chem. 2023;38(1):2206581. h t t p s : / / d o i . o r g / 1 0 . 1 0 8 0 / 1 4 7 5 6 3 6 6 . 2 0 2 3 . 2 2 0 6 5 8 1 . 93. Le KN, Benor A, Decherney A. An update on epigenetic mecha- nisms in endometriosis. Minerva Obstet Gynecol. 2025;77(4):300– 8. https:/ /doi.or g/10.23 736/s 2724-606x.24.05631-8. 94. Cheshmazar N, Hamzeh-Mivehroud M, Nozad Charoudeh H, et al. Current trends in development of HDAC-based chemothera - peutics. Life Sci. 2022;308:120946. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . l f s . 2 0 2 2 . 1 2 0 9 4 6 . 95. Bass AKA, El-Zoghbi MS, Nageeb EM, et al. Comprehensive review for anticancer hybridized multitargeting HDAC inhibi - tors. Eur J Med Chem. 2021;209:112904. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . e j m e c h . 2 0 2 0 . 1 1 2 9 0 4 . 96. Roy R, Ria T, Roymahapatra D, et al. Single inhibitors ver - sus dual inhibitors: role of HDAC in cancer. ACS Omega. 2023;8(19):16532–44. h t t p s : / / d o i . o r g / 1 0 . 1 0 2 1 / a c s o m e g a . 3 c 0 0 2 2 2 . 97. Xue X, Zhang Y , Liao Y , et al. Design, synthesis and biological evaluation of dual HDAC and VEGFR inhibitors as multitargeted anticancer agents. Invest New Drugs. 2022;40(1):10–20. h t t p s : / / d o i . o r g / 1 0 . 1 0 0 7 / s 1 0 6 3 7 - 0 2 1 - 0 1 1 6 9 - 4 . 98. King J, Patel M, Chandrasekaran S. Metabolism, HDACs, and HDAC inhibitors: a systems biology perspective. Metabolites. 2021;11(11). https:/ /doi.or g/10.33 90/me tabo11110792. 99. Shanmukha KD, Paluvai H, Lomada SK, et al. Histone deacety - lase (HDACs) inhibitors: Clinical applications. Prog Mol Biol Transl Sci. 2023;198:119–52. h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / b s . p m b t s . 2 0 2 3 . 0 2 . 0 1 1 . 100. Chelladurai P, Dabral S, Basineni SR, et al. Isoform-specific characterization of class I histone deacetylases and their therapeutic modulation in pulmonary hypertension. Sci Rep. 2020;10(1):12864. https:/ /doi.or g/10.10 38/s4 1598-020-69737-x. 101. Fan G, Zhang Y , Li Q, et al. BCL6 confers resistance to HDAC inhibitors in DLBCL. Biochem Pharmacol. 2024;227:116466. https: //d oi. or g/10 . 10 1 6/j. bcp.2024.116466. Publisher’s Note Springer Nature remains neutral with regard to juris- dictional claims in published maps and institutional affiliations.