Epigenetic regulation of nuclear receptors: Implications for endocrine-related diseases and therapeutic strategies.

Yixin Song: Conceptualization, Methodology, Visualization, Writing – original draft, Formal analysis. Kexin Zhang: Conceptualization, Data curation, Methodology, Visualization, Formal analysis. Jingwen Zhang: Data curation, Investigation, Methodology. Qinying Li: Data curation, Funding acquisition, Investigation. Na Huang: Data curation, Formal analysis, Investigation, Methodology. Yujie Ma: Data curation, Investigation. Ningning Hou: Data curation, Investigation, Supervision. Fang Han: Data curation, Investigation. Chengxia Kan: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing – review & editing, Investigation. Xiaodong Sun: Conceptualization, Data curation, Funding acquisition, Supervision, Validation, Writing – review & editing.

This work was supported by the 10.13039/501100001809 National Natural Science Foundation of China (No. 82170865 , 82370856 , 32101029 ), the 10.13039/501100007129 Natural Science Foundation of Shandong Province, China (No. ZR2020QB164 ), Shandong Province Medical and Health Science and Technology Development Project of China (No. 202203060805 , 202203060917 ), and Taishan Scholars Project of Shandong Province, China (No. tsqn202211365 ).

The ER plays a crucial role in BC and is encoded by two genes, ESR1 and ESR2 (estrogen receptor 1/2), which produce ER-α and ER-β, respectively. 54 , 55 In BC cases involving ESR1, genes like progesterone receptor (PR), epoxy hydrolase 2, lipocalin 2, and interferon α-inducible protein 27 are silenced due to CpG island methylation. 55 , 56 , 57 Recent research suggests that DNA methylation regulates ER-mediated intercellular adhesion genes, potentially promoting metastatic BC involvement. 58 ER-α contributes to DNA methylation processes by recruiting DNMTs, which alter transcription initiation and drive methylation at specific sites. 59 In BC, DNA demethylation is a primary trigger for gene transcription, with ER-α actively removing methyl groups from cytosine residues to promote hypomethylation in ER-α-positive BC cells. 60 , 61 ESR2 promoter methylation has been noted in Chinese female ER-β BC patients, suggesting a role in ER-β regulation and BC pathology. 62 Histone modifications also influence ER-α activity. The epigenetic regulator KMT2D (lysine methyltransferase 2D), a H3K4-methyltransferase, is associated with increased ER-α activity in PIK3CA mutant BC. 63 As a transcription factor, ER synergizes with co-regulators and co–regulatory complexes, producing diverse epigenetic effects that variably impact BC development. ER-α recruits corepressors, such as HDAC1 and the polycomb repressive complex 2, and utilizes complexes like the nucleosome-remodeling and deacetylase complex to facilitate CpG island methylation during estrogen response element formation. 64 However, this methylation alone is insufficient for complete transcriptional repression. ER-α further silences gene transcription by altering chromatin structure, leading to H3K27me, a marker of transcriptional repression. 65 Conversely, GATA binding 1 acts as a transcriptional repressor by modulating ER-α interactions with histone modification complexes, preventing histone deacetylation and obstructing ER-α DNA binding at estrogen response element sites 66 ( Fig. 2 A). Figure 2 Epigenetic regulation of receptors in endocrine-related diseases. (A) Epigenetic mechanisms of estrogen receptor in endocrine-related diseases. (B) Epigenetic mechanisms of androgen receptor in endocrine-related diseases. (C) Epigenetic mechanisms of other hormone receptors in endocrine-related diseases. AC, acetylation; AP-1, activator protein-1; ARE, androgen response element; AR, androgen receptor; APM, antigen-processing machinery; DNMT, DNA methyltransferase; ERE, estrogen response element; EZH2, enhancer of zeste homolog 2; ESR1, estrogen receptor 1; FOXA1, Forkhead box A1; FXRE, FXR response element; HDAC, histone deacetylase; HATs, histone acetyltransferases; HDMs, histone demethylases; HMTs, histone methyltransferases; IRF, interferon regulatory factor; IFNα, interferon alpha; lncRNA, long noncoding RNA; GRHL2, Grainyhead like 2; GATA6, GATA-binding factor 6; GATA3, GATA-binding factor 3; GRE, glucocorticoid response element; LSD-1, lysine-specific histone demethylase 1; TRPS1, trichorhinophalangeal syndrome-1; MBD, methyl-CpG-binding domain; MeCP2, methyl-CpG binding protein 2; ME, methylation; NF-kB, nuclear transcription factor-kappa B; NCOR, nuclear receptor co-repressor; NurD, the nucleosome-remodeling and deacetylase; PRC2, Polycomb repressive complex 2; PGR, progesterone receptor; PGC-1, peroxisome proliferator-activated receptor-gamma coactivator-1; SRC-1, steroid receptor coactivator 1; SRA1, steroid receptor RNA activator 1; SF-1, steroidogenic factor 1; TET, ten-eleven translocation; TSHR, thyrotropin receptor; Sin3a, suppressor interacting 3a; 5 mC, 5-methylcytosine; 5hmC, 5-hydroxymethylcytosin. Figure 2 Epigenetic regulation of receptors in endocrine-related diseases. (A) Epigenetic mechanisms of estrogen receptor in endocrine-related diseases. (B) Epigenetic mechanisms of androgen receptor in endocrine-related diseases. (C) Epigenetic mechanisms of other hormone receptors in endocrine-related diseases. AC, acetylation; AP-1, activator protein-1; ARE, androgen response element; AR, androgen receptor; APM, antigen-processing machinery; DNMT, DNA methyltransferase; ERE, estrogen response element; EZH2, enhancer of zeste homolog 2; ESR1, estrogen receptor 1; FOXA1, Forkhead box A1; FXRE, FXR response element; HDAC, histone deacetylase; HATs, histone acetyltransferases; HDMs, histone demethylases; HMTs, histone methyltransferases; IRF, interferon regulatory factor; IFNα, interferon alpha; lncRNA, long noncoding RNA; GRHL2, Grainyhead like 2; GATA6, GATA-binding factor 6; GATA3, GATA-binding factor 3; GRE, glucocorticoid response element; LSD-1, lysine-specific histone demethylase 1; TRPS1, trichorhinophalangeal syndrome-1; MBD, methyl-CpG-binding domain; MeCP2, methyl-CpG binding protein 2; ME, methylation; NF-kB, nuclear transcription factor-kappa B; NCOR, nuclear receptor co-repressor; NurD, the nucleosome-remodeling and deacetylase; PRC2, Polycomb repressive complex 2; PGR, progesterone receptor; PGC-1, peroxisome proliferator-activated receptor-gamma coactivator-1; SRC-1, steroid receptor coactivator 1; SRA1, steroid receptor RNA activator 1; SF-1, steroidogenic factor 1; TET, ten-eleven translocation; TSHR, thyrotropin receptor; Sin3a, suppressor interacting 3a; 5 mC, 5-methylcytosine; 5hmC, 5-hydroxymethylcytosin. In addition, ER recruits the primary steroid receptor coactivator 3 (SRC3), along with secondary coactivators p300/CBP and CARM1, to activate transcription. 67 ER-α also interacts with histone acetyltransferases, such as p160 and p300, which support transcriptional activation by acetylating histones. 68 Aberrant DNA methylation, histone modifications, and chromatin remodeling arising from this complex interplay of ER-α activity and associated receptor complexes provide insights into BC mechanisms, offering potential targets for therapeutic interventions. Forkhead box A1 (FOXA1) and Grainyhead-like 2 (GRHL2) function as pioneer factors that facilitate chromatin accessibility and regulate ER-⍺ signaling in hormone receptor-positive BC. Elevated FOXA1 levels are linked to metastasis in endocrine therapy-resistant BC, as it promotes a pro-metastatic secretome. 69 , 70 Together with GRHL2, FOXA1 collaborates with GATA-binding protein 3 and ER-⍺ to utilize enhancer elements in modulating ER-⍺ transcription and contribute to therapeutic resistance. 71 , 72 , 73 Non-coding RNAs, including miRNAs, play a role in regulating metastatic niche formation and metabolic reprogramming by modulating target genes, thereby influencing BC initiation and progression. 74 The lncRNA HOTAIR, associated with polycomb repressive complex 2 and LSD1, induces epigenetic changes that promote tumor growth and metastasis. 74 In ER-positive BC, 28 functional open reading frames encoded by cryptic lncRNAs are up-regulated, particularly in ductal BC. 75 The peptide GT3-INCP, encoded by LINC00992 and regulated by estrogen and ER, promotes tumor growth by modulating susceptibility and risk genes through the transcription factor GATA-binding protein 3. 76 Exosome-derived miRNAs also show potential for clinical diagnosis and treatment by influencing tumor growth, progression, and organ-specific targeting 77 ( Fig. 2 A). The epigenetic control of receptor expression could be crucial in the development of endometriosis. Steroidogenic factor 1 (SF-1), a crucial transcription factor, activates numerous steroid synthesis genes to facilitate steroid production. Differential methylation of the SF-1 gene promoter and CpG islands surrounding the exon I region modulate its expression. 78 In proliferative stromal cells, the methyl-CpG-binding protein 2 fails to bind to the unmethylated SF-1 promoter. Moreover, increased acetylation of H3 and H4 is observed in the SF-1 promoter, potentially leading to SF-1 overexpression 79 ( Fig. 2 A). GATA-binding factor-6 (GATA6) serves as a biomarker for endometriosis induction. Notably, in proliferative stromal cells, hypomethylation in both the promoter and coding region of GATA6 is significantly elevated. 80 SF-1 and GATA6 are pivotal for initiating cascade reactions linked to steroidogenic proteins and enzymes, ultimately contributing to the development of endometriosis. 81 DNA methylation levels also directly influence the expression of ESR2, ESR1, and PR. Reduced acetylation at the H3 and H4 sites of the ESR1 promoter, particularly at H3, may result in decreased expression of ESR1. 82 Furthermore, miR-196a is overexpressed in endometrial stromal cells in endometriosis, inhibiting PR expression and exacerbating the condition. 83 Additionally, steroid receptor RNA activator1 lncRNAs regulate ER expression, where suppression of ER-α via this mechanism hinders cell growth and promotes apoptosis in endometrial stromal cells as endometriosis progresses 84 , 85 ( Fig. 2 A). Recent research in China found that 41 % of primary prostate cancers (PC) harbor FOXA1 mutations, which are critical for AR signaling regulation during prostate development and transformation. FOXA1 reprograms AR binding, accelerating carcinogenic transcription. 86 , 87 The NSD2 subunit is essential for AR/FOXA1 neo-enhancer-driven prostate tumors. 88 miR-194, initially a circulating marker for post-surgical PC recurrence, also targets FOXA1, activating ERK signaling and potentially contributing to resistance against AR-targeted therapies and metastasis. 89 , 90 AR regulates the expression of TET proteins, which convert DNA 5-methylcytosine into 5-hydroxymethylcytosine and are involved in DNMT production and function. 91 Various lncRNAs also play significant roles in PC progression by modulating both AR-dependent and -independent pathways. 92 Notably, lncRNAs like PCA3, HOTAIR, and CTBP1-AS are linked to AR pathway stimulation, 93 with HOTAIR promoting cancer growth by directly interacting with AR, inhibiting its ubiquitination and degradation, and enhancing AR target gene expression independently of androgens. 94 Furthermore, CBR3-AS1 can support AR signaling by preventing miRNA-mediated AR degradation. 95 Recent findings also indicate that microRNA-193a-5p-induced reactive oxygen species production, along with the disrupted colocalization of STAT3 and AR, is crucial for cornin-induced apoptosis. 96 Finally, it has been demonstrated that AR-regulated lncRNA 1 stabilizes AR transcripts and promotes the translation of AR mRNA transcripts, thereby increasing AR expression. 97 The results indicate that lncRNAs might be key targets for epigenetic medications aimed at reducing tolerance to androgen deprivation therapy and resistance to prostate cancer in cancerous cells 98 ( Fig. 2 B). The role of ER epigenetic regulation is recognized in various ovarian cancer cases. 99 In clear cell ovarian carcinoma, DNA methylation at the ESR1 promoter is particularly enriched, potentially locking cells in a secretory state. 100 Lysine-specific histone demethylase 1A (KDM1A) acts as a key epigenetic modulator and fundamental regulator of steroid hormone receptors. By recruiting KDM1A to the ERβ promoter, its expression is suppressed, which may increase the risk of ovarian cancer metastasis. 101 Additionally, E2F6, a significant target of ER, plays a crucial role in the epigenetic silencing of miR-193a, a mechanism implicated in ovarian cancer development. 102 Another histone modifier, SMYD2 (SET and MYND domain containing 2), a histone methyltransferase, enhances cell vitality in clear cell ovarian carcinoma through ER methylation, whereas inhibiting SMYD2 induces apoptosis in these cancer cells. 103 , 104 In relation to AR regulation, LSD1 interacts with AR, leading to the monomethylation and dimethylation of H3K4 and H3K9. This interaction prevents demethylation of these markers, thereby inhibiting the transcription of AR-related genes. LSD1's involvement has also been linked to the development of ovarian cancer. 101 A number of genetic single nucleotide polymorphisms in genes regulated by DNA methylation may lead to malfunction and irregular DNA methylation, heightening the host's vulnerability to autoimmune thyroid diseases. 105 Methylation of gene promoters in patients with autoimmune thyroid diseases correlates with alterations in chromatin architecture, resulting in the suppression of gene activity. 106 Furthermore, hypermethylation of the TRβ (thyroid hormone receptor beta) gene is prevalent in thyroid cancer, serving as an alternative mechanism for gene silencing. 107 miRNAs contribute to the activation of nuclear transcription factor-kappa B (NF-kB), interferon regulatory factor (IRF), and activator protein-1 (AP-1), which in turn promote the production of regulatory genes and autoimmune antibodies 108 ( Fig. 2 C). At the molecular level, the epigenetic process governing the regulation of thyrotropin receptor gene expression involves a single-nucleotide polymorphism within intron 1. Interferon alpha triggers widespread alterations in the monomethylation on H3K4me within thyroid cells, coinciding with a pair of adjacent single nucleotide polymorphisms within thyrotropin receptor intron 1 (rs1210255 and rs12101261). 109 Individuals harboring the Graves' disease risk T allele of the rs12101261 exhibit reduced thyrotropin receptor mRNA expression, promoting thyrotropin receptor-responsive T cell escape from central tolerance ( Fig. 2 C). In the islets of type 2 diabetes mellitus, the promoter of PGC-1α gene exhibits a two-fold increase in DNA methylation rate. 110 Increasing evidence points to a connection between histone acetylation and obesity. MOF, a lysine acetyltransferase, is involved in H4K16ac. Activation of H4K16ac by MOF modulates glucose absorption and fat storage in adipocytes through its interaction with PPARγ, exacerbating obesity progression. 14 Eliminating the histone demethylase JHDM2A/KDM3A suggests that vulnerability to obesity and metabolic syndrome might result in disruptions in fat build-up and glucose processing. 111 This reduces H3K9me2 through the binding of Jhdm2a to PPAR-responsive elements. Research has shown increased cytosine nucleotide methylation in the CpG island of the adrenal VDR promoter in patients with adrenal cortical carcinoma, resulting in diminished protective effects of the VDR protein against malignant tumors. 112 Acetylation of lysine 91 in VDR serves as a docking site for the ATP-dependent chromatin remodeling complex (the BRG1/BRM associated factors complex), which is crucial in type 2 diabetes mellitus. 113 There is an inverse relationship between the methylation level of the growth presumptive promoter and both the growth rate and mRNA expression levels of growth hormone. 114 Additionally, recent findings indicate that methylation of CG in the P2 promoter of the insulin-like growth factor-1 gene (CG-137) correlates negatively with the response of growth and circulation of insulin-like growth factor-1 23 ( Fig. 2 C). Persistent stress regulates the expression of the epigenetic writer-induced ubiquitin ligase NEDD4 and reduces AMPA receptor activity via GR-dependent control. These proteins could serve as therapeutic targets for alleviating chronic stress and/or glucocorticoid-related cognitive impairment. 115 Observations show hypermethylation at NR's hepatic X receptor, crucial in controlling cholesterol and fatty acid metabolism, linked to changes in the expression of genes targeted by the hepatic X receptor. 65 , 116 PPARγ activation can promote bladder cancer by enhancing cell proliferation, survival, and migration. 117 This occurs through the transcriptional regulation of genes involved in inflammation and cell cycle control, thereby contributing to tumor growth and metastatic potential. 118 Additionally, PPARγ′s modulation of the tumor microenvironment and angiogenesis further supports cancer progression. 119 Treatment with the PPARγ agonist rosiglitazone effectively suppresses tumor growth, and when combined with trametinib (a MEK inhibitor), it induces apoptosis, leading to a significant reduction in tumor size. 120 However, therapeutic targeting of PPARγ in bladder cancer remains controversial, as its effects may vary depending on the tumor context and the specific PPARγ ligands used. 121

The endocrine system, a complex network of glands like the pituitary, thyroid, adrenal glands, and pancreas, regulates various bodily functions by releasing hormones directly into the bloodstream. 1 , 2 These hormones bind to specific receptors, initiating biological effects crucial for metabolism, growth, stress response, immune function, and mental health. 3 , 4 Hormones and their receptors are pivotal components of this system. 1 Recent research underscores the significance of epigenetic control in regulating hormone receptor function. 5 Hormones and their receptors primarily function through genomic and non-genomic signaling pathways. Upon ligand binding, nuclear receptors (NRs) undergo conformational changes, leading to their migration into the nucleus where they bind to DNA. 6 Subsequently, accessory regulators, chromatin remodeling factors, and normal transcription mechanisms regulate the expression of NR target genes. Steroid hormones often elicit non-genomic signals, wherein their interaction with hormone receptors typically triggers diverse protein kinase pathways. These pathways can indirectly influence gene expression through the phosphorylation of transcription factors. 7 Steroid hormones are ligand-induced transcription factors that achieve synchronized and precise functional responses by regulating the expression of genetic programs. 8 Epigenetics, which modifies DNA without altering coding areas, influences receptor expression and functionality through DNA methylation, histone modification, chromatin restructuring, and non-coding RNA (ncRNA) regulation. 9 , 10 , 11 These mechanisms can affect, in a stable and potentially heritable manner, NRs that regulate transcription and cell surface receptors that modulate transcription factor responsiveness by altering chromatin structure. 12 , 13 NRs serve as sensors for intrinsic cellular changes that impact the transcription of genes involved in key biological processes, such as inflammation, proliferation, apoptosis, and susceptibility to chronic conditions like diabetes. 12 The transcriptional activity of receptor genes and the functionality of enzymes related to receptor epigenetics are regulated by four major epigenetic mechanisms, which together control receptor expression levels and influence the onset and progression of endocrine-related diseases. 14 , 15 This review seeks to elucidate the epigenetic control processes involved in various receptor types in endocrine diseases, providing essential scientific insights that may inform the development of innovative therapeutic approaches. Understanding the complex interplay between epigenetics and hormone receptors is crucial for unraveling the pathogenesis of these diseases and advancing treatment strategies.

Epigenetics research mainly focuses on changes in gene expression, centering on processes that regulate gene expression rather than altering the DNA sequence. These mechanisms include DNA methylation, histone modification, ncRNA regulation, and modulation of receptor gene expression, which collectively influence the functionality of internal systems. Receptors are crucial in controlling diverse internal mechanisms, with their expression and functionality intricately governed by epigenetic processes. This review explores the epigenetic mechanisms involved in receptor-related diseases and potential treatment strategies. For instance, certain drugs can inhibit the activity of DNMT, thereby affecting receptor expression. Furthermore, ncRNAs are recognized for their role in controlling receptor expression and functionality. Despite the progress made in epigenetic therapy for receptors, several challenges remain. Firstly, there is a need to deepen our understanding of the specific epigenetic mechanisms that govern receptor expression and function. Secondly, more effective drugs are required to modulate receptor expression and function through epigenetic mechanisms. Finally, the efficacy and safety of these treatments need to be thoroughly validated through clinical trials. In summary, epigenetic therapy targeting receptors holds promise as a therapeutic approach for endocrine-related diseases. However, further research and practical implementation are necessary to refine and optimize this treatment strategy to better serve patients.

None competing interests to declare in this study.

Tamoxifen was the first ER-α targeted medication to receive clinical approval. It functions selectively by competing with E2 to bind to ER-α, thereby hindering the recruitment of coactivators mediated by the ER-α ligand-binding domain. 122 Additionally, tamoxifen facilitates the activation of the AF1 domain independently of ligands, leading to weak transcriptional activation in E2-deficient scenarios and partial inhibition under E2 conditions in vitro . 123 Furthermore, tamoxifen can trigger interactions between ER and SRC3, thereby regulating the transcriptional activation of ER. 124 Dysregulation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway, including PIK3CA activation mutations, is frequent in BC. 125 PI3K pathway regulates ER-dependent transcription in BC through AKT phosphorylation of lysine methyltransferase KMT2D. 126 The combination of the PI3Kα inhibitor alpelisib with an anti-ER inhibitor has been approved for treatment. 127 Recently, a methylation site has also been identified on KMT2D, catalyzed by the lysine methyltransferase SMYD2. SMYD2 deletion attenuated alpelisib-induced KMT2D chromatin binding and alpelisib-mediated changes in gene expression, including ER-dependent transcription. 128 This opens up the possibility of SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors for the treatment of ER-positive PIK3CA-mutant BC ( Fig. 3 ). Figure 3 Mechanisms of epigenetic therapy in ER-positive PIK3CA-mutant breast cancer. AKT, protein kinase B; FOXA1, Forkhead box protein A1; mTOR, mechanistic target of rapamycin; PI3K, phosphatidylinositol-3-kinase; PBX1, Pre-B-cell leukemia homeobox transcription factor 1. Figure 3 Mechanisms of epigenetic therapy in ER-positive PIK3CA-mutant breast cancer. AKT, protein kinase B; FOXA1, Forkhead box protein A1; mTOR, mechanistic target of rapamycin; PI3K, phosphatidylinositol-3-kinase; PBX1, Pre-B-cell leukemia homeobox transcription factor 1. Epigenetic modifications play a critical role in ER-positive BC, especially concerning endocrine therapy resistance. Small molecule inhibitors, such as HDAC inhibitors (entinostat, vorinostat) and DNA hypomethylation agents (decitabine, 5-azacytidine), have been investigated as re-sensitizing agents. 129 , 130 Approximately 20% of patients with hypermethylation of the ESR1 promoter exhibit reduced ER-α expression, exacerbating disease progression. 131 By restoring ER-α expression, HDAC and aromatase inhibitors show promise in reversing resistance to endocrine therapy. 132 Decitabine significantly inhibited preclinical metastasis of ER-positive BC, resulting in a notable reduction in tumor growth in the xenograft model. 133 Additionally, combination therapies involving estrogens, HDAC inhibitors, and tamoxifen have been effective in re-establishing endocrine sensitivity. 134 Recent studies highlight novel approaches to overcoming endocrine resistance in ER-positive BC. Fulvestrant, an ER degrader, has shown efficacy in sensitizing cells to ferroptosis. 135 For patients with tamoxifen-resistant infiltrating lobular carcinoma, the FOXA1-ER pathway is associated with this resistance. 136 Moreover, targeting LYPD3 (LY6/PLAUR domain containing 3), which is regulated downstream of FOXA1 and GRHL2, can reduce tumor proliferation in cases that resist endocrine treatments. Thus, LYPD3 represents a viable target for endocrine-resistant BC. 72 KAT6A and KAT6B (lysine acetyltransferase 6A/B) are histone acetyltransferases with oncogenic roles in BC. The KAT6A/KAT6B inhibitor CTx-648 (PF-9363) blocked histone tail modifications, demonstrating anti-tumor activity in ER-positive BC, including cases resistant to endocrine therapy. 69 To overcome endocrine resistance in ER-positive BC, therapies targeting epigenetic modifications during the dormant state post-endocrine therapy and subsequent reactivation have shown potential. 137 Differential DNA methylation of estrogen response enhancers is associated with endocrine sensitivity. 138 Several new therapeutic strategies have shown promise for ER-positive BC. Large tumor suppressor kinase (LATS) inhibitors, such as VT02956, target the Hippo pathway to suppress ESR1 expression, particularly in endocrine therapy-resistant cases. 139 Additionally, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors ( e.g. , abemaciclib) and AKT inhibitors ( e.g. , capivasertib) show efficacy when combined with anti-ER agents like fulvestrant. 140 , 141 A novel therapeutic agent, ERX-11, binds to ER and modulates ER co–regulator interactions to inhibit the proliferation of BC cells that are resistant to endocrine therapy and CDK4/6 inhibitors. 142 Targeting these epigenetic modifications can effectively counteract endocrine resistance, thereby enhancing the efficacy of endocrine resistance. 131 Chromatin profiling has identified various castration-resistant prostate cancer (CRPC) subtypes, unveiling potential therapeutic targets tailored to specific epigenetic landscapes. 143 AR function in PC, particularly in CRPC, is significantly influenced by a range of enzymatic epigenetic co-regulators, including KDMs, bromodomain-containing protein 4 (BRD4), and enhancer of zeste homolog 2 (EZH2). 144 KDMs, especially KDM4 and KDM1, have emerged as critical players in apoptosis regulation, with KDM-targeting inhibitors showing effectiveness in inducing apoptosis in PC cells. 145 This positions KDMs as promising therapeutic targets for epigenetic treatments in PC. BRD4, a member of the bromodomain and extra-terminal domain subfamily, is another key player. By binding to acetylated lysine residues on histones, BRD4 recruits RNA polymerase and facilitates transcription. 146 In CRPC, BRD4 collaborates with AR to drive AR-mediated transcriptional activity. Inhibiting BRD4 disrupts AR's ability to bind to its target genes, making it a compelling therapeutic target for advanced PC. Additionally, some CRPC cases exhibit acquired GR activity, which activates the cAMP/PKA signaling pathway, influencing downstream gene expression. 147 EZH2, a methyltransferase, acts as an AR co-activator in CRPC by binding to the AR promoter region, enhancing AR signaling. 148 Notably, inhibiting EZH2 can counteract resistance to enzalutamide, a widely used anti-androgen medication in CRPC. 149 This highlights the therapeutic potential of EZH2 inhibitors in combating drug resistance. Moreover, methylation and degradation of EZH2 by SET domain-containing 2 (SETD2) have been linked to metastasis prevention, further underscoring the therapeutic implications of targeting EZH2. 150 Pioneer factors such as FOXA1 and GRHL2 play crucial roles in PC progression and endocrine resistance. Enzalutamide-induced FOXA1 activity, for instance, can open chromatin and drive AR-driven transcription. 151 Targeting FOXA1 to inhibit AR activity represents a promising therapeutic avenue in CRPC. Irregular FOXA1 activity is also implicated in PC progression through its effects on the AR cis-regulatory network. 152 Other emerging therapeutic approaches include targeting heat shock protein 70 (Hsp70), which binds to the AR N-terminal domain, reducing endogenous AR expression and inhibiting its transcriptional activity. 151 This could be particularly useful in overcoming resistance to enzalutamide in CRPC. Recently, ARNTL, a circadian clock component, has been proposed as a novel therapeutic target, while TET2 inhibitors show promise in overcoming resistance to AR-targeted therapies in ZNF397-deficient tumors. 153 As the understanding of these epigenetic regulators deepens, epigenetic therapies could provide new strategies for managing drug-resistant PC and other endocrine-related diseases. These insights offer a path to developing more effective treatments for CRPC, addressing resistance mechanisms, and potentially extending these strategies to other forms of PC and endocrine-related conditions. 154 In interventions for endometriosis, drug research has consistently targeted enzymes that regulate epigenetic alterations. Targeted suppression of prostaglandin E2 receptors EP2 and EP4 has been shown to involve DNMT3A and DNMT3B, with no effect on DNMT1 expression. 155 Researchers propose that focusing on EP2 and EP4 receptors could serve as a non-steroidal treatment for active endometrial lesions in women. 155 Additionally, demethylating agents have been found to increase ER-β mRNA levels in endometrial tissue, indicating a potential target for epigenetic therapy. 156 Known alternatively as 5-aza-2′-deoxycytidine, decitabine stands as the most potent DNMT inhibitor. Additionally, decitabine suppresses the methylation of PPARγ1 promoter DNA, enhancing macrophage activation and reducing insulin resistance in overweight individuals. 157 Furthermore, class I HDAC inhibitors, like MS-275, enhance hyperglycemia and body mass in diabetic mice with insulin-induced obesity. 158 This is accomplished through the regulation of mitochondrial function transcription factors and cofactors like PGC-1α and PPARγ, in addition to gene expression linked to glucose and lipid metabolism, encompassing glucose transporter. 159 Research also suggests that targeting DNA methylation could be an effective strategy in treating diabetic osteoporosis. Decitabine aids in the osteogenic differentiation of adipose-derived stromal cells by reducing the degree of methylation in osteogenic genes like osteopontin (OPN) and Runt-related transcription factor 2 (RUNX2). 160 Vorinostat, by acetylating histone 4, enhances the regulation and phosphorylation of insulin receptor β, AKT, and the forkhead box O1 (FOXO1). 161 Additionally, C646 acts as a targeted blocker of P300 acetyltransferase, obstructing insulin receptor substrate 1/2 (IRS1/2) acetylation and facilitating IRS1/2's movement across membranes, resulting in the stimulation of the insulin pathway. 162 Methylation of 12 CpG at the start point of the glucagon-like peptide 1 (GLP1) gene transcription has been observed in type 2 diabetes mellitus human islets. The expression of GLP1 receptor can be managed using the GLP1 receptor agonist rivenatide. 163 While a range of medications targeting DNA methylation and histone acetylation has been formulated, their application in clinical medical practice is infrequent. 164 Despite numerous investigations into ncRNAs and various histone alterations, there has been no authorization for an epigenetic medication targeting metabolic disorders. 165 Furthermore, the adverse impacts of these epigenetic medications could stem from modifications in genes that are not targeted. 166 Consequently, delving deeper into the function of epigenetic medications in metabolic disorders is of utmost significance ( Table 2 ). Table 2 Receptor-based epigenetic therapy and mechanisms for endocrine-related diseases. Table 2 Epigenetic therapeutic targets Epigenetics drugs Therapeutic mechanisms Reference AF1 Tamoxifen Disrupts receptors' competition with E2 for ERα binding and hinders ERα-LBD coactivator recruitment 123 KMT2D SMYD2 PI3Kα/AKT inhibitors SMYD2 inhibitors Sensitizes BC to PI3K/AKT inhibition and endocrine therapy, in part through KMT2D K1330 methylation 125 , 128 DNMT Decitabine, 5-azacytidine Suppressed the ethylation of PPARγ1 promoter DNA, enhancing macrophage activation 129 , 130 Enterestat and letrozole Restored ER-α and enzyme expression in ER-BC cell lines, leading to growth inhibition 132 Fulvestrant Sensitized ER-positive BC cells to ferroptosis through down-regulating MBOAT1 135 FOXA1/GRHL2 LYPD3 inhibitors Inhibits proliferation of endocrine-resistant tumors 72 KAT6A/KAT6B KAT6A/6B HAT inhibitors Blocks histone modification, showing anti-tumor activity in ER-positve BC 69 LATS LATS inhibitors (VT02956) Suppresses ESR1, controlling ER-positve BC growth via Hippo pathway 139 CDK4/6 AKT CDK4/6 inhibitors (abemaciclib) AKT inhibitors (capivasertib) Reverses endocrine resistance with fulvestrant 140 , 141 ER coregulator ERX-11 Binds to ER, modulates coregulator interactions, and inhibits BC proliferation 142 DMA Increases ER-β mRNA levels in endometrium 156 IL-1β, TGF-β Inhibits DNMT1 +32204 GG genotype remission in patients with Graves' disease 105 KDM4 and KDM1 Induces PC cells apoptosis 145 BRD4 Obstructs AR binding and transcriptional activity 146 EZH2 SETD2 Blocks PC metastasis by methylation and EZH2 degradation (SETD2) 150 FOXA1 Provides treatment strategy for CRPC via AR cis-antigenome impact 152 Hsp70 Hsp70 inhibitors Binds to AR N-terminal domain and reduces AR expression and transcriptional activity 151 TET2 TET2 inhibitors Eliminates resistance in ZNF397-deficient tumors to AR therapy 153 HDAC MS-275 Regulates genes in glucose and lipid metabolism 158 OPN and RUNX2 Decitabine Promotes osteogenic differentiation by reducing methylation 160 Histone 4 Vorinostat Enhances regulation and phosphorylation of insulin receptor β, AKT, and FOXO1 161 P300 acetyltransferase C646 Blocks IRS1/2 acetylation and aids IRS1/2 membrane movement 162 GLP1R Rivenatide Suppresses 12 CpG sites methylated at GLP1 transcription start 163 Note: AKT, protein kinase B; AR, androgen receptor; BRD4, bromodomain-containing protein 4; CDK, cyclin-dependent kinases; DNMT, DNA methyltransferases; DMA, demethylating agent; ERXs, estrogen receptor coregulator binding modulators; EZH2, enhancer of zeste homolog 2; ER, estrogen receptor; ERα-LBD, estrogen receptor-α ligand binding domain; FOXO1, Forkhead box O1; FOXA1, Forkhead box A1; GRHL2, Grainyhead like 2; GLP1, glucagon-like peptide-1; GLP1R, glucagon-like peptide-1 receptor; HDAC, histone deacetylase; IL-1β, interleukin-1beta; IRS1/2, insulin receptor substrate 1/2; KDM, histone lysine demethylase; LYPD3, LY6/PLAUR domain containing 3; LATS, large tumor suppressor kinase; MBOAT1, membrane-bound O-acyltransferase domain-containing 1; PPARγ1, peroxisome proliferator-activated receptor gamma 1; RUNX2, Runt-related transcription factor 2; SETD2, SET domain-containing 2; TGF-β, transforming growth factor-beta. Receptor-based epigenetic therapy and mechanisms for endocrine-related diseases. Note: AKT, protein kinase B; AR, androgen receptor; BRD4, bromodomain-containing protein 4; CDK, cyclin-dependent kinases; DNMT, DNA methyltransferases; DMA, demethylating agent; ERXs, estrogen receptor coregulator binding modulators; EZH2, enhancer of zeste homolog 2; ER, estrogen receptor; ERα-LBD, estrogen receptor-α ligand binding domain; FOXO1, Forkhead box O1; FOXA1, Forkhead box A1; GRHL2, Grainyhead like 2; GLP1, glucagon-like peptide-1; GLP1R, glucagon-like peptide-1 receptor; HDAC, histone deacetylase; IL-1β, interleukin-1beta; IRS1/2, insulin receptor substrate 1/2; KDM, histone lysine demethylase; LYPD3, LY6/PLAUR domain containing 3; LATS, large tumor suppressor kinase; MBOAT1, membrane-bound O-acyltransferase domain-containing 1; PPARγ1, peroxisome proliferator-activated receptor gamma 1; RUNX2, Runt-related transcription factor 2; SETD2, SET domain-containing 2; TGF-β, transforming growth factor-beta. It is well-recognized that demethylation of CpG sites in the promoter region enhances gene expression. 167 The ability of Graves' disease patients with the +32204 GG genotype to fully methylate their DNA may correlate with the methylation levels of interleukin-1beta (IL-1β) and transforming growth factor-beta (TGF-β) promoter regions, impacting IL-1β and TGF-β production. 105 This mechanism could potentially impede the remission initiation of patients with Graves' disease who have the DNMT1 +32204 GG genotype.