p53-mediated epigenetic regulation in the pathogenesis of endometriosis

DNA methylation is a chemical modification that controls gene expression and maintains genomic stability, thereby determining cellular differentiation lineages [ 14 ]. Aberrant global hypomethylation or locus‑specific hypermethylation can disrupt the balance between cell proliferation and cell death [ 15 ]. p53 indirectly influences DNA methylation patterns by transcriptionally controlling the expression of DNA methyltransferases (DNMTs) and TET dioxygenases, as well as by affecting the availability of the methyl donor S‑adenosylmethionine (SAM) [ 16 ]. Abnormal DNA methylation is closely associated with EMs pathogenesis. DNMTs are upregulated in ectopic endometrial lesions [ 17 ]; and the levels of DNMT1 and DNMT3B are elevated in secretory‑phase endometrial cells of EMs patients [ 18 ]. Moreover, aberrant CpG island methylation can inactivate tumor suppressor genes, contributing to EMs progression [ 19 ]. Although genome‑wide methylation profiles are highly similar between ectopic endometrium and normal endometrial stromal cells, significant differences in CpG methylation rates exist, suggesting that DNA methylation abnormalities may drive EMs initiation and development. Furthermore, multiple immune‑related genes and estrogen metabolism genes in ectopic endometrium exhibit aberrant methylation, which may prolong lesion persistence and enhance invasiveness. In EMs pathogenesis, aberrant DNA methylation is closely intertwined with p53 functional status, and the two act synergistically. Methylation dysregulation of estrogen receptor genes is a hallmark of epigenetic abnormalities in EMs. p53 indirectly regulates cellular methylation levels by transcriptionally repressing DNMT expression, thereby participating in epigenetic regulation through these enzymes [ 20 ]. In ovarian endometriomas, the tissue‑dependent differentially methylated region of ESR1 (encoding ERα) shows abnormal hypermethylation, leading to significant suppression of ESR1 expression [ 21 , 22 ]. By contrast, hypomethylation of the ESR2 (encoding ERβ) promoter CpG island in ectopic endometrial stromal cells results in ERβ upregulation, while hypermethylation of the ESR1 promoter and intronic CpG islands reduces ERα expression [ 23 ]. Notably, aberrant enrichment of DNMT3B further promotes ESR1 hypermethylation and its transcriptional repression [ 24 ]. Mechanistically, p53 transcriptionally represses DNMT3A and DNMT3B expression, thereby indirectly maintaining a hypomethylated state in target gene promoter regions via these DNMTs [ 20 ] and sustaining the expression of downstream tumor suppressors [ 25 ]. In vitro experiments in mouse embryonic stem cells have confirmed this regulatory role, showing that p53 maintains low expression of DNMT3A and DNMT3B, promoting a hypomethylated state. p53 directly binds to the promoter regions of DNMT3A/3B, recruits transcriptional corepressor complexes to block transcription initiation, and simultaneously upregulates TET1/2 expression to promote oxidation of 5‑methylcytosine, further reducing methylation levels [ 26 ]. Loss of p53 leads to abnormal DNMT upregulation. Consistent with these mechanistic findings, clinical studies have reported high expression of DNMT3A/3B [ 27 ] and multiple loci of aberrant hypermethylation in EMs lesions [ 28 ]. In endometrial carcinoma, the TP53 mutation rate is higher than in normal endometrium [ 29 ], and p53 mutations result in protein inactivation or dysfunction. Therefore, p53 deficiency may promote EMs progression by relieving transcriptional repression of DNMT3A/3B, inducing local DNA hypermethylation, silencing anti‑proliferative and DNA repair genes, and ultimately driving disease development. In summary, p53 negatively regulates DNA methylation via DNMTs and TETs. Given the tumor‑like properties of EMs, p53 inactivation likely promotes EMs initiation and progression through these intermediary molecules. Histone modifications are epigenetic mechanisms that determine gene transcriptional states by regulating chromatin conformation and the accessibility of genomic loci [ 30 ]. Amino acid residues on the N‑terminal tails of core histones can undergo covalent modifications [ 31 ]—including methylation, acetylation, phosphorylation, glycosylation, and ubiquitination–catalyzed by various histone‑modifying enzymes. These modifications can induce DNA unwinding and loosening of nucleosome structure, thereby initiating gene transcription. Aberrant histone modification patterns, such as imbalanced methylation at key sites or abnormal acetylation, may disrupt chromatin stability and lead to disordered gene expression [ 32 ]. Before discussing how p53 influences histone modifications, it is important to note that p53 itself is subject to extensive post‑translational modifications that directly impact its ability to regulate histone‑modifying enzymes. For example, acetylation of p53 at lysine residues within its C‑terminal regulatory domain (e.g., K320, K382) enhances its recruitment of p300/CBP to target gene promoters, thereby promoting local histone acetylation [ 11 ]. Conversely, deacetylation by HDAC1/2 reduces p53 transcriptional activity. Similarly, phosphorylation of p53 at Ser46 has been linked to the induction of specific histone methyltransferases. Thus, the crosstalk between p53 PTMs and histone modifications is bidirectional and critical for epigenetic regulation in EMs [ 7 , 8 ]. p53 indirectly modulates histone modifications through multiple mechanisms, primarily by regulating the expression or activity of histone‑modifying enzymes such as HATs, HDACs, and EZH2 [ 7 ]. Although p53 can physically interact with these enzymes, it does not itself possess catalytic activity toward histones; rather, it serves as a scaffold or transcriptional regulator that directs enzymatic activities to specific genomic loci [ 33 ]. Through these mechanisms, p53 modulates the dynamic balance of key histone modifications (e.g., methylation, acetylation, phosphorylation), thereby controlling the activation or repression of downstream target genes involved in cell‑cycle arrest, DNA damage repair, and apoptosis. Aberrant histone modifications are closely associated with EMs pathogenesis, and p53 dysfunction may cooperate with histone modification imbalance to promote lesion progression. In EMs, acetylation and methylation are the most frequently reported histone modification types [ 34 ]. Aberrant methylation and histone acetylation in lesion tissues can lead to dysregulation of genes related to cell proliferation and differentiation. Histone acetylation, which depends on the coordinated action of histone acetyltransferases (HATs) and histone deacetylases (HDACs), regulates gene expression by inducing open or closed chromatin states [ 35 ]. Acetylation reduces the positive charge of histone tails, weakens their interaction with the negatively charged DNA backbone, maintains an open chromatin conformation, and promotes gene expression [ 5 ]. In EMs lesions, global acetylation levels of histones H3 and H4 are significantly reduced, and dysregulated expression of HATs and HDACs is considered a pathogenic factor. In ectopic endometrial stromal cells, acetylation levels of H3 and H4 are markedly lower than in normal endometrial cells [ 18 ]. Specifically, H3K9ac and H4K16ac are reduced at the ESR1 promoter, correlating with ERα silencing [ 36 ]; in contrast, the promoter region of SF‑1 exhibits hyperacetylation of H3 and H4, resulting in its upregulation and promoting local estrogen production [ 37 ]. In addition, genome-wide profiling has revealed reduced H3K4me3 (a mark of active transcription) at differentiation-associated gene promoters in ectopic lesions, further contributing to transcriptional silencing [ 38 ]. Moreover, HDAC activity is increased in EMs cells, which may cause promoter hypoacetylation and induce abnormal cell‑cycle progression [ 39 ]. HDAC1 expression is elevated in both epithelial and stromal cells of EMs patients, and high HDAC1 levels may further aggravate clinical symptoms [ 40 ]. Thus, dysregulation of HATs and HDACs may lead to global histone hypoacetylation in EMs, promoting transcription of genes that support ectopic endometrial growth and abnormal proliferation [ 35 ]. p53 itself is a prototypical transcription factor regulated by acetylation [ 41 ]. Lysine residues at the C‑terminus of p53 can be acetylated by HATs such as PCAF and CBP/p300, enhancing its DNA‑binding ability and transcriptional activity [ 42 ]. p53 also recruits histone modifiers to specific genomic sites, influencing chromatin structure and gene expression, and playing key roles in genome stability, chromatin remodeling, and DNA repair [ 7 , 43 ]. In endometrial carcinoma, p53 missense mutations lead to accumulation of mutant p53 protein, which upregulates EZH2 (the core catalytic subunit of the PRC2 histone methyltransferase complex) [ 44 , 45 ]. This results in increased trimethylation of histone H3 at lysine 27 (H3K27me3) at the promoters of differentiation‑associated genes, creating a repressive chromatin state. Additionally, mutant p53 can recruit HDAC1/2 to deacetylate histones H3 and H4, particularly at lysine residues K9 and K16, further suppressing tumor suppressor transcription [ 46 ]. Notably, wild‑type p53 acetylation at K320 and K382 is required to counteract HDAC activity; this acetylation is reduced in EMs lesions, contributing to p53 dysfunction [ 11 ]. Collectively, the histone modifications affected by p53 dysfunction in EMs include reduced acetylation at H3K9 and H4K16, increased trimethylation at H3K27, and altered recruitment of HDACs to H3K9 and H4K16, as well as p53 acetylation at K320/K382. Therefore, p53 dysfunction, whether due to mutations, reduced expression, or aberrant post‑translational modifications (e.g., hypoacetylation, hyperubiquitination), together with EZH2‑ and HDAC‑mediated histone modification imbalances, establishes a pro‑proliferative, anti‑apoptotic microenvironment in the endometrium, accelerating EMs progression. Chromatin remodeling is an ATP‑dependent process that alters nucleosome architecture, modulates protein–DNA interactions, and increases DNA accessibility, thereby regulating gene expression [ 5 ]. Eukaryotic chromatin remodeling complexes are classified into four families: SWI/SNF, ISWI, CHD, and INO80 [ 47 ]. Among these, the ISWI, CHD, and INO80 complexes have not yet been reported in EMs. In contrast, the SWI/SNF complex has been implicated in EMs through its subunit ARID1A [ 48 ]. ARID1A, which encodes the BAF250a protein, is a key component of the SWI/SNF complex and is involved in suppressing inflammation, maintaining uterine immune homeostasis, and regulating progesterone receptor signaling. Mutations or downregulation of ARID1A have been identified in EMs lesions, suggesting that chromatin remodeling plays an important role in the disease. p53 functionally interacts with ARID1A, and their co‑dysregulation indirectly drives EMs progression by disrupting chromatin remodeling at p53 target genes. p53 can mediate local epigenetic remodeling of chromatin [ 49 ], and the SWI/SNF complex and its subunits are both regulators and targets of p53 function [ 50 ]. Specifically, ARID1A directly binds p53 and recruits it to chromatin remodeling complexes, thereby controlling the transcription of downstream target genes involved in cell‑cycle arrest and apoptosis [ 5 ]. Conversely, the activation status of the p53 pathway is modulated by ARID1A expression; loss of ARID1A enhances the transcriptional activity of p53‑associated genes and exerts tumor‑suppressive effects in certain contexts [ 50 , 51 ]. However, in EMs, ARID1A is frequently mutated or downregulated in ectopic endometrial tissues, leading to impaired p53 recruitment and reduced chromatin accessibility. This results in the suppression of p53‑mediated apoptotic pathways and promotes abnormal proliferation of ectopic endometrial cells. Moreover, co‑existing mutations of TP53 and ARID1A may synergistically disrupt the chromatin remodeling network, further enhancing lesion invasiveness. Collectively, through functional interactions with core components of chromatin remodeling complexes, p53 indirectly regulates chromatin structural dynamics and downstream gene expression via its interaction with ARID1A and the SWI/SNF complex, forming an epigenetic regulatory network whose dysregulation is a key driver of EMs pathogenesis. Non‑coding RNAs (ncRNAs) are key components of epigenetic regulation [ 52 ] and important contributors to EMs pathogenesis [ 53 ]. ncRNAs include long non‑coding RNAs (lncRNAs) and small non‑coding RNAs (sncRNAs), the latter comprising microRNAs (miRNAs), transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), and others. ncRNAs regulate critical pathological processes in EMs, such as cell proliferation, invasion, angiogenesis, and immune modulation. Dysregulated ncRNA expression is an important trigger of disease development. p53 and ncRNAs engage in bidirectional interactions, but p53 does not directly alter the epigenome. Wild‑type p53 directly activates the transcription of tumor‑suppressive ncRNAs (e.g., lincRNA‑p21, miR‑34 family), which in turn inhibit proliferation and promote apoptosis through epigenetic or post‑transcriptional mechanisms. Conversely, mutant p53 alters the expression of ncRNAs–including the induction of oncogenic miRNAs (e.g., miR‑155, miR‑205‑5p) and the repression of tumor‑suppressive miRNAs (e.g., miR‑223, let‑7i)–thereby exerting oncogenic effects indirectly via these ncRNA mediators. In EMs, specific miRNAs and lncRNAs have been shown to mediate the effects of p53 on ectopic endometrial cell behavior. The following sections discuss how p53‑associated miRNAs and lncRNAs contribute to EMs pathogenesis. miRNAs regulate mRNA expression by binding to complementary sequences, thereby controlling RNA splicing, degradation, and translation [ 54 ]. In EMs, miRNAs modulate key pathways including inflammation, angiogenesis, tissue repair, and extracellular matrix remodeling. Several p53‑related miRNAs are dysregulated in EMs. For instance, the let‑7b family targets mRNAs of genes such as IGF1R, KRAS, and HMGA2, participating in cell‑cycle regulation, growth, and migration. In EMs, let‑7b is downregulated, partly due to sponging by lncRNA H19, leading to increased IGF1R expression and enhanced proliferation of endometrial stromal cells [ 55 ]. The miR‑200 family (miR‑200a, miR‑200b, miR‑141) is also decreased in EMs tissues. This family normally suppresses epithelial‑mesenchymal transition (EMT) by targeting the transcription factors ZEB1 and ZEB2. Downregulation of miR‑200 thus derepresses ZEB1/2, inducing EMT, reducing E‑cadherin expression, and conferring invasive and migratory capacity to ectopic cells [ 56 ]. Conversely, miR‑135a, which targets HOXA10 and ROCK1, is elevated in EMs and may contribute to altered endometrial receptivity [ 57 ]. Other miRNAs, such as miR‑451, miR‑199a, and miR‑125b, are upregulated in both blood and ectopic tissues of EMs patients, where they regulate inflammatory pathways (e.g., IL‑8/NF‑κB) and promote cell survival [ 58 ]. p53 bidirectionally regulates miRNA expression, thereby influencing EMs pathogenesis [ 59 ]. p53 acts as a transactivator of tumor‑suppressive miRNAs and a repressor of oncogenic miRNAs. miRNAs upregulated by p53 generally target anti‑apoptotic or pro‑proliferative genes, reinforcing p53 function [ 60 ]. Conversely, miRNAs can modulate p53 activity by directly targeting p53 or its regulators [ 61 ]. For example, miR‑605 is transcriptionally activated by p53 under stress conditions; it then silences MDM2, creating a positive feedback loop that elevates p53 levels and drives cell‑cycle arrest or apoptosis [ 62 ]. Although direct evidence in EMs is limited, this regulatory circuit likely operates in the disease. Additionally, p53‑dependent changes in miRNA expression can affect inflammation and tissue remodeling, further linking p53 to EMs pathology [ 63 ]. lncRNAs are differentially expressed in the serum, ectopic endometrium, and eutopic endometrium of EMs patients [ 64 ]. Altered lncRNA expression regulates EMT, angiogenesis, proliferation, and invasion through multiple mechanisms: acting as molecular sponges (ceRNAs) for miRNAs, interacting with chromatin or transcription factors, or modulating signaling pathways [ 65 ]. Several lncRNAs have been implicated in EMs and show connections to p53‑related pathways. lncRNA H19 is overexpressed in both ectopic and eutopic endometrium of EMs patients compared to normal endometrium [ 66 ]. H19 regulates multiple EMs‑associated pathways, including IGF1R, ITGB3, IER3, and ACTA2, and functions as a ceRNA for let‑7 family miRNAs. High H19 expression is a prognostic factor for EMs recurrence. lncRNA MALAT1 is also upregulated in ectopic endometrial stromal cells, where it promotes EMT and cell proliferation/migration by sponging miR‑200 family members, thereby derepressing ZEB1 and ZEB2. In endometrial cells, downregulation of MALAT1 activates ERK/MAPK signaling and induces p21/p53‑mediated cell‑cycle arrest, suggesting that MALAT1 can indirectly modulate the p53 network. lncRNA AFAP1‑AS1, which is elevated in EMs, activates the EMT transcription factor ZEB1 [ 67 ]. lncRNA SRA1 promotes growth of EMs stromal cells [ 68 ]. Conversely, lncRNA MEG3‑210 is decreased in EMs and may suppress migration and invasion while promoting apoptosis; p53 can induce MEG3 expression in other contexts, suggesting a potential direct link [ 69 ]. A key feedback loop involves p53 and miR‑34a [ 70 ]. miR‑34a is a direct transcriptional target of p53 [ 61 ] and inhibits SIRT1, a deacetylase that suppresses p53 activity [ 70 ]. In EMs tissues, miR‑34a and p53 are coordinately downregulated, while SIRT1 is upregulated, and p53 levels are negatively correlated with SIRT1 [ 71 ]. This imbalance reduces the activity of pro‑apoptotic factors such as FoxO‑1, leading to apoptosis resistance, aberrant angiogenesis, and enhanced lesion survival. Thus, the p53/miR‑34a/SIRT1 feedback loop is a critical determinant of EMs progression. Collectively, p53 and ncRNAs form a complex regulatory network that governs key pathogenic processes in EMs, offering potential diagnostic and therapeutic targets ( Table 1 ). Table 1. p53‑associated non‑coding RNAs involved in the pathogenesis of endometriosis: expression patterns, regulatory mechanisms, downstream targets, and functional implications. ncRNA Type Expression in EMs p53 regulation Direct/Indirect Downstream target/pathway Biological function in EMs Clinical/therapeutic potential Ref. let‑7b miRNA Decreased (due to H19 sponging) p53 induces let‑7 family transcription Direct IGF1R, KRAS, HMGA2 Promotes stromal cell proliferation; inhibits apoptosis Let‑7 replacement therapy; H19 targeting [ 72 , 73 ] miR‑34a miRNA Decreased (coordinated with p53) p53 directly activates miR‑34a promoter Direct SIRT1→FoxO‑1, BCL2, CDK4/6 Induces apoptosis resistance, promotes angiogenesis, cell cycle dysregulation miR‑34a mimic; SIRT1 inhibitor [ 71 ] miR‑200a/b miRNA Decreased p53 regulates EMT‑related transcription factors (indirect) Indirect ZEB1, ZEB2, E‑cadherin Induces EMT, increases invasiveness and migration miR‑200 replacement; ZEB inhibitors [ 54 , 74 ] miR‑141 miRNA Decreased Indirect via EMT network Indirect ZEB1, ZEB2, TGF‑β pathway EMT, invasion Diagnostic biomarker (plasma) [ 54 ] miR‑135a miRNA Increased Unknown (possibly p53‑independent) Unknown HOXA10, ROCK1 Modulates endometrial receptivity; tumor‑suppressive role Potential biomarker for receptivity [ 75 , 76 ] miR‑451 miRNA Increased Not reported – Inflammatory cytokines (IL‑6, TNF‑α) Regulates inflammation, macrophage function Anti‑inflammatory therapeutic target [ 77 ] miR‑199a miRNA Increased Not reported – IL‑8, IKKβ/NF‑κB Controls inflammatory pathways, angiogenesis Therapeutic target for pain/inflammation [ 77 , 78 ] miR‑125b miRNA Increased p53 represses miR‑125b in some cancers (unknown in EMs) Unknown ERBB2, BAK1, p53 itself Anti‑apoptotic, promotes cell survival Prognostic biomarker [ 77 ] miR‑605 miRNA Not reported in EMs; stress‑induced p53 directly activates miR‑605 Direct MDM2 (positive feedback loop) Enhances p53 activity, promotes cell cycle arrest/apoptosis Potential to restore p53 function [ 79 ] miR‑17‑5p miRNA Increased (via DNMT3B‑mediated hypomethylation) p53 may regulate pri‑miR‑17‑92 cluster Indirect KLF12 → Wnt/β‑catenin Promotes proliferation, invasion DNMT3B inhibitor [ 17 ] H19 lncRNA Increased (in ectopic and eutopic endometrium) Not directly regulated by p53; functions as ceRNA Indirect let‑7/IGF1R, ITGB3, IER3, ACTA2 Promotes stromal cell proliferation; associated with recurrence Prognostic biomarker; H19‑targeting ASO [ 65 , 66 , 80 ] MALAT1 lncRNA Increased Indirect (via ERK/MAPK → p21/p53 pathway) Indirect miR‑200 family/ZEB1/ZEB2 Promotes EMT, proliferation, migration MALAT1‑targeting siRNA [ 65 , 81 ] SRA1 lncRNA Increased Unknown – Steroid receptor coactivator Promotes stromal cell growth Potential hormonal therapy target [ 65 ] AFAP1‑AS1 lncRNA Increased Unknown – ZEB1 (EMT transcription factor) Induces EMT, invasion Therapeutic target for invasive EMs [ 67 ] MEG3‑210 lncRNA Decreased p53 can induce MEG3 in other contexts Possibly direct p53 pathway, apoptosis‑related genes Suppresses migration, invasion; promotes apoptosis Tumor‑suppressive lncRNA replacement [ 65 ] lincRNA‑p21 lncRNA Not reported p53 directly activates lincRNA‑p21 Direct p21, CDK2, apoptosis machinery Induces cell cycle arrest and apoptosis (anti‑EMs potential) Synthetic lincRNA‑p21 mimic [ 82 ] p53‑associated non‑coding RNAs involved in the pathogenesis of endometriosis: expression patterns, regulatory mechanisms, downstream targets, and functional implications.

Endometriosis (EMs) is a benign gynecological disorder that exhibits both autoimmune features and malignant‑like biological behaviors, including invasive implantation, migration, and resistance to apoptosis [ 1 ]. It affects a large proportion of reproductive‑aged women and severely impairs reproductive health and daily life [ 2 ]. EMs is characterized by the ectopic growth of endometrial glands and stroma outside the uterine cavity, clinically manifesting as progressive dysmenorrhea, chronic pelvic pain, adnexal masses, menstrual disorders, and infertility. The core pathological events involve abnormal proliferation, invasion, and impaired apoptosis of ectopic endometrial cells, coupled with immune dysregulation [ 3 , 4 ]. Although multiple pathogenic hypotheses have been proposed, the exact molecular mechanisms remain unclear [ 5 , 6 ]. The tumor suppressor p53 is a master regulator of cell cycle arrest, apoptosis, DNA repair, and genomic stability [ 7 , 8 ]. Its activity is finely tuned by a range of post‑translational modifications (PTMs), including phosphorylation, acetylation, and ubiquitination, which control its stability, localization, and transcriptional output [ 9–11 ]. In EMs, p53 expression is significantly decreased in ectopic lesions, leading to excessive cell proliferation and resistance to apoptosis [ 12 ]. Epigenetic modifications—heritable changes in gene expression without alterations in DNA sequence—act as a critical bridge between p53 dysfunction and EMs pathogenesis [ 6 , 13 ]. As a transcription factor, p53 does not directly alter the epigenome; rather, it orchestrates epigenetic outcomes by regulating the expression or activity of downstream molecules such as DNA methyltransferases, histone modifiers, chromatin remodelers, and non‑coding RNAs.

EMs is a complex gynecological disorder with a high prevalence among reproductive‑aged women [ 83 ]. Although its pathogenesis remains incompletely understood [ 84 ], accumulating evidence positions p53 dysfunction and epigenetic dysregulation as central drivers [ 85 , 86 ]. In normal endometrium, p53 expression follows a cyclic pattern and supports periodic apoptosis [ 87 ]; in EMs lesions, p53 is significantly downregulated, leading to apoptosis resistance and hyperproliferation of ectopic endometrial cells – features that mirror malignant tumor biology [ 77 , 88 ]. Epigenetic modifications act as the primary conduit through which p53 exerts its effects on EMs [ 13 ], and this review has systematically examined four epigenetic dimensions: DNA methylation, histone modification, chromatin remodeling, and non‑coding RNA networks ( Table 2 ). Table 2. p53-associated epigenetic regulators in DNA methylation, histone modification, and chromatin remodeling in endometriosis. Epigenetic layer p53-interacting molecule p53 regulation type Expression/activity in EMs Downstream effect Ref. DNA methylation DNMT3A/3B Transcriptional repression Upregulated Hypermethylation of ESR1 promoter, ERα silencing [ 20 ] DNA methylation TET1/2 Transcriptional activation Not well studied Potential demethylation of tumor suppressors [ 26 ] Histone modification PCAF / CBP/p300 Recruitment/p53 acetylation Dysregulated Reduced H3K9ac and H4K16ac at ESR1 promoter [ 11 , 42 ] Histone modification EZH2 (mutant p53) Protein – protein interaction Upregulated Increased H3K27me3, silencing of differentiation genes [ 44 , 45 ] Histone modification HDAC1/2 Recruited by mutant p53 HDAC activity increased Deacetylation of H3/H4 at K9/K16 [ 46 ] Chromatin remodeling ARID1A (SWI/SNF) Physical binding Mutated/downregulated Impaired p53 recruitment, reduced chromatin accessibility [ 50 , 51 ] p53-associated epigenetic regulators in DNA methylation, histone modification, and chromatin remodeling in endometriosis. Beyond its epigenetic regulatory roles, p53 directly controls fundamental cellular stress responses that are critically disrupted in EMs. Specifically, p53-mediated cell cycle arrest (via p21 induction) prevents the proliferation of damaged cells; its pro-apoptotic function (via BAX, PUMA) eliminates ectopic endometrial cells; and its DNA repair capacity (via p53R2, GADD45) maintains genomic integrity. In EMs lesions, p53 dysfunction, whether due to reduced expression, mutations, or aberrant post-translational modifications, compromises these protective mechanisms. Consequently, ectopic endometrial cells escape G1/S checkpoint control, resist apoptosis despite inflammatory and hypoxic stress, and accumulate DNA damage, collectively driving lesion growth, recurrence, and potential malignant transformation. Thus, restoring p53’s global functions represents a therapeutic strategy complementary to targeting its epigenetic networks [ 12 , 71 , 85 , 86 , 88 ]. Regarding DNA methylation, p53 indirectly maintains a hypomethylated state by negatively regulating DNMT3A/3B expression and activating TET1/2 [ 20 ]; in EMs, p53 loss relieves this repression, causing locus‑specific hypermethylation (e.g., ESR1 promoter) and silencing of tumor suppressors, which promotes estrogen signaling imbalance and cell proliferation [ 17 ]. For histone modification, p53 indirectly influences histone acetylation by recruiting HATs (e.g., PCAF, CBP/p300) to target genes and by regulating HDAC expression; p53 itself is activated by acetylation [ 7 ]. In EMs, global hypoacetylation of H3/H4 and HDAC overexpression are observed [ 38 ], and mutant p53 cooperates with EZH2 and HDAC1/2 to establish a pro‑proliferative, anti‑apoptotic chromatin environment [ 44 ]. Notably, HDAC inhibitors that restore p53 acetylation have shown therapeutic efficacy in preclinical models [ 89 ]. In terms of chromatin remodeling, p53 indirectly affects chromatin accessibility through its functional interaction with ARID1A, a core subunit of the SWI/SNF complex [ 50 ]. ARID1A is frequently mutated or downregulated in EMs, impairing p53 recruitment and reducing chromatin accessibility at apoptosis‑related genes [ 5 ], and co‑existing TP53 and ARID1A mutations may synergistically drive lesion invasiveness [ 90 ]. Regarding non‑coding RNAs, p53 bidirectionally regulates miRNAs and lncRNAs at the transcriptional level, and these ncRNAs then mediate downstream epigenetic or post‑transcriptional effects [ 82 ]. In EMs, dysregulated ncRNAs – such as downregulated miR‑34a and let‑7b, and upregulated H19, MALAT1, AFAP1‑AS1—contribute to EMT, angiogenesis, apoptosis resistance, and recurrence [ 54 ]. The p53/miR‑34a/SIRT1 feedback loop is a critical determinant of disease progression [ 71 ]. Collectively, these four epigenetic mechanisms do not operate in isolation but form an interconnected network [ 8 ]. p53 deficiency simultaneously promotes DNA hypermethylation, histone hypoacetylation, chromatin inaccessibility, and aberrant ncRNA expression [ 85 ]. These changes converge on key cellular processes: enhanced proliferation and survival, sustained local estrogen production, epithelial‑mesenchymal transition and invasion, and immune evasion with inflammation [ 77 ]. Thus, p53 acts as a master epigenetic coordinator whose dysfunction reprograms the endometrium toward a malignant‑like phenotype [ 86 ]. An emerging layer of complexity is the role of p53 post‑translational modifications in EMs. Phosphorylation (e.g., Ser15, Ser20), acetylation (e.g., K320, K382), and ubiquitination (e.g., K48‑linked) collectively determine p53 stability, localization, and transcriptional output [ 9–11 ]. In EMs, altered expression of modifying enzymes such as MDM2 (E3 ubiquitin ligase) and SIRT1 (deacetylase) may disrupt this balance. For example, elevated SIRT1 in EMs lesions deacetylates p53, reducing its activity and thereby promoting DNMT3B expression and hypermethylation [ 71 ]. Restoring p53 acetylation with HDAC inhibitors or SIRT1 inhibitors could thus reverse multiple epigenetic aberrations simultaneously. Future studies should map the p53 PTM landscape in ectopic versus eutopic endometrium and test whether PTM‑targeting drugs (e.g., MDM2 inhibitors, SIRT1 inhibitors) have therapeutic efficacy in EMs models. The mechanistic insights reviewed here suggest several translational opportunities. HDAC inhibitors (e.g., MHY2256, Romidepsin) that restore p53 acetylation and activate the p53‑p21 axis have demonstrated efficacy in preclinical EMs models, warranting clinical evaluation [ 89 , 91 ]. DNMT inhibitors could potentially reverse aberrant hypermethylation of tumor suppressors, although their systemic toxicity requires careful consideration [ 92 ]. ncRNA‑based strategies—such as miR‑34a mimics, let‑7 replacement, or antisense oligonucleotides targeting H19 or MALAT1—are emerging as precision tools [ 65 , 93 ]. Additionally, the expression levels of p53, ARID1A, or specific ncRNAs may serve as prognostic or diagnostic biomarkers, particularly for predicting recurrence or assessing endometrial receptivity. Despite this progress, several limitations must be acknowledged. Most studies are correlative and do not establish causality; functional validation using patient‑derived organoids or animal models with conditional p53 knockout is needed. The four epigenetic layers are discussed separately, but their cross‑talk—for example, how DNA methylation affects lncRNA expression or how histone modifications influence chromatin remodeler recruitment—remains largely unexplored in EMs. Moreover, the majority of evidence comes from ectopic lesions; the role of p53‑epigenetic networks in eutopic endometrium and in different EMs subtypes (peritoneal, ovarian, deep infiltrating) is poorly characterized. Large‑scale, multi‑center clinical cohorts are required to validate biomarker candidates and to assess the heterogeneity of epigenetic alterations among patients. Future studies should employ single‑cell and spatial epigenomic approaches to map p53‑dependent chromatin landscapes in specific cell types, investigate the therapeutic window of epigenetic drugs in combination with hormonal therapies, explore whether p53‑restoring agents (e.g., MDM2 inhibitors) can synergize with HDAC or DNMT inhibitors, and translate ncRNA signatures into non‑invasive liquid biopsy tests for early diagnosis and recurrence monitoring. In summary, p53 orchestrates a broad epigenetic regulatory network that governs DNA methylation, histone modifications, chromatin remodeling, and non‑coding RNA expression. Dysfunction of p53 disrupts this network, driving the hallmark features of EMs: persistent proliferation, apoptosis resistance, EMT, angiogenesis, and immune dysregulation. Recognizing p53 as a central epigenetic hub opens new avenues for mechanism‑based diagnosis and therapy, and addressing the current gaps through integrated multi‑omics and functional studies will be essential to translate these findings into clinical benefit for patients with EMs.