The hypoxia-epigenetics-ncRNA axis in endometriosis: from molecular cascades to self-sustaining pathogenic circuits

Endometriosis is a debilitating chronic inflammatory disorder driven by extensive molecular reprogramming. Despite significant bench research into its pathogenesis, translating these molecular discoveries into clinical practices that improve patient outcomes remains a critical challenge. This comprehensive review bridges the gap between basic life sciences and clinical application by delineating the hypoxia-epigenetics-non-coding RNA (ncRNA) axis as the primary engine of endometriosis pathogenesis. We elucidate how microenvironmental stress, specifically hypoxia via HIF-1α stabilization, initiates a coordinated cascade of aberrant DNA methylation, post-translational histone modifications, and ncRNA dysregulation. We illustrate how these isolated molecular events converge into a highly integrated, self-sustaining pathogenic circuit that drives hallmark clinical phenotypes, including progesterone resistance, chronic inflammation, and tissue invasiveness. To overcome traditional disciplinary silos, we propose a four-stage dynamic progression model that maps the transition from acute epigenetic stress to chronic disease manifestation, offering a robust framework for clinical stratification. Disrupting this specific axis offers new avenues for non-hormonal precision therapeutics and the development of non-invasive diagnostic biomarkers to address significant unmet clinical needs in endometriosis management. 1 Introduction Endometriosis (EMs) is a chronic inflammatory disorder characterized by ectopic endometrial tissue implantation. The disease affects approximately 10% of women of reproductive age and causes severe pelvic pain, infertility, and a reduced quality of life (). Despite extensive research, the precise pathogenesis remains incompletely elucidated (), highlighting the necessity to identify novel molecular drivers of the disease. Current evidence identifies aberrant epigenetic regulation as a core mechanistic link between genetic susceptibility and environmental risk factors, providing a dynamic framework for disease initiation and progression (). Epigenetic modifications, including DNA methylation, histone post-translational modifications, and non-coding RNA (ncRNA) networks, are fundamental to the initiation, progression, and maintenance of EMs (). These mechanisms reprogram gene expression within endometrial cells and the surrounding microenvironment without altering the underlying DNA sequence (, ). Microenvironmental hypoxia functions as a primary signal driving this epigenetic reprogramming. Hypoxia stabilizes hypoxia-inducible factor 1α (HIF-1α). HIF-1α acts as a transcriptional hub that recruits epigenetic modifiers to specific genomic loci and regulates the expression of numerous ncRNAs. This interaction forms a hypoxia-epigenetics-ncRNA axis that regulates the molecular reprogramming central to EMs pathogenesis (, ). This review explores the role of epigenetic regulatory networks in shaping the EMs phenotype, focusing on the hypoxia-induced interactions between epigenetic machinery and the ncRNA axis. We summarize how the integrated dysregulation of these elements drives disease progression. Building upon this mechanistic framework, we further examine the translational potential of these findings. Targeting these epigenetic aberrations provides a strong rationale for developing targeted epigenetic drugs, non-hormonal therapies, and non-invasive diagnostic markers to address unmet clinical needs in EMs. To provide a balanced perspective, the clear distinction is made between experimentally validated mechanisms, correlative observations, and speculative hypotheses, particularly in areas where direct evidence in endometriosis remains limited. 2 DNA methylation: foundational programming of gene expression and epigenetic therapy DNA methylation involves the covalent addition of a methyl group to the fifth carbon of cytosine residues, predominantly within CpG dinucleotides, catalyzed by DNA methyltransferases (DNMTs). The TET family of dioxygenases dynamically reverses this process by initiating active demethylation pathways (). Precisely regulated DNA methylation in the female reproductive system is essential for orchestrating endometrial cycling, decidualization, and establishing a receptive state for embryo implantation (). In EMs, substantial deviations in the epigenetic landscape drive the complex pathophysiology underlying the clinical manifestations of the disease. Genome-wide methylation profiling confirms widespread epigenetic reprogramming in both eutopic and ectopic endometrial cells from patients (). Ectopic cells exhibit over a 10-fold difference in CpG methylation rates compared to normal endometrial stromal cells (). This reprogramming disrupts cellular proliferation, immune evasion, extracellular matrix remodeling, and hormonal responsiveness, constituting the core hallmarks of endometriotic lesions. The expression profile of DNMTs in ectopic lesions varies across studies (), likely reflecting the heterogeneity of patient populations, lesion subtypes, and environmental exposures. The following subsections detail how specific methylation alterations regulate distinct pathological processes in EMs (). 2.1 Estrogen synthesis and signaling pathway Ectopic endometrial tissues in EMs patients exhibit elevated estrogen levels while systemic serum concentrations remain normal, indicating a reliance on a localized hyperestrogenic microenvironment (). Absent in normal endometrium, the aromatase and steroidogenic acute regulatory protein (StAR) confer the capacity for local estrogen production in ectopic tissues. Steroidogenic factor 1 (NR5A1, encoding SF-1) transcriptionally regulates these steroidogenic genes and is overexpressed in endometriotic stromal cells (). Increased SF1 expression enhances StAR and CYP19A1 activity, promoting localized estrogen production. Altered SF1 expression in ectopic tissues may be driven by promoter methylation, highlighting its role as a master regulator in EMs (). DNMT3B binds to the promoter regions of key steroidogenic genes in both normal endometrium and EMs lesion stromal cells (). Abnormal DNA methylation patterns in DNMT3B promoter interactions within ectopic tissues potentially underlie dysregulated SF1 expression (). GATA6 expression is elevated in ectopic lesion cells and regulated by hypomethylated CpG sites within intron 2. Izawa et al. identified a distinct hypomethylated CpG cluster within this region, proposing these elements serve as transcriptional enhancers (). While GATA2 regulates hormone driven spontaneous differentiation in normal endometrial cells, GATA6 reduces hormone sensitivity and suppresses GATA2 activity. EMs tissues exhibit higher GATA2 methylation levels alongside reduced mRNA and protein expression. Hypermethylation of the GATA2 promoter and coding regions in ectopic stromal cells correlates with decreased transcript levels, whereas GATA6 remains hypomethylated and significantly upregulated, further enhancing estrogen secretion (). 2.2 Hormone receptors and endometrial receptivity Epigenetic mechanisms regulate the expression of estrogen and progesterone receptors (). Estrogen exerts its effects through nuclear estrogen receptors ERα and ERβ, encoded by the genes ESR1 and ESR2 respectively. Bedrick et al. demonstrated that the promoter region of the ESR1 gene in ectopic endometrial stromal cells is profoundly hypermethylated, which systematically drives the silencing and low expression of ERα (). Conversely, extensive epigenetic profiling reveals that the promoter and exon regions of the ESR2 gene exhibit marked hypomethylation in ectopic lesion cells compared to normal endometrium, providing a permissive chromatin landscape for its robust transcriptional activation. However, it is critical to note that the relationship between ESR1 or ESR2 locus methylation and functional protein expression is not strictly linear and appears to be context-dependent. Although promoter hypermethylation is generally a hallmark of transcriptional repression, ER protein levels do not always exhibit a simple inverse, binary correlation with methylation status. This discrepancy likely reflects cell-type-specific regulatory mechanisms, including alternative promoter usage, alternative splicing, and post-translational regulation, rather than a simple binary silencing effect. Therefore, altered ERβ expression in endometriosis should be interpreted within the broader context of multilayered epigenetic and transcriptional control. While ectopic stromal cells exhibit significantly lower ESR1 expression due to epigenetic silencing, the ESR2-to-ESR1 ratio is markedly elevated at both the mRNA and protein levels (). Aberrantly elevated ESR2 expression contributes to EMs pathophysiology through mechanisms involving inflammation, proliferation, apoptosis inhibition, and hyperalgesia, thereby advancing ectopic lesion formation. Progesterone exerts its effects via progesterone receptors PR-A and PR-B (). PR-A acts as a dominant negative repressor of PR-B and other steroid receptors, while PR-B functions as a dominant transcriptional activator of progesterone-responsive promoters. Studies examining methylation patterns of PR-A/B in secretory-phase ectopic endometrium from infertile women with EMs and secretory-phase normal endometrium found no methylation within the PR-A promoter across both groups (). In the same vein, research has demonstrated elevated PR-A levels in ectopic endometrium and stromal cells of women with EMs, while PR-B protein expression remains undetectable, suggesting that progesterone resistance is a hallmark of the disease (). Although the absence of PR-A promoter methylation suggests that progesterone resistance is not driven by classical transcriptional silencing, accumulating evidence indicates that alternative epigenetic and non-epigenetic mechanisms are involved. These include altered PR isoform ratios (PR-A/PR-B imbalance), miRNA-mediated repression of PR signaling components, and histone modification changes affecting PR target chromatin. Consequently, progesterone resistance in endometriosis represents a network-level dysregulation rather than a single epigenetic defect at the promoter level. While global progesterone resistance involves multilayered mechanisms, specific lesion subtypes retain a prominent dependence on DNA methylation for gene silencing. In particular, the hypermethylation-mediated silencing of key regulators epitomized by PGR and HOXA10 establishes a distinct epigenetic vulnerability that underpins the differential therapeutic responses observed among endometriosis subtypes. In lesions where progesterone resistance is primarily driven by DNA methylation, exemplified by ovarian endometriosis (OE), the pathological silencing of these genes creates a marked dependency on the DNA methylation machinery. Thus, these lesions exhibit heightened sensitivity to DNA methyltransferase inhibitors (DNMTis), which can potentially reverse the methylation locks and restore gene expression. In contrast, deep infiltrating endometriosis (DIE) is characterized by a distinct epigenetic landscape in which histone modifications rather than DNA methylation predominate in gene regulation. This mechanistic divergence accounts for why DIE lesions generally respond more favorably to HDAC inhibitors compared to DNMTis. Therefore, stratifying patients based on the specific epigenetic signatures of their lesions is crucial for optimizing the clinical efficacy of epigenetic therapies. 2.3 TET proteins and active demethylation The ten-eleven-translocation (TET) protein family, comprising TET1, TET2, and TET3, plays a critical role in active DNA demethylation by catalyzing the conversion of 5-methylcytosine (5mC) to cytosine through its enzymatic activity (). TET1 is essential for maintaining hypomethylation at transcriptionally active gene promoters and participates in transcriptional repression via direct chromatin binding and histone modifications facilitated by protein complexes (). Investigations into TET gene expression in eutopic endometrium from infertile EMs patients and healthy women have found significantly reduced TET1 transcript and protein levels in EMs patients (). Consistent results indicate decreased TET1 gene expression accompanied by increased promoter DNA methylation in infertile EMs patients compared to normal controls, although no differences in overall TET1 transcript levels were observed between mild and severe EMs cases (). Notably, during the mid-secretory phase, significant alterations were observed in TET1 mRNA levels, protein expression, and CpG island methylation, whereas no differences were detected during the proliferative phase. Increased methylation levels of the TET1 promoter during the implantation window in EMs patients are associated with its reduced expression. Given that TET1-mediated demethylation is crucial for activating genes essential for endometrial receptivity, its diminution may contribute to impaired decidualization and embryo implantation, potentially explaining one facet of EMs-associated infertility (). 2.4 Invasion and extracellular matrix remodeling Matrix Metalloproteinase 2 (MMP-2) plays a essential role in degrading the extracellular matrix, facilitating the invasion and establishment of ectopic lesions. Tarki et al. demonstrated that the promoter region of MMP2 is significantly hypomethylated at specific CpG sites (CpG2, 3, and 4) in ectopic endometrium compared to normal tissue (). This hypomethylation correlates strongly with increased MMP2 mRNA and protein expression, directly linking epigenetic alteration to enhanced proteolytic activity and invasiveness in EMs (). In addition, hypoxia-induced HIF-1α can further upregulate MMP2 transcription, creating a synergistic pro-invasive mechanism. 2.5 Homeobox genes and endometrial function Homeobox (HOX) genes play pivotal roles in endometrial development, with DNA methylation representing key regulatory mechanisms. The HOX gene family comprises four loci (HOXA, HOXB, HOXC, HOXD) that critically regulate endometrial growth, differentiation, and receptivity (). Studies demonstrate aberrant methylation patterns across multiple HOXA-HOXD genes in EMs patients compared to healthy controls. Methylation alterations correlate with aberrant transcriptional activity of HOX genes in EMs, including conserved methylation changes in half of the HOXA cluster genes (HOXA2, HOXA4, HOXA7, and HOXA11). Research links HOXA10 mutations or dysregulated expression to impaired fertility, with abnormal HOXA10 observed in multiple reproductive disorders including EMs, polycystic ovary syndrome, leiomyoma, polyps, adenomyosis, and hydrosalpinx (). HOXA10 is highly expressed in endometrial luminal epithelium, glandular epithelium, and stromal cells, where it regulates functional differentiation. Reduced HOXA10 expression significantly compromises endometrial receptivity (). Studies further identify HOXA10 promoter hypermethylation and transcriptional downregulation in EMs, which disrupts the uterine microenvironment. Collectively, these findings suggest HOXA10 as a potential diagnostic biomarker for EMs (). 2.6 Other methylated genes in EMs Beyond the genes discussed above, genome-wide methylation studies have identified a plethora of other genes aberrantly methylated in EMs. For instance, tumor suppressor genes including RASSF1A and CDKN2A are frequently hypermethylated and silenced, promoting cell survival and proliferation (). Conversely, hypomethylation of pro-inflammatory genes including IL1β and TNF contributes to the inflammatory microenvironment characteristic of EMs (). Additionally, epigenetic silencing of PRKD1, a regulator of cellular adhesion and invasion, has been linked to enhanced invasiveness of ectopic stromal cells (). This broader landscape of methylation alterations underscores the pervasive role of epigenetic dysregulation across multiple hallmarks of EMs (Figure 1). Figure 1 3 Post-translational modifications: a dynamic regulatory network for cellular signaling and function Studies demonstrate dysregulated post-translational modifications (PTMs) of multiple pathogenic factors in EMs (). As essential mediators of biological functions, proteins require precise processing and modification to achieve functional maturation. Eukaryotic cells utilize diverse PTM types, with common modifications including acetylation, phosphorylation, glycosylation, ubiquitination and methylation. These modifications regulate protein conformation, activity, and intermolecular interactions, thus modulating cellular physiological and pathological processes (). Emerging evidence highlights the critical involvement of PTM dysregulation in EMs pathogenesis (Figure 2). Figure 2 3.1 Acetylation and phosphorylation: synergistic regulation of signaling and transcription 3.1.1 Acetylation and transcriptional control Acetylation on histone lysine residues is dynamically regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Physiologically, HATs promote chromatin relaxation to facilitate transcription factor binding and gene activation (). Beyond histones, non-histone proteins including HOXA10 and p53 undergo acetylation-mediated regulation. Psilopatis et al. identified reduced histone acetylation coupled with HDAC1 overexpression in ectopic stromal cells, linking these aberrations to disease progression (). In ectopic lesions, the ESR1 to ESR2 ratio decreases significantly, positioning ESR2 as the dominant mediator of invasion and inflammation (). Elevated HDAC1 expression in ectopic tissues catalyzes the removal of acetyl groups from histones H3 and H4 at the ESR1 promoter, leading to a condensed chromatin state that suppresses its transcription (). This receptor imbalance promotes ectopic lesion development. Abnormal expression of SIRT1, a class III HDAC, occurs in EMs (). Compared to controls, eutopic endometrium from patients exhibits increased SIRT1 expression. SIRT1 co recruits with BCL6 to the promoter of GLI1 to repress its transcriptional activity (). This SIRT1 mediated deacetylation potentially underlies progesterone resistance. Acetylation homeostasis requires balanced HAT/HDAC regulation. For instance, the HAT NCOA1 is upregulated in ectopic lesions to maintain local hyperestrogenic microenvironments (). 3.1.2 Phosphorylation in survival and signal transduction Phosphorylation involves the enzymatic transfer of phosphate groups to substrate protein residues, critically regulating signal transduction and protein dynamics (). In EMs, locally elevated estrogen in ectopic lesions upregulates SGK1 expression (). Concurrently, ESR2 enhances SGK1 transcriptional activity, resulting in elevated levels in ectopic versus control endometrium (). SGK1-mediated phosphorylation of the pro-apoptotic factor FOXO3 inactivates this protein, reducing apoptosis and promoting ectopic lesion implantation (). Mitochondrial homeostasis dysregulation constitutes another pathogenic mechanism. MST1, a Hippo pathway regulator, controls cell proliferation, differentiation and cytoskeletal organization (). Notably, MST1 expression is significantly reduced in ectopic endometrium (). Diminished MST1-mediated DRP1 phosphorylation thus disrupts mitochondrial dynamics, facilitating lesion development. The eutopic endometrium determinism hypothesis posits distinct molecular characteristics in patients’ eutopic endometrium (). Phosphoproteomic analyses identify 516 proteins with dysregulated phosphorylation in eutopic endometrium (). Kotlyar et al. reported enhanced signal transducer and activator of transcription (STAT) phosphorylation (), which increases hypoxia-inducible factor expression. This cascade inhibits dual-specificity phosphatase 2 (DUSP2), aberrantly activating ERK and p38 MAPK pathways to promote cytokine secretion, proliferation, and angiogenesis. Collectively, these phosphorylation abnormalities in eutopic endometrium drive EMs pathogenesis. 3.2 Glycosylation and ubiquitination: modulating adhesion, immunity, and protein turnover 3.2.1 Glycosylation in cell adhesion and immune recognition Glycosylation plays precise roles in EMs pathogenesis by actively driving disease progression through specific molecular signatures (). Specific glycosylation patterns govern the initial adhesion of refluxed endometrial cells to the peritoneal mesothelium. The interaction between CD44 on endometrial cells and hyaluronic acid on mesothelial cells depends on CD44 glycosylation (). Upregulated glycosyltransferases synthesize specific glycan structures on CD44 to enhance its binding affinity. This hyper adhesive state is further amplified by hypoxia. Experimentally, inhibiting these key enzymes disrupts the glycan signature and impairs ectopic cell adhesion, establishing a direct causal role for glycosylation in early lesion development (). Aberrant glycosylation also shapes the immunosuppressive niche. Abnormal glycan signatures on endometriotic cells engage lectin receptors on immune cells, to promote immune evasion. In the context of infertility, glycosylation is essential for successful embryo implantation. The mid secretory phase endometrium in patients shows globally altered glycosylation patterns which impair embryo attachment (). Abnormal glycosylation of hormone receptors could also affect their stability, contributing to progesterone resistance. 3.2.2 Ubiquitination and protein stability Ubiquitination involves the covalent conjugation of ubiquitin to substrate proteins for recognition and degradation by the 26S proteasome (). Current understanding of ubiquitination in EMs remains limited. Yang et al. observed cyclic ubiquitin expression patterns with elevated levels in ectopic cells during the secretory phase, correlating with reduced apoptosis (). This implicates enhanced ubiquitination in promoting ectopic cell survival. Upregulated in ectopic tissues, the deubiquitinase USP10 removes ubiquitin chains from RAF1 to prevent its proteasomal degradation. This stabilization leads to sustained activation of the Raf/MEK/ERK signaling pathway, promoting the proliferation and growth of endometriotic lesions (62). 3.3 PTMs as emerging therapeutic targets Aberrant PTMs dysregulate protein function to promote EMs progression. Unlike irreversible genetic mutations, most PTMs are dynamically reversible, making their regulatory enzymes promising therapeutic targets. Current research focuses on HDAC and kinase inhibitors. HDAC inhibitors increase histone acetylation, suppress CYP19A1 transcription, and inhibit proliferation via cell cycle arrest (63, 64). The p38 inhibitor SB203580 attenuates MAPK pathway activation to reduce lesion volume in murine models (65). The JNK1 inhibitor AS602801 suppresses inflammatory cytokine secretion and progesterone resistance (66). Inhibiting the histone lysine demethylase LSD1 reduces lesion volume by decreasing VEGF and PCNA expression while inhibiting epithelial mesenchymal transition (67). In summary, dysregulation of phosphorylation, acetylation, and methylation in signaling proteins characterizes EMs pathogenesis. Developing clinically viable PTM-targeted therapeutics demands deeper mechanistic understanding and translational validation of the hypoxia induced PTM crosstalk. Despite encouraging preclinical efficacy, substantial translational challenges must be addressed before these PTM-targeted agents can be adopted clinically. A central obstacle is achieving adequate delivery specificity to ectopic lesions, particularly within the dense fibrotic stroma characteristic of deep infiltrating endometriosis (DIE), where systemic drug penetration remains suboptimal. Moreover, chronic inhibition of evolutionarily conserved pathways, including p38 and JNK MAPK signaling, raises considerable concerns regarding systemic toxicity, notably hepatotoxicity and widespread immunosuppression. Overcoming these barriers will likely depend on advanced drug delivery strategies, specifically nanoparticle-based carriers or localized sustained-release platforms, designed to maximize lesion-targeted accumulation while limiting off-target adverse effects, thereby improving the overall therapeutic index. 4 Non-coding RNA networks: multi-layered and interactive epigenetic regulators Accumulating clinical evidence implicates epigenetic dysregulation, particularly non coding RNAs (ncRNAs), in EMs pathogenesis. Lacking protein coding capacity, ncRNAs primarily comprise microRNAs (miRNAs), long non coding RNAs (lncRNAs), and circular RNAs (circRNAs). Substantial research establishes functional links between aberrant ncRNA expression and EMs progression. These transcripts drive pathogenesis by potentiating angiogenesis, regulating apoptosis, inducing cellular proliferation, enhancing invasion, facilitating EMT, modulating inflammation, and disrupting hormonal balance (Figure 3). Figure 3 4.1 miRNAs: central hubs in epigenetic and transcriptional regulation 4.1.1 Biogenesis and function MicroRNAs (miRNAs) function as highly conserved endogenous regulators of gene expression. Distinct miRNA expression profiles in endometriotic lesions versus normal endometrium implicate these transcripts in EMs pathogenesis (68, 69). These single stranded RNAs form RNA induced silencing complexes (RISCs) that bind complementary sequences in target mRNA untranslated regions, inducing degradation or translational repression (70). Conversely, certain miRNAs exhibit dual functionality by binding promoter regions to enhance target gene expression (71). miRNAs regulate virtually all biological processes through the modulation of epigenetic modifiers and broad gene networks (72). Reciprocally, epigenetic mechanisms dictate miRNA function, forming integrated regulatory circuits with DNA methylation and histone modifications (73). 4.1.2 miRNAs in pathogenic mechanisms EMs pathogenesis involves interconnected endocrine dysfunction, immuno-inflammatory responses, and microenvironmental alterations. Dysregulated miRNAs contribute fundamentally to these processes. For example, aberrant miR-138 expression modulates inflammatory cytokines and apoptotic factors via the VEGF/NF-κB pathway (68). Similarly, miR-125b-5p, miR-146b, and miR-182 regulate inflammatory pathways (74, 75). Meng et al. identified the overexpression of BCAR3, a promoter of migration and EMT, in both eutopic and ectopic endometrium (76). Concurrent downregulation of miR-126-5p, which targets the BCAR3 transcript, facilitates disease progression by enhancing cellular invasion. Furthermore, miR-34a-5p expression positively correlates with pro apoptotic factors (FOXO1, TP53) and inversely with anti-apoptotic factors (SIRT1, BCL2L1) (77). Mechanistically, miR-34a targets TP53 and regulates FOXO1 through SIRT1 in ectopic tissues, effectively suppressing apoptosis. These findings reveal a complex miRNA mediated crosstalk between pro inflammatory and anti-apoptotic pathways. 4.2 circRNAs: stable sponges and regulators in ceRNA networks 4.2.1 Epigenetic regulation of circRNA biogenesis Circular RNAs (circRNAs) are generated through back splicing of pre mRNA transcripts, a highly regulated process constituting an important epigenetic mechanism in EMs. Biogenesis of specific circRNAs is controlled by chromatin level modifications and RNA binding protein (RBP) networks responsive to the hypoxic microenvironment. Host gene transcription is regulated by histone acetylation and DNA methylation alterations well documented in EMs. RBPs facilitating back splicing are regulated by estrogen and hypoxia signaling. Hypoxia induced HIF-1α directly modulates splicing factors that govern circRNA biogenesis. Competition between canonical linear splicing and back splicing represents a perturbed regulatory node in the disease state. These upstream epigenetic disturbances establish distinct circRNA expression profiles in ectopic endometrium, subsequently functioning as miRNA sponges to drive progression. Thus, circRNA dysregulation creates a self-reinforcing pathogenic circuit linked directly to microenvironmental stress. circRNAs in EMT and Hypoxia: Functional studies reveal that specific circRNAs act as key mediators in EMs progression, primarily functioning as miRNA sponges and protein interactors (Table 1). Epithelial mesenchymal transition (EMT) drives morphogenesis by remodeling cell structure, reducing apoptosis, and conferring invasive capabilities (78). Hypoxia induced EMT constitutes a critical early event in lesion formation (79). Wang et al. reported significant upregulation of hsa_circ_0007299 (circATRNL1) and YAP1 in ectopic tissues, alongside downregulation of miR-141-3p and miR-200a-3p (80). circATRNL1 promotes cellular proliferation, invasion, and stromal fibrosis, driving EMT via the miR-141-3p and miR-200a-3p to YAP1 axis. Another study identified eight EMT associated circRNAs, with validation confirming the downregulation of circ_103470 and CIRC101102. Derived from RAB3IP, hsa_circ_0005571 (hsa_circ_101102) influences pathogenesis by regulating autophagy. Network analyses confirm these circRNAs modulate EMT via miR-141-5p across multiple signaling pathways, highlighting hsa_circ_0063526 as a potential biomarker (81). Jiang et al. identified upregulated CIRC0008433 modulating EMT, stromal cell survival, and angiogenesis via a circRNA-miRNA-mRNA axis (82). Table 1 | circRNA | Target | Aim miRNA | Regulation in EMs | Impact on EMs | Signaling pathway/Molecular Axis | PMID | |---|---|---|---|---|---|---| | circZFPM2 | ZEB1 | miR-205-5p | Upregulated; Positive | Promotes cell proliferation, migration, invasion, and EMT; exerts oncogene-like effects. | circZFPM2/miR-205-5p/ZEB1 pathway | 34517087 | | circ_0026129 | ATP6V1A | miR-15a-5p | Upregulated; Positive | Central hub in exosomal ceRNA network; promotes ATP6V1A release, contributing to EMs pathogenesis. | circ_0026129/miR-15a-5p/ATP6V1A | 33901012 | | circATRNL1 | YAP1 | miR-141-3p/miR-200a-3p | Upregulated; Positive | Promotes cell proliferation, migration, invasion, stromal fibrosis, and accelerates EMT. | circATRNL1/miR-200a-3p-YAP1 axis | 32728069 | | circ_0007299 | CREB1 | miR-424-5p | Upregulated; Positive | Downregulation inhibits proliferation and invasion, promotes apoptosis; upregulation increases CREB1 expression by sponging miR-424-5p. | circ_0007299/miR-424-5p/CREB1 | 35708774 | | circATRNL1 | ASIC1 | miR-103a-3p | Upregulated; Positive | Downregulates miR-103a-3p, increases ASIC1 expression, promotes EMT, cell proliferation, migration, and invasion | circATRNL1/miR-103a-3p/ASIC1 | 35504053 | | circ_0004712 | ROCK1 | miR-488-3p | Upregulated; Positive | Knockdown inhibits cell survival and migration; promotes ROCK1 expression by downregulating miR-488-3p, accelerating EMT. | circ_0004712/miR-488-3p/ROCK1 | 35717759 | | circ_0007331 | HIF-1α | miR-200c-3p | Upregulated; Positive | Promotes EMT; Knockdown inhibits cell survival, proliferation, and invasion. | circ_0007331/miR-200c-3p/HIF-1α axis | 32960511 | | circ_0075503 | KLF12 | miR-15a-5p | Upregulated; Positive | Knockdown inhibits E2-induced migration and invasion of endometrial stromal cells (ESCs). | circ_0075503/miR-15a-5p/KLF12 axis | 34117589 | | circ_0061140 | Notch-2 | miR-140-3p | Upregulated; Positive | Downregulation inhibits cell proliferation, migration, and invasion. | circ_0061140/miR-140-3p/Notch-2 | 32621951 | | circ_0004712 | SOS2 | miR-148a-3p | Upregulated; Positive | E2 upregulates its expression and promotes EMT via the β-catenin pathway. | circ_0004712/miR-148a-3p/SOS2 | 32667746 | | circZFPM2 | ZFPM2 | miR-205-5p | Upregulated; Positive | Enhance cell invasion and metastasis | ZMB1/EMT | 34517087 | | circPIP5K1A | TMSB4X | miR-153-3p | Upregulated; Positive | Activation of TGF-β2, accelerates EMs progression | circPIP5K1/miR-153-3p/TMSB4X Axis | 32548806 | | hsa_circ_0063526 | - | miR-141-5p | Upregulated; Positive | Knockdown inhibits cell invasion, migration, proliferation, and downregulates estrogen receptors. | circ_0063526/miR-141-5p/EMT/ER axis | 34967761 | | circ_0000673 | PTEN | miR-616-3p | Downregulated; Negative | Downregulation promotes cell proliferation and migration via the miR-616-3p/PTEN axis | circ_0000673/miR-616-3p/PTEN axis | 34522177 | | hsa_circ_0067301 | Notch-1, Hes-1 | miR-141e-5p | Downregulated; Negative | Knockdown promotes cell proliferation and migration, upregulates Notch-1/Hes-1, and promotes EMT. | hsa_circ_0067301/miR-141e-5p/Notch-1 pathway | 31023528 | | circ_103470 | - | miR-141-5p | Downregulated; Negative | Regulates EMT. | mTOR/Hippo/HIF-1/PI3K-Akt pathways | 30566420 | | circ_101102 | - | miR-141-5p/miR-503 | Downregulated; Negative | Induces apoptosis and cell cycle arrest; inhibits proliferation and angiogenesis; regulates autophagy and EMT. | mTOR/Hippo/HIF-1/PI3K-Akt pathways | 30566420 | Molecular regulatory mechanism of circRNAs in endometriosis. 4.2.2 CircRNAs in estrogen-mediated invasion EMs relies heavily on aberrant estrogen secretion (83). Using an estradiol stimulated in vitro model, Liu et al. revealed that hsa_circ_0075503, overexpressed in ectopic endometrium, sponges miR-15a-5p (84). This miRNA targets KLF12, a mediator of decidualization and apoptosis (85). Knockdown of hsa_circ_0075503 suppressed estrogen induced migration by regulating the miR-15a-5p/KLF12 axis. Matrix metalloproteinase 9 (MMP9), a key driver of metastasis, is highly expressed in EMs lesions. Li et al. identified potential binding sites for hsa-miR-1231, hsa-miR-223, and 19 other miRNAs in hsa_circ_0001649 (86). Oncogenic circRNAs such as hsa_circ_0004712 promote lesion progression, and silencing them with siRNA nanoparticles reduces invasion in vivo (87). The stability of EMs specific circRNAs in peripheral blood highlights their potential as non-invasive liquid biomarkers (88). 4.3 lncRNAs: architectural regulators and miRNA sponges Long non-coding RNAs (lncRNAs) function as essential regulatory components within the epigenetic landscape of endometriosis. Extensive profiling reveals distinct lncRNA expression signatures in endometriotic tissues compared to matched healthy controls. Mechanistically, these transcripts mediate ectopic cellular proliferation, migration, cell cycle progression, and epithelial-mesenchymal transition (EMT), ultimately remodeling the pelvic microenvironment and compromising reproductive function. 4.3.1 LncRNAs regulate cell proliferation, invasion, and apoptosis H19, an imprinted transcript at locus 11p15.5, functions as a multidimensional regulator of endometriotic cell dynamics. It potentiates eutopic endometrial stromal cell (euESC) invasion via the estrogen-dependent miR-216a-5p/ACTA2 axis (89). H19 drives ectopic lesion expansion by sequestering miR-124-3p to upregulate integrin β3 (ITGB3), while its targeted suppression liberates let-7 to repress the insulin-like growth factor receptor, thereby abrogating cellular proliferation (90). Similarly, the upregulated transcript HOTAIR mediates an aggressive invasive phenotype in ectopic tissues through competitive inhibition of miR-519b-3p, subsequently activating the PRRG4 signaling cascade (91). Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) stimulates euESC proliferation and inflammatory responses while suppressing apoptosis via the microRNA-142-3p/CXCR7 axis (92). Li et al. revealed that NEAT1 overexpression induces NLRP3 inflammasome-mediated pro-apoptotic cell death through the miR-141-3p/HTRA1 axis, thereby accelerating EMs progression (93). The oncogenic lncRNA AFAP1-AS1, known to promote tumor cell proliferation, invasion, and migration (94), was shown by Huan et al. to suppress euESC proliferation and induce apoptosis by targeting miR-424-5p to regulate the STAT3/TGF-β/Smad signaling pathway (95). 4.3.2 LncRNAs promote angiogenesis The angiogenesis-associated lncRNA AHIF demonstrates aberrant elevation in EMs patients and stimulates neovascularization by activating vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) (95). Dysregulation of insulin-like growth factor 2 (IGF2) has been implicated in increased EMs susceptibility. Jin et al. demonstrated that IGF2 antisense RNA (IGF2-AS) drives EMs progression by modulating the miR-370-3p/IGF2 axis and activating the PI3K/AKT/mTOR signaling pathway (96). 4.3.3 LncRNAs function as miRNA sponges in Ems Accumulating evidence indicates that long non-coding RNAs (lncRNAs) can serve as competitive endogenous RNAs (ceRNAs) in EMs, wherein both lncRNAs and protein-coding transcripts compete for shared miRNA binding sites, often displaying coordinated expression patterns. The prototypical example of this mechanism in EMs involves the H19 lncRNA; decreased H19 expression correlates with enhanced let-7 miRNA activity, which post-transcriptionally suppresses IGF1R expression and consequently inhibits endometrial stromal cell proliferation (97). These findings suggest that the H19/let-7/IGF1R axis may underlie impaired endometrial receptivity in affected individuals. Furthermore, H19 facilitates ectopic endometrial cell proliferation and invasion by sequestering miR-124-3p, leading to upregulated integrin β3 (ITGB3) expression (98). In immune modulation, H19 functions as a molecular sponge for miR-342-3p, thereby regulating the IER3 pathway to influence Th17 cell differentiation and stromal cell proliferation in ectopic lesions (99). Another significant example is CDKN2B-AS1, which modulates AKT3 expression by competitively binding miR-424-5p in ovarian EMs models (100). LINC01116 promotes endometrial stromal cell proliferation and migration by targeting FOXP1 through miR-9-5p sequestration, thereby accelerating lesion formation (101). Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) acts as a miR-200c sponge, upregulating ZEB1 and ZEB2 expression to regulate stromal cell proliferation and migration in EMs (102). This regulatory network potentially extends to the entire miR-200 family (miR-200a, miR-200b, miR-200c, miR-141, miR-429) (103). It is important to note that, to date, robust ncRNA signatures independently validated across multiple large patient cohorts and all major lesion subtypes, including ovarian, peritoneal, and deep infiltrating endometriosis, remain to be established. Similarly, the reproducibility of methylation and ncRNA alterations across these distinct lesion subtypes remains insufficiently characterized. Most reported candidates are derived from heterogeneous, single-center studies with limited subtype stratification, underscoring the need for prospective, multi-cohort validation to confirm their generalizability. 4.3.4 Therapeutic and diagnostic potential LncRNAs hold substantial promise as diagnostic biomarkers and therapeutic targets for EMs. The serum levels of H19 and MALAT1 have been shown to correlate with disease severity, positioning them as potential non-invasive diagnostic tools (104). Using genome-wide microarray approach, Wang et al. in 2015 found 1,277 lncRNAs that were dysregulated in the secretory-phase eutopic endometrium of patients compared with the menstrual-phase-matched endometrium from a control cohort (105). In therapeutic applications, silencing of HOTAIR using antisense oligonucleotides has been demonstrated to reduce lesion growth in preclinical models through the suppression of EMT and cell invasion (106). Similarly, the restoration of MEG3 has been found to inhibit cell proliferation by modulating the miR-21-5p/PTEN signaling pathway (107). Challenges persist in achieving delivery specificity and conducting clinical validation; however, lncRNA-based liquid biopsies and targeted therapies embody emerging precision medicine strategies for EMs. 5 Hypoxia-induced epigenetic reprogramming in endometriosis Consistent with the retrograde menstruation theory, detached endometrial tissue encounters hypoxic conditions following vascular disruption. Hypoxia represents a master regulator that drives epigenetic reprogramming, facilitating the establishment and progression of EMs. HIFs, particularly HIF-1α, mediate cellular adaptation to low oxygen and initiate extensive transcriptional changes. Critically, HIF-1α directly interacts with epigenetic machinery, recruiting DNMTs, HDACs, and HATs to specific gene promoters, and regulates the expression of numerous ncRNAs, thereby forming a robust hypoxia-epigenetic-ncRNA axis that underpins EMs pathogenesis (79, 108). The enzymatic activities of these recruited epigenetic modifiers are dynamically fine-tuned by post-translational modifications (PTMs), notably phosphorylation and ubiquitination, which regulate HIF-1α stability and the catalytic efficiency of chromatin remodeling complexes. 5.1 Hypoxia-driven epigenetic reprogramming of steroid hormone signaling EMs, as a hormone-dependent disorder, exhibits enhanced local estrogen biosynthesis closely associated with the hypoxic microenvironment, in which HIF-1α plays an essential regulatory role (109). As illustrated in Figure 4, hypoxia induces estrogen production in EMs via a central HIF-1α-COX-2/PGE2 axis, which is further amplified by platelet activation. Hypoxia stabilizes HIF-1α, which upregulates COUP-TFII and stimulates ERK/p38 MAPK signaling (estrogen-dependent), ultimately driving COX-2-mediated estrogen synthesis; estrogen then activates platelets, creating a self-reinforcing loop that fuels EMs progression. Regarding the regulation of key steroidogenic genes, for example, aromatase (CYP19A1) and steroidogenic acute regulatory protein (STAR), while studies in cancer models indicate that HIF-1α can upregulate their expression by directly recruiting histone acetyltransferases (HATs) and increasing promoter histone acetylation (110), this specific mechanism lacks direct experimental confirmation in EMs tissues. In EMs, the aberrant overexpression of CYP19A1 and STAR is more strongly attributed to promoter hypomethylation and the aberrant activation of transcription factors like steroidogenic factor-1, which constitutes the currently more widely accepted EMs-specific epigenetic explanation. Similarly, although the downregulation of the transcriptional repressor NR2F2 (COUP-TFII) in EMs relieves inhibition of estrogen biosynthetic pathways (), the hypothesis that hypoxia directly suppresses NR2F2 via histone deacetylase (HDAC)-mediated mechanisms or promoter hypermethylation remains inadequately supported by direct experimental evidence in EMs and is largely inferred from knowledge of correlative signaling pathways. Concerning the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) axis, a critical amplifier of local estrogen biosynthesis, hypoxia-mediated epigenetic regulation demonstrates a clearer chain of evidence in EMs. Beyond stabilizing PTGS2 mRNA, hypoxia upregulates miR-20a, which in turn suppresses the expression of its target gene, DUSP2 (111). DUSP2, a nuclear phosphatase, is downregulated, leading to sustained activation of the ERK/p38 MAPK signaling pathway, which further amplifies PTGS2 gene expression. This hypoxia–miR-20a–DUSP2-COX-2 axis represents a relatively well-characterized example of non-coding RNA-mediated epigenetic regulation in EMs, establishing a self-sustaining loop that stimulates local estrogen and prostaglandin production, exacerbates inflammatory responses, and fuels EMs progression. Beyond this axis, accumulating EMs-specific evidence implicates hypoxia-regulated non-coding RNAs in shaping the estrogen-dominant and progesterone-resistant phenotype. For instance, HIF-1α induced molecules, for example, miR-210 can post-transcriptionally modulate the expression levels of estrogen receptors (ESR1, ESR2) and progesterone receptor (PGR), directly contributing to the characteristic hormonal microenvironment of EMs. Figure 4 In summary, hypoxia is a central microenvironmental driver of dysregulated steroid hormone signaling in EMs, but its epigenetic regulatory actions exhibit pathway and mechanistic heterogeneity. While pathways involving DNA methylation changes and specific miRNA-mediated regulation possess a relatively solid evidence base in EMs, mechanisms implicating the direct recruitment of histone modifiers by HIF-1α are often extrapolated from models of other pathologies. The universality and direct causality of these latter mechanisms in EMs necessitate further in-depth investigation for definitive confirmation. 5.2 Epigenetic regulation of autophagy by hypoxia in EMs pathogenesis Hypoxia exerts a significant influence on autophagic flux in EMs through a combination of transcriptional and post-transcriptional mechanisms. Critically, the specific pathways linking hypoxia to epigenetic reprogramming of autophagy in EMs are often inferred from other disease models and require careful contextualization. 5.2.1 LncRNA-mediated pathways The long non-coding RNA MALAT1 is transcriptionally upregulated under hypoxic conditions in EMs, primarily driven by HIF-1α stabilization (112). By modulating complex downstream ceRNA networks, MALAT1 significantly contributes to cell survival and ectopic lesion progression under metabolic stress. However, the precise non-coding RNA axes directly linking hypoxia-induced MALAT1 to autophagic flux regulation in EMs remain an area requiring further in-depth experimental elucidation. 5.2.2 Transcriptional and direct epigenetic mechanisms HIF-1α stabilization is a key mediator of autophagy-related gene expression in hypoxic EMs lesions. In other systems, HIF-1α can directly bind to the promoters of core autophagy genes including MAP1LC3A and BNIP3 and recruit epigenetic modifiers. For instance, HIF-1α can induce the expression of histone demethylases including KDM3A, which removes the repressive H3K9me2 mark from these promoters to facilitate transcription (113). Notably, direct evidence of such HIF-1α promoter occupancy and the recruitment of specific histone-modifying enzymes to autophagy gene loci in EMs tissues or primary cells is currently lacking. This model, while well-supported in oncology and ischemia research, remains to be conclusively demonstrated in the specific context of EMs pathogenesis. 5.2.3 Functional integration and pathogenic role Despite the need for further mechanistic validation within EMs, the observed functional outcome of enhanced autophagy, which is regulated at both the epigenetic and transcriptional levels, promotes cellular survival under metabolic stress and facilitates invasion. This aligns with the aggressive phenotype characteristic of ectopic lesions. The interplay between hypoxia, epigenetic regulation, and autophagy collectively forms a sophisticated adaptive network that is likely instrumental in maintaining the viability and supporting the progression of EMs. Future research employing techniques like chromatin immunoprecipitation sequencing (ChIP-seq) and targeted epigenetic editing in EMs models is essential to definitively map and verify these proposed hypoxia-epigenetic-autophagy connections. 5.3 Epigenetic mechanism of hypoxia-induced invasion and angiogenesis Hypoxia promotes invasion and angiogenesis in EMs largely through HIF-1α-mediated epigenetic reprogramming (109). HIF-1α recruits DNA methyltransferases (DNMTs) and HDACs to the promoters of tumor suppressor genes and tissue inhibitors of metalloproteinases (TIMPs), leading to their silencing via hypermethylation and histone deacetylation (114). This epigenetic silencing enhances the expression and activity of matrix metalloproteinases (MMPs), facilitating ECM degradation and invasion. In angiogenesis, HIF-1α transactivates key pro-angiogenic genes like VEGFA. Beyond transcriptional activation (115), HIF-1α also orchestrates epigenetic changes to sustain angiogenic signaling. It induces the expression of the histone demethylase KDM4B, which removes repressive H3K9me3 marks from the VEGFA promoter, creating a permissive chromatin environment (116). In parallel, hypoxia downregulates microRNAs that target VEGFA through promoter hypermethylation, further amplifying VEGF signaling (117). A novel epigenetic angle involves the angiopoietin (ANG) signaling. Hypoxia relieves the transcriptional repression of ANG by downregulating NR2F2 (a repressor) through HDAC-mediated mechanisms, thereby potentiating Ang-mediated angiogenesis (118). This underscores how hypoxia employs multiple epigenetic layers, namely DNA methylation, histone modification, and ncRNA regulation, to drive the vascularization essential for ectopic lesion survival and growth. 5.4 Targeting hypoxia-mediated gene networks: therapeutic potential and translational challenges Given the central role of epigenetic mechanisms in hypoxia-driven EMs pathogenesis, targeting the hypoxia-epigenetics axis represents a promising therapeutic strategy as highlighted by recent advances in dual targeting approaches (119). This axis encompasses not only transcriptional and chromatin-level regulation but also post-translational modifications that stabilize key drivers like HIF-1α and modulate the activity of epigenetic enzymes. For instance simultaneous inhibition of CXCR4 and EZH2 more effectively reduces cell proliferation and migration in models by concurrently limiting inflammation and epigenetic dysregulation (120, 121). EZH2 inhibitors target the histone methyltransferase responsible for the repressive H3K27me3 mark, reversing the hypoxia-driven silencing of tumor suppressor genes. HDAC inhibitors counteract hypoxia induced histone deacetylation reactivating pro-apoptotic genes and suppressing CYP19A1 (122). DNMT inhibitors can reverse hypoxia-mediated hypermethylation of genes like HOXA10 and PGR potentially restoring endometrial receptivity and progesterone sensitivity (123). The herbal formulation Luoshi Neiyi Prescription attenuates the HIF 1α EZH2 SF1 axis mitigating both inflammatory and hypoxic stress demonstrating translational potential (124). Concurrently identifying robust predictive biomarkers is essential for patient stratification and enabling precision trials. Given the redundancy of epigenetic networks rational combination regimens integrating epigenetic modulators with hormonal or anti-inflammatory agents are needed for sustained efficacy. Employing advanced models is crucial to better replicate the complex hypoxic stromal immune niche of human lesions. 6 Epigenetic heterogeneity: divergent profiles among endometriosis subtypes Epidemiological data confirm stark differences in malignant transformation risk between the three subtypes. Ovarian EMs, particularly the ovarian endometrioma subtype, is specifically linked to a markedly elevated risk of endometrioid and clear-cell ovarian carcinoma. In contrast, PE and DIE show no association with an overall increased ovarian cancer risk (125). The three subtypes also have distinct genetic predisposition profiles. Whole-genome epigenetic profiling has revealed globally divergent DNA methylome landscapes, histone modification codes, and non-coding RNA expression profiles across the three core EMs subtypes. These subtype-specific epigenetic signatures are established in the early stages of lesion formation and stably maintained throughout disease progression (). Notably, lesions of different subtypes exhibit distinct epigenetic age deceleration patterns measured by Horvath’s pan-tissue epigenetic clock, further confirming subtype-specific epigenetic programming in EMs. These subtype-specific epigenetic alterations directly shape the unique pathobiological behaviors of each EMs subtype, and are closely correlated with disease progression, recurrence risk, and clinical prognosis. The epigenetic abnormalities of OE are predominantly concentrated in the regulation of genes related to steroid hormone synthesis and estrogen signaling pathways, driving the formation of a local hyperestrogenic microenvironment within lesions. In DIE, epigenetic reprogramming is mainly centered on pathways related to cell invasion, epithelial-mesenchymal transition, extracellular matrix remodeling, and fibrosis, conferring strong invasive and tissue infiltration capabilities to lesions. The epigenetic changes in PE are primarily focused on molecular pathways related to inflammatory response, cell adhesion, and ectopic colonization, mediating the survival and colonization of refluxed endometrial cells on the peritoneal surface. The most prominent epigenetic feature of PE is aberrant DNA methylation of inflammatory cytokine genes, including promoter hypomethylation of PTGS2, interleukin-6, and interleukin-8 genes. This drives sustained high expression of these pro-inflammatory factors and establishes a chronic inflammatory microenvironment that supports ectopic lesion survival (126). Unlike OE, PE lesions exhibit only mild epigenetic age deceleration, consistent with their relatively low proliferative and invasive potential (127). These subtype-specific epigenetic characteristics also determine differential responses to epigenetic-targeted interventions across EMs subtypes, forming an important molecular basis for precise stratified diagnosis, treatment, and individualized disease management. Preclinical studies have demonstrated that OE is highly sensitive to DNA methyltransferase inhibitors, which can reverse PR and HOXA10 hypermethylation and restore progesterone responsiveness in lesions. DIE shows a superior response to histone deacetylase inhibitors, which block EMT and fibrotic progression by regulating histone acetylation levels. For PE, the combination of anti-inflammatory therapy and epigenetic modulators targeting inflammatory cytokine genes has achieved significant efficacy in preclinical models (). In-depth dissection of the epigenetic heterogeneity between different EMs subtypes not only improves the systematic understanding of EMs pathogenesis, but also provides a core theoretical direction for screening subtype-specific non-invasive diagnostic biomarkers and developing targeted epigenetic therapeutic strategies. This is of great significance for addressing the unmet clinical needs in the current diagnosis and management of EMs. 7 Integrated pathogenesis of endometriosis: a cascade from epigenetic disruption to clinical phenotypes Building upon the preceding in-depth examination of DNA methylation, histone modifications, non-coding RNA (ncRNA) regulatory networks, and hypoxia signaling pathways, this review proposes a conceptual, multi-stage framework to integrate current epigenetic evidence into a coherent pathogenic scenario. It is important to emphasize that this model is presented as a working hypothesis rather than a definitively validated temporal sequence, and that direct longitudinal evidence in human endometriosis remains limited (128, 129). 7.1 Acute epigenetic stress and initial reprogramming Pathogenesis is initiated when retrograde endometrial cells encounter the lethal pelvic microenvironment characterized by hypoxia, inflammation, and iron overload. This acute stress triggers rapid and extensive epigenetic reprogramming. HIF-1α stabilization acts as the master switch for this reprogramming, swiftly recruiting and modulating histone-modifying enzymes including HDACs, HATs, and KDM4B/6A to remodel chromatin accessibility at key gene loci. Concurrently, hypoxia-sensitive miRNAs are rapidly upregulated, and lncRNAs, including HOTAIR and MALAT1 increase in expression, forming a rapid-response network that confers a preliminary survival advantage to the refluxed cells (130). This stage is characterized by reversible histone modifications and ncRNA alterations, completing the initial reprogramming of cell fate. 7.2 Epigenetic memory establishment and microenvironment remodeling Surviving cells are proposed to secrete factors epitomized by VEGF, MMPs, and IL-6, which, together with sustained hypoxia, may contribute to the establishment of a chronic pathological microenvironment. This microenvironment is hypothesized to function as a driver of further epigenetic alterations, potentially inducing more stable DNA methylation changes. Altered DNMT activity under persistent stimulation is proposed to remodel the promoter methylation status of key genes: hypermethylation and silencing of HOXA10, PR, and ESR1are hypothesized to mediate endometrial receptivity failure and progesterone resistance, whereas hypomethylation and activation of steroidogenic genes, including CYP19A1and STAR, may establish local estrogen synthesis capacity (131). The synergistic interaction between DNA methylation and histone modifications is hypothesized to consolidate transient adaptations into relatively stable epigenetic states. It remains challenging to disentangle whether these epigenetic alterations represent stable, lesion-intrinsic changes or are continuously reinforced by ongoing chronic inflammation and hypoxia. Both scenarios are likely to coexist, with microenvironmental stress and epigenetic reprogramming acting in a reciprocal, self-reinforcing manner. 7.3 Epigenetic network integration and self-sustaining circuit formation As the disease progresses, different epigenetic layers are proposed to integrate into a complex regulatory network. The circRNA system is hypothesized to emerge as a core network integrator: for instance, circPIP5K1A is reported to spongemiR-153-3p to upregulate TMSB4X and activate the TGF-β pathway, and circ_0007299 is shown to spongemiR-424-5p to upregulate CREB1 and promote proliferation. These circRNAs, together with lncRNAs and miRNAs, are proposed to forma ceRNA network that may provide regulatory redundancy, ensuring the stability of pathogenic signals. Rather than functioning as independent events, these multilayered epigenetic alterations are proposed to converge upon a limited number of high-priority biological nodes that define the core pathophysiology of endometriosis. Three fundamental convergent outcomes emerge consistently across the literature: (i) dysregulated steroid hormone biosynthesis and progesterone resistance, (ii) attenuated immune surveillance and chronic inflammation, and (iii) enhanced extracellular matrix remodeling and tissue invasiveness. Prioritizing these core nodes over exhaustive pathway enumeration provides a more tractable framework for understanding disease progression and identifying actionable therapeutic targets. At this stage, a putative positive feedback loop between aberrant epigenetic states and the pathological microenvironment is suggested to arise: epigenetic alterations may drive increased secretion of inflammatory factors, exacerbating microenvironmental abnormalities, whereas the worsened microenvironment is hypothesized to induce further epigenetic reprogramming (132). Collectively, these interactions are hypothesized to constitute a putative self-reinforcing circuit linking estrogen synthesis, inflammation, hypoxia, and epigenetic reprogramming. 7.4 Clinical phenotype diversification and disease heterogeneity manifestation Driven by anatomy-specific microenvironments, differential epigenetic adaptive programming based on the same core circuit is proposed to give rise to distinct clinical subtypes. Peritoneal lesions are hypothesized to be enriched for inflammation-related epigenetic features, ovarian lesions for metabolism- and hormone synthesis-related alterations, and deep infiltrating lesions for invasion- and nerve-related epigenetic programs. This spatiotemporal heterogeneity in epigenetic programming is hypothesized to manifest as the four core clinical phenotypes: hormone insensitivity, tissue invasiveness, angiogenesis, and immune microenvironment remodeling (133). Although certain molecular alterations, specifically hypermethylation of HOXA10 and PGR and hypoxia-driven histone modifications, are directly validated in endometriosis models, robust stage-specific molecular signatures remain to be fully defined. Current candidate biomarkers are largely derived from cross-sectional studies and do not yet allow precise assignment of lesions to a specific stage within this conceptual framework. Moreover, the overarching architecture of epigenetic memory and self-sustaining circuits is largely extrapolated from cancer biology and requires validation in the benign context of endometriosis. To systematically delineate the current state of evidence and distinguish empirically supported mechanisms from conceptual inferences, Table 2 provides a structured overview categorizing these mechanisms and therapeutic targets according to their validation status and evidence strength. Table 2 | Category | Representative Examples | Evidence Strength in EMs | References | |---|---|---|---| | Validated Mechanisms | DNA Methylation: HOXA10, PGR, ESR2 hypermethylation; CYP19A1/STAR hypomethylation; MMP2 hypomethylation. | High: Directly confirmed in human EMs tissues and functional assays. | () () () (), (),,, | | ncRNA Expression: H19, MALAT1, miR-34a, miR-126-5p dysregulation. | High: Consistently observed across multiple patient cohorts. | (89) (92) (77) (76),,, | | | Histone Modifications: Global HDAC1 overexpression; H3/H4 hypoacetylation at ESR1 promoter. | High: Observed in ectopic lesions vs. controls. | () (), | | | Hypoxia Signaling: HIF-1α stabilization and downstr eam target activation. | High: Universal feature of the EMs microenvironment. | (79) (108), | | | Speculative /Inferred Pathways | HIF-1α recruitment of epigenetic modifiers: Direct recruitment of HATs/DNMTs to steroidogenic gene promoters. | Moderate/Low: Largely inferred from cancer models; direct proof in EMs lacking. | (110) (114), | | Direct Histone Modifier Recruitment: HIF-1α recruiting KDMs for autophagy gene regulation. | Low: Based on oncology/ischemia models; not confirmed in EMs tissues. | (113) | | | Epigenetic Memory: Stable, lesion-intrinsic methylation changes vs. continuous microenvironmental reinforcement. | Moderate: Mechanistically plausible but hard to dissect in humans. | (131) | | | Self-Sustaining Circuits: Feedback loops between epigenetics and hypoxia/inflammation. | Moderate: Conceptual framework; direct longitudinal evidence limited. | (128) (129), | | | Therapeutic Targets (Preclinical) | DNMT Inhibitors: Decitabine/5-aza; reverse PGR/HOXA10 silencing. | Preclinical: Effective in cell/animal models; no large-scale RCTs in EMs. | (123) (124), | | HDAC Inhibitors: Vorinostat; suppress CYP19A1, reactivate pro-apoptotic genes. | Preclinical: Demonstrated efficacy in reducing lesion volume. | (63) (64) (122),, | | | EZH2 Inhibitors: Reverse hypoxia-driven gene silencing. | Preclinical: Dual targeting (CXCR4+EZH2) shows synergy. | (120) (121), | | | Kinase Inhibitors: p38 (SB203580), JNK1 (AS602801), LSD1 inhibitors. | Preclinical: Efficacy shown in murine models; translational hurdles remain. | (65) (66) (67),, | | | Subtype-Specific Vulnerabilities | Ovarian EMs (OE): Sensitivity to DNMT inhibitors due to methylation-driven silencing. | Emerging: Based on subtype epigenetic profiling. | () (125), | | Deep Infiltrating EMs (DIE): Sensitivity to HDAC inhibitors due to histone modification dominance. | Emerging: Requires validation in clinical settings. | () (125), | | | Peritoneal EMs (PE): Anti-inflammatory combined with epigenetic modulators. | Emerging: Preclinical efficacy demonstrated. | () (126), | Classification of key epigenetic mechanisms and therapeutic targets in endometriosis. 8 Conclusion and perspectives This review systematically elucidates that EMs represents a complex systemic pathology arising from genetic susceptibility and progressing through a dynamic interplay between pathological microenvironmental cues and multi-layered epigenetic reprogramming. The disease is fundamentally mediated by a hypoxia-initiated epigenetic cascade, wherein the concerted dysregulation of DNA methylation, histone modifications, and non-coding RNA networks collectively reshapes steroid hormone responsiveness, perpetuates inflammatory cascades, and establishes invasive phenotypes. This integrated framework explains the temporal progression from initial lesion establishment to stable, heterogeneous clinical manifestations. Based on the synthesized evidence, we propose a coherent four-stage progression model that encapsulates the pathogenesis: initial hypoxia-driven reprogramming, establishment of stable epigenetic memory, formation of self-sustaining regulatory networks, and ultimate phenotypic diversification. This model provides a scaffold for understanding the transition from acute cellular adaptation to chronic disease state, offering a mechanistic basis for the clinical heterogeneity observed across different endometriosis subtypes (128). The inherent reversibility of epigenetic modifications presents unique therapeutic opportunities that align with our stage-specific pathogenesis model. Emerging therapeutic modalities, including CRISPR-based epigenetic editing, nanoparticle-delivered RNA therapeutics, and dual-pathway inhibitors, show particularly promising for overcoming current treatment3limitations. Statements Author contributions YYZ: Writing – original draft, Writing – review & editing. YTZ: Writing – original draft. HW: Writing – review & editing. WH: Writing – original draft. JD: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – review & editing. Funding The author(s) declared that financial support was received for this work and/or its publication. This study was supported by grants from the Natural Science Foundation of Sichuan Province (Grant No. 2024NSFSC1825); Medical Research Project of the Health Commission of Sichuan Province (Grant No. 24QNMP002) and Medical Research Project of the Health Commission of Chengdu (Grant No. 202317033292). Acknowledgments We sincerely thank the collaborators for their contributions to the publications cited in this field. Conflict of interest The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Generative AI statement The author(s) declared that generative AI was not used in the creation of this manuscript. Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. 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1 KrentelHDe WildeRLde WildeMS. Recent advances and clinical outcomes of endometriosis. J Clin Med. (2025) 14:798. doi: 10.3390/jcm14030798 2 MuraokaAYokoiAKajiyamaH. Emerging bacterial factors for understanding pathogenesis of endometriosis. iScience. (2024) 27:108739. doi: 10.1016/j.isci.2023.108739 3 MortlockSHoushdaranSKostiIRahmiogluNNezhatCVitonisAFet al. Global endometrial DNA methylation analysis reveals insights into mQTL regulation and associated endometriosis disease risk and endometrial function. Commun Biol. (2023) 6:780. doi: 10.1038/s42003-023-05070-z 4 FarsettiAIlliBGaetanoC. How epigenetics impacts on human diseases. Eur J Internal Med. (2023) 114:15–22. doi: 10.1016/j.ejim.2023.05.036 5 BureIVNemtsovaMVKuznetsovaEB. Histone modifications and non-coding RNAs: Mutual epigenetic regulation and role in pathogenesis. Int J Mol Sci. (2022) 23:5801. doi: 10.3390/ijms23105801 6 YangZXuFTeschendorffAEZhaoYYaoLLiJet al. Insights into the role of long non-coding RNAs in DNA methylation mediated transcriptional regulation. Front Mol Biosci. (2022) 9:1067406. doi: 10.3389/fmolb.2022.1067406 7 JalouliM. Emerging role of hypoxia-inducible factors (HIFs) in modulating autophagy: Perspectives on cancer therapy. Int J Mol Sci. (2025) 26:1752. doi: 10.3390/ijms26041752 8 ZhangPChengSShengXDaiHHeKDuY. The role of autophagy in regulating metabolism in the tumor microenvironment. Genes Dis. (2023) 10:447–56. doi: 10.1016/j.gendis.2021.10.010 9 MaXChenXMuXCaoMZhangY. Epigenetics of maternal-fetal interface immune microenvironment and placental related pregnancy complications. Front Immunol. (2025) 16. doi: 10.3389/fimmu.2025.1549839 10 AdetunjiAOOwusuHAdewaleEFAdesinaPAXedzroCSaliuTPet al. DNA methylation: A key regulator in male and female reproductive outcomes. Life. (2025) 15:1109. doi: 10.3390/life15071109 11 AdamczykMRawłuszko-WieczorekAWirstleinPNowackaMNowickiMJagodzińskiPPet al. H3K27me3-mediated epigenetic regulation of TET1 in the eutopic endometrium of women with endometriosis and infertility. Sci Rep. (2025) 15:29282. doi: 10.1038/s41598-025-13618-8 12 ErrajiHEl GhanmiALouanjliNBenahmedMEl MansouriFZarqaouiMet al. Leveraging epigenetic aberrations in the pathogenesis of endometriosis: From DNA methylation to non-coding RNAs. Front Genet. (2025) 16. doi: 10.3389/fgene.2025.1597287 13 OuYWangHZhouCChenYLyuJFengMet al. Endometriosis-associated infertility: Multi-omics insights into pathogenesis and precision therapeutics. Front Endocrinol. (2025) 16. doi: 10.3389/fendo.2025.1613334 14 KudlayDKiselevVSukhikhG. HOXA10 and HOXA11 methylation: Epigenetic barriers to endometrial receptivity in ART. Genes (Basel). (2025) 16:1230. doi: 10.3390/genes16101230 15 VannucciniSClemenzaSRossiMPetragliaF. Hormonal treatments for endometriosis: The endocrine background. Rev Endocr Metab Disord. (2021) 23:333. doi: 10.1007/s11154-021-09666-w 16 ZhuJXuZWuPZengCPengCZhouYet al. MicroRNA-92a-3p inhibits cell proliferation and invasion by regulating the transcription factor 21/steroidogenic factor 1 axis in endometriosis. Reprod Sci. (2023) 30:2188–97. doi: 10.1007/s43032-021-00734-9 17 ChantalatEValeraM-CVaysseCNoirritERusidzeMWeylAet al. Estrogen receptors and endometriosis. Int J Mol Sci. (2020) 21:2815. doi: 10.3390/ijms21082815 18 BernardiLADysonMTTokunagaHSisonCOralMRobinsJCet al. The essential role of GATA6 in the activation of estrogen synthesis in endometriosis. Reprod Sci. (2019) 26:60–9. doi: 10.1177/1933719118756751 19 SasakiKHaraSYamakamiRSatoYHasegawaSKonoTet al. Ectopic expression of DNA methyltransferases DNMT3A2 and DNMT3L leads to aberrant hypermethylation and postnatal lethality in mice. Mol Reprod Dev. (2019) 86:614. doi: 10.1002/mrd.23137 20 IzawaMTaniguchiFHaradaT. GATA6 expression promoted by an active enhancer may become a molecular marker in endometriosis lesions. Am J Reprod Immunol. (2019) 81:e13078. doi: 10.1111/aji.13078 21 ChenHMalentacchiFFambriniMHarrathAHHuangHPetragliaF. Epigenetics of estrogen and progesterone receptors in endometriosis. Reprod Sci. (2020) 27:1967–74. doi: 10.1007/s43032-020-00226-2 22 BedrickBSCourtrightLZhangJSnowMAmendolaILSNylanderEet al. A systematic review of epigenetics of endometriosis. F S Rev. (2024) 5:100070. doi: 10.1016/j.xfnr.2024.01.003 23 HanSJJungSYWuS-PHawkinsSMParkMJKyoSet al. Estrogen receptor β modulates apoptosis complexes and the inflammasome to drive the pathogenesis of endometriosis. Cell. (2015) 163:960–74. doi: 10.1016/j.cell.2015.10.034 24 KalkanUBiyikISimsekS. T-cadherin, E-cadherin, PR-A, and ER-α levels in deep infiltrating endometriosis. Int J Gynecol Pathol. (2022) 41:593–9. doi: 10.1097/PGP.0000000000000860 25 Rocha-JuniorCVDa BroiMGMiranda-FurtadoCLNavarroPAFerrianiRAMeolaJ. Progesterone receptor B (PGR-B) is partially methylated in eutopic endometrium from infertile women with endometriosis. Reprod Sci (thousand Oaks Calif). (2019) 26:1568–74. doi: 10.1177/1933719119828078 26 BogdanovicOVermeulenM. Correction to: TET proteins and DNA demethylation. Methods Mol Biol. (2021) 2272:C1. doi: 10.1007/978-1-0716-1294-1_18 27 WuHD’AlessioACItoSXiaKWangZCuiKet al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature. (2011) 473:389–93. doi: 10.1038/nature09934 28 AdamczykMRawłuszko-WieczorekAAWirstleinPNowickiMJagodzińskiPPWender-OzegowskaEet al. Assessment of TET1 gene expression, DNA methylation and H3K27me3 level of its promoter region in eutopic endometrium of women with endometriosis and infertility. BioMed Pharmacother. (2022) 150:112989. doi: 10.1016/j.biopha.2022.112989 29 TarkiSEFarISAminimoghaddamSFooladiBSarhangiNFarahaniMSet al. Investigating the association of matrix metalloproteinase-2 gene variants with endometriosis in an Iranian population. Eur J Obstet Gynecol Reprod Biol. (2021) 258:353–7. doi: 10.1016/j.ejogrb.2020.12.013 30 TangLXiangYZhouYMuJZaiMXingQet al. The DNA methylation status of genes encoding matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in endometriosis. Mol Reprod Dev. (2018) 85:17–25. doi: 10.1002/mrd.22931 31 EsfandiariFChitsazianFJahromiMGFavaediRBazrgarMAflatoonianRet al. HOX cluster and their cofactors showed an altered expression pattern in eutopic and ectopic endometriosis tissues. Reprod Biol Endocrinol. (2021) 19:132. doi: 10.1186/s12958-021-00816-y 32 LazimNEliasMHSutajiZAbdul KarimAKAbuMAUgusmanAet al. Expression of HOXA10 gene in women with endometriosis: A systematic review. Int J Mol Sci. (2023) 24:12869. doi: 10.3390/ijms241612869 33 MishraAModiD. Role of HOXA10 in pathologies of the endometrium. Rev Endocr Metab Disord. (2025) 26:81–96. doi: 10.1007/s11154-024-09923-8 34 EkanayakeDLMałopolskaMMSchwarzTTuzRBartlewskiPM. The roles and expression of HOXA/Hoxa10 gene: A prospective marker of mammalian female fertility? Reprod Biol. (2022) 22:100647. doi: 10.1016/j.repbio.2022.100647 35 MengWHuebnerAShabsighAChakravartiALautenschlaegerT. Combined RASSF1A and RASSF2A promoter methylation analysis as diagnostic biomarker for bladder cancer. Mol Biol Int. (2012) 2012:1–8. doi: 10.1155/2012/701814 36 QinYLiYHaoYLiYKangS. Hypomethylation of the ENPP3 promoter region contributes to the occurrence and development of ovarian endometriosis via the AKT/mTOR/4EBP1 signaling pathway. Biomol BioMed. (2024) 24:848–56. doi: 10.17305/bb.2023.9989 37 AgborbesongELiLXLiLLiX. Molecular mechanisms of epigenetic regulation, inflammation, and cell death in ADPKD. Front Mol Biosci. (2022) 9:922428. doi: 10.3389/fmolb.2022.922428 38 AshishAMishraSRaiSKusumKRaiGSinghRet al. Advances in endometriosis research: From pathogenesis to prevention. In: A Comprehensive Overview of Endometriosis. London: IntechOpen (2024). doi: 10.5772/intechopen.1007830 39 LiuYFengWWangYWuB. Crosstalk between protein post-translational modifications and phase separation. Cell Commun Signaling. (2024) 22:110. doi: 10.1186/s12964-023-01380-1 40 DoughtyBRHinksMMSchaepeJMMarinovGKThurmARRios-MartinezCet al. Single-molecule states link transcription factor binding to gene expression. Nature. (2024) 636:745–54. doi: 10.1038/s41586-024-08219-w 41 PsilopatisIVrettouKFleckensteinFNTheocharisS. The impact of histone modifications in endometriosis highlights new therapeutic opportunities. Cells. (2023) 12:1227. doi: 10.3390/cells12091227 42 SmolarzBSzyłłoKRomanowiczH. The genetic background of endometriosis: Can ESR2 and CYP19A1 genes be a potential risk factor for its development? Int J Mol Sci. (2020) 21:8235. doi: 10.3390/ijms21218235 43 BahlSLingHAcharigeNPNSantos-BarriopedroIPflumMKHSetoE. EGFR phosphorylates HDAC1 to regulate its expression and anti-apoptotic function. Cell Death Dis. (2021) 12:1–17. doi: 10.1038/s41419-021-03697-6 44 LuoLZhaoLCuiLPengCOuSZengYet al. The roles of chromatin regulatory factors in endometriosis. J Assist Reprod Genet. (2024) 41:863–73. doi: 10.1007/s10815-024-03026-8 45 ZhangPWangG. Progesterone resistance in endometriosis: Current evidence and putative mechanisms. Int J Mol Sci. (2023) 24:6992. doi: 10.3390/ijms24086992 46 MilazzoGMercatelliDDi MuzioGTriboliLDe RosaPPeriniGet al. Histone deacetylases (HDACs): Evolution, specificity, role in transcriptional complexes, and pharmacological actionability. Genes (Basel). (2020) 11:556. doi: 10.3390/genes11050556 47 BarskeTHagemannM. The regulatory impact of serine/threonine-specific protein phosphorylation among cyanobacteria. Front Plant Sci. (2025) 16:1540914. doi: 10.3389/fpls.2025.1540914 48 LangFRajaxavierJSinghYBruckerSYSalkerMS. The enigmatic role of serum & glucocorticoid inducible kinase 1 in the endometrium. Front Cell Dev Biol. (2020) 8:556543. doi: 10.3389/fcell.2020.556543 49 HuLZhangJLuYFuBHuW. Estrogen receptor beta promotes endometriosis progression by upregulating CD47 expression in ectopic endometrial stromal cells. J Reprod Immunol. (2022) 151:103513. doi: 10.1016/j.jri.2022.103513 50 ZhuRYangGCaoZShenKZhengLXiaoJet al. The prospect of serum and glucocorticoid-inducible kinase 1 (SGK1) in cancer therapy: A rising star. Ther Adv Med Oncol. (2020) 12:1758835920940946. doi: 10.1177/1758835920940946 51 FengPLuoLYangQMengWGuanZLiZet al. Hippo kinases Mst1 and Mst2 maintain NK cell homeostasis by orchestrating metabolic state and transcriptional activity. Cell Death Dis. (2024) 15:1–15. doi: 10.1038/s41419-024-06828-x 52 ZhaoQYeMYangWWangMLiMGuCet al. Effect of Mst1 on endometriosis apoptosis and migration: Role of Drp1-related mitochondrial fission and Parkin-required mitophagy. Cell Physiol Biochem. (2018) 45:1172–90. doi: 10.1159/000487450 53 AdamczykMWender-OzegowskaEKedziaM. Epigenetic factors in eutopic endometrium in women with endometriosis and infertility. Int J Mol Sci. (2022) 23:3804. doi: 10.3390/ijms23073804 54 NezhatCROskotskyTTRobinsonJFFisherSJTsueiALiuBet al. Real world perspectives on endometriosis disease phenotyping through surgery, omics, health data, and artificial intelligence. NPJ Womens Health. (2025) 3:1–16. doi: 10.1038/s44294-024-00052-w 55 KotlyarAMMamillapalliRFloresVATaylorHS. Tofacitinib alters STAT3 signaling and leads to endometriosis lesion regression. Mol Hum Reprod. (2021) 27:gaab016. doi: 10.1093/molehr/gaab016 56 TianMLiXYuLQianJBaiXYangJet al. Glycosylation as an intricate post-translational modification process takes part in glycoproteins related immunity. Cell Commun Signaling. (2025) 23:214. doi: 10.1186/s12964-025-02216-w 57 McLaughlinJESantosMTBinkleyPASultanaMTekmalRRSchenkenRSet al. Inhibition of hyaluronic acid synthesis decreases endometrial cell attachment, migration, and invasion. Reprod Sci. (2020) 27:1058–63. doi: 10.1007/s43032-019-00100-w 58 KocurkovaANesporovaKSandanusovaMKerberovaMLehkaKVelebnyVet al. Endogenously-produced hyaluronan and its potential to regulate the development of peritoneal adhesions. Biomolecules. (2021) 12:45. doi: 10.3390/biom12010045 59 ChenSZhangALiNWuHLiYLiuSet al. Elevated high-mannose N-glycans hamper endometrial decidualization. iScience. (2023) 26:108170. doi: 10.1016/j.isci.2023.108170 60 ArkinsonCDongKCGeeCLMartinA. Mechanisms and regulation of substrate degradation by the 26S proteasome. Nat Rev Mol Cell Biol. (2025) 26:104–22. doi: 10.1038/s41580-024-00778-0 61 YangXYanKZhanQChenHPeiC-ZZhuL. Exploration of diagnostic deubiquitinating enzymes in endometriosis and its immune infiltration. Biochem Genet. (2024) 62:4359–79. doi: 10.1007/s10528-023-10653-w 62 LeeC-SKimSHwangGSongJ. Deubiquitinases: Modulators of different types of regulated cell death. Int J Mol Sci. (2021) 22:4352. doi: 10.3390/ijms22094352 63 SanaeiMKavoosiF. Histone deacetylases and histone deacetylase inhibitors: Molecular mechanisms of action in various cancers. Adv BioMed Res. (2019) 8:63. doi: 10.4103/abr.abr_142_19 64 GujralPMahajanVLissamanACPonnampalamAP. Histone acetylation and the role of histone deacetylases in normal cyclic endometrium. Reprod Biol Endocrinol. (2020) 18:84. doi: 10.1186/s12958-020-00637-5 65 BoraGYabaA. The role of mitogen-activated protein kinase signaling pathway in endometriosis. J Obstet Gynaecol Res. (2021) 47:1610–23. doi: 10.1111/jog.14710 66 LiZSunCTaoSOsunkoyaAOArnoldRSPetrosJAet al. The JNK inhibitor AS602801 synergizes with enzalutamide to kill prostate cancer cells in vitro and in vivo and inhibit androgen receptor expression. Transl Oncol. (2020) 13:100751. doi: 10.1016/j.tranon.2020.100751 67 CuiLSangCLiRZhaoS. Inhibition of lysine-specific histone demethylase 1A suppresses adenomyosis through reduction in ectopic endometrial stromal cell proliferation, migration, and invasion. Cytojournal. (2024) 21:50. doi: 10.25259/Cytojournal_48_2024 68 BegumMIAChuanLHongS-TChaeH-S. The pathological role of miRNAs in endometriosis. Biomedicines. (2023) 11:3087. doi: 10.3390/biomedicines11113087 69 HonJ-XWahabNAKarimAKAMokhtarNMMokhtarMH. MicroRNAs in endometriosis: Insights into inflammation and progesterone resistance. Int J Mol Sci. (2023) 24:15001. doi: 10.3390/ijms241915001 70 GuJLiYTianYZhangYChengYTangY. Noncanonical functions of microRNAs in the nucleus. Acta Biochim Biophys Sin (Shanghai). (2024) 56:151–61. doi: 10.3724/abbs.2023268 71 BilliMDe MarinisEGentileMNerviCGrignaniF. Nuclear miRNAs: Gene regulation activities. Int J Mol Sci. (2024) 25:6066. doi: 10.3390/ijms25116066 72 EngelAWagnerVHahnOFoltzAGAtkinsMBeganovicAet al. A spatio-temporal brain miRNA expression atlas identifies sex-independent age-related microglial driven miR-155-5p increase. Nat Commun. (2025) 16:4588. doi: 10.1038/s41467-025-59860-6 73 SuNYuXDuanMShiN. Recent advances in methylation modifications of microRNA. Genes Dis. (2025) 12:101201. doi: 10.1016/j.gendis.2023.101201 74 ZhangZLiHZhaoZGaoBMengLFengX. miR-146b level and variants is associated with endometriosis related macrophages phenotype and plays a pivotal role in the endometriotic pain symptom. Taiwan J Obstet Gynecol. (2019) 58:401–8. doi: 10.1016/j.tjog.2018.12.003 75 NematianSEMamillapalliRKadakiaTSMajidi ZolbinMMoustafaSTaylorHS. Systemic inflammation induced by microRNAs: endometriosis-derived alterations in circulating microRNA 125b-5p and let-7b-5p regulate macrophage cytokine production. J Clin Endocrinol Metab. (2018) 103:64–74. doi: 10.1210/jc.2017-01199 76 MengXLiuJWangHChenPWangD. MicroRNA-126-5p downregulates BCAR3 expression to promote cell migration and invasion in endometriosis. Mol Cell Endocrinol. (2019) 494:110486. doi: 10.1016/j.mce.2019.110486 77 RezkNALashinMBSabbahNA. MiRNA 34-a regulate SIRT-1 and Foxo-1 expression in endometriosis. Non-coding RNA Res. (2021) 6:35–41. doi: 10.1016/j.ncrna.2021.02.002 78 DongreAWeinbergRA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. (2019) 20:69–84. doi: 10.1038/s41580-018-0080-4 79 DaiWGuoRNaXJiangSLiangJGuoCet al. Hypoxia and the endometrium: An indispensable role for HIF-1α as therapeutic strategies. Redox Biol. (2024) 73:103205. doi: 10.1016/j.redox.2024.103205 80 WangDLuoYWangGYangQ. CircATRNL1 promotes epithelial-mesenchymal transition in endometriosis by upregulating Yes-associated protein 1 in vitro. Cell Death Dis. (2020) 11:594. doi: 10.1038/s41419-020-02784-4 81 ZhangMRenCXiaoYXiaXFangX. Expression profile analysis of circular RNAs in ovarian endometriosis by microarray and bioinformatics. Med Sci Monit. (2018) 24:9240–50. doi: 10.12659/MSM.913885 82 JiangNPanWLiJCaoTShenH. Upregulated circular RNA hsa_circ_0008433 regulates pathogenesis in endometriosis via miRNA. Reprod Sci. (2020) 27:2002–17. doi: 10.1007/s43032-020-00219-1 83 DelbandiA-AMahmoudiMShervinAHeidariSKolahdouz-MohammadiRZarnaniA-H. Evaluation of apoptosis and angiogenesis in ectopic and eutopic stromal cells of patients with endometriosis compared to non-endometriotic controls. BMC Womens Health. (2020) 20:3. doi: 10.1186/s12905-019-0865-4 84 LiuDLiangYChenMYangFYaoS. Knockdown of circ_0075503 suppresses cell migration and invasion by regulating miR-15a-5p and KLF12 in endometriosis. Mol Cell Biochem. (2021) 476:3845–56. doi: 10.1007/s11010-021-04202-5 85 ZhangYYanJPanX. miR-141-3p affects apoptosis and migration of endometrial stromal cells by targeting KLF-12. Pflugers Arch. (2019) 471:1055–63. doi: 10.1007/s00424-019-02283-2 86 LiQLiNLiuHDuYHeHZhangLet al. Estrogen-decreased hsa_circ_0001649 promotes stromal cell invasion in endometriosis. Reproduction. (2020) 160:511–9. doi: 10.1530/REP-19-0540 87 XuKChenYLiSChenLHuangX. Circ_0004712 promotes endometriotic epithelial cell proliferation, migration and invasion by regulating miR-488-3p/ROCK1 axis in vitro. Reprod Biol. (2022) 22:100667. doi: 10.1016/j.repbio.2022.100667 88 WuJLiLXuWXiaXWuY. Circular RNAs in the pathogenesis of SARS-CoV-2: Potential diagnostic biomarkers and therapeutic targets. Funct Integr Genomics. (2025) 25:4. doi: 10.1007/s10142-024-01509-6 89 PengYGuoRShiBLiD. The role of long non-coding RNA H19 in infertility. Cell Death Discov. (2023) 9:1–7. doi: 10.1038/s41420-023-01567-y 90 XiaYPeiTZhaoJWangZShenYYangYet al. Long noncoding RNA H19: Functions and mechanisms in regulating programmed cell death in cancer. Cell Death Discov. (2024) 10:1–13. doi: 10.1038/s41420-024-01832-8 91 BaoQZhengQWangSTangWZhangB. LncRNA HOTAIR regulates cell invasion and migration in endometriosis through miR-519b-3p/PRRG4 pathway. Front Oncol. (2022) 12:953055. doi: 10.3389/fonc.2022.953055 92 TanKMoHGuoLWangB. MALAT1 accelerates proliferation and inflammation and suppresses apoptosis of endometrial stromal cells via the microRNA-142-3p/CXCR7 axis. Reprod Biol. (2022) 22:100675. doi: 10.1016/j.repbio.2022.100675 93 LiLYeKWangD. Upregulation of HTRA1 mediated by the lncRNA NEAT1/miR-141-3p axis contributes to endometriosis development through activating NLRP3 inflammasome-mediated pyroptotic cell death and cellular inflammation. In Vitro Cell Dev Biol Anim. (2023) 59:166–78. doi: 10.1007/s11626-023-00760-8 94 XiongFZhuKDengSHuangHYangLGongZet al. AFAP1-AS1: A rising star among oncogenic long non-coding RNAs. Sci China Life Sci. (2021) 64:1602–11. doi: 10.1007/s11427-020-1874-6 95 HuanQChengS-CDuZ-HMaH-FLiC. LncRNA AFAP1-AS1 regulates proliferation and apoptosis of endometriosis through activating STAT3/TGF-β/Smad signaling via miR-424-5p. J Obstet Gynaecol Res. (2021) 47:2394–405. doi: 10.1111/jog.14801 96 JinXFengJChengX. LncRNA IGF2-AS promotes endometriosis progression through targeting miR-370-3p/IGF2 axis and activating PI3K/AKT/mTOR signaling pathway. J Assist Reprod Genet. (2022) 39:2699–710. doi: 10.1007/s10815-022-02638-2 97 GhazalSMcKinnonBZhouJMuellerMMenYYangLet al. H19 lncRNA alters stromal cell growth via IGF signaling in the endometrium of women with endometriosis. EMBO Mol Med. (2015) 7:996–1003. doi: 10.15252/emmm.201505245 98 LiuSQiuJTangXCuiHZhangQYangQ. LncRNA-H19 regulates cell proliferation and invasion of ectopic endometrium by targeting ITGB3 via modulating miR-124-3p. Exp Cell Res. (2019) 381:215–22. doi: 10.1016/j.yexcr.2019.05.010 99 LiuZLiuLZhongYCaiMGaoJTanCet al. LncRNA H19 over-expression inhibited Th17 cell differentiation to relieve endometriosis through miR-342-3p/IER3 pathway. Cell Biosci. (2019) 9:84. doi: 10.1186/s13578-019-0346-3 100 WangSYiMZhangXZhangTJiangLCaoLet al. Effects of CDKN2B-AS1 on cellular proliferation, invasion and AKT3 expression are attenuated by miR-424-5p in a model of ovarian endometriosis. Reprod BioMed Online. (2021) 42:1057–66. doi: 10.1016/j.rbmo.2021.02.004 101 CuiLChenSWangDYangQ. LINC01116 promotes proliferation and migration of endometrial stromal cells by targeting FOXP1 via sponging miR‐9‐5p in endometriosis. J Cell Mol Med. (2021) 25:2000–12. doi: 10.1111/jcmm.16039 102 HudsonQJProestlingKPerricosAKuesselLHussleinHWenzlRet al. The role of long non-coding RNAs in endometriosis. Int J Mol Sci. (2021) 22:11425. doi: 10.3390/ijms222111425 103 SharmaASinghPJhaRAlmatroodiSAAlrumaihiFRahmaniAHet al. Exploring the role of miR-200 family in regulating CX3CR1 and CXCR1 in lung adenocarcinoma tumor microenvironment: implications for therapeutic intervention. Sci Rep. (2023) 13:16333. doi: 10.1038/s41598-023-43484-1 104 BaiJWangBWangTRenW. Identification of functional lncRNAs associated with ovarian endometriosis based on a ceRNA network. Front Genet. (2021) 12:534054. doi: 10.3389/fgene.2021.534054 105 WangYLiYYangZLiuKWangD. Genome-wide microarray analysis of long non-coding RNAs in eutopic secretory endometrium with endometriosis. Cell Physiol Biochem. (2015) 37:2231–45. doi: 10.1159/000438579 106 NazariMBabakhanzadehEMollazadehAAhmadzadeMMohammadi SoleimaniEHajimaqsoudiE. HOTAIR in cancer: diagnostic, prognostic, and therapeutic perspectives. Cancer Cell Int. (2024) 24:415. doi: 10.1186/s12935-024-03612-x 107 XuJWangXZhuCWangK. A review of current evidence about lncRNA MEG3: a tumor suppressor in multiple cancers. Front Cell Dev Biol. (2022) 10:997633. doi: 10.3389/fcell.2022.997633 108 ZhouYJinYWangYWuR. Hypoxia activates the unfolded protein response signaling network: an adaptive mechanism for endometriosis. Front Endocrinol (Lausanne). (2022) 13:945578. doi: 10.3389/fendo.2022.945578 109 ChenP-SChiuW-THsuP-LLinS-CPengI-CWangC-Yet al. Pathophysiological implications of hypoxia in human diseases. J BioMed Sci. (2020) 27:63. doi: 10.1186/s12929-020-00658-7 110 BenakDAlanovaPHolzerovaKChalupovaMOpletalovaBKolarFet al. Epitranscriptomic regulation of HIF-1: bidirectional regulatory pathways. Mol Med. (2025) 31:105. doi: 10.1186/s10020-025-01149-x 111 WuM-HLinS-CHsiaoK-YTsaiS-J. Hypoxia-inhibited dual-specificity phosphatase-2 expression in endometriotic cells regulates cyclooxygenase-2 expression. J Pathol. (2011) 225:390–400. doi: 10.1002/path.2963 112 KobayashiHImanakaSYoshimotoCMatsubaraSShigetomiH. Molecular mechanism of autophagy and apoptosis in endometriosis: current understanding and future research directions. Reprod Med Biol. (2024) 23:e12577. doi: 10.1002/rmb2.12577 113 PizzimentiCFiorentinoVRuggeriCFranChinaMErcoliATuccariGet al. Autophagy involvement in non-neoplastic and neoplastic endometrial pathology: the state of the art with a focus on carcinoma. Int J Mol Sci. (2024) 25:12118. doi: 10.3390/ijms252212118 114 ZhangJYaoMXiaSZengFLiuQ. Systematic and comprehensive insights into HIF-1 stabilization under normoxic conditions: implications for cellular adaptation and therapeutic strategies in cancer. Cell Mol Biol Lett. (2025) 30:2. doi: 10.1186/s11658-024-00682-7 115 WlodarczykJLengAAbadchiSNShababiNMokhtari-EsbuieFGheshlaghiSet al. Transfection of hypoxia-inducible factor-1α mRNA upregulates the expression of genes encoding angiogenic growth factors. Sci Rep. (2024) 14:6738. doi: 10.1038/s41598-024-54941-w 116 BoCWangY. Angiogenesis signaling in endometriosis: molecules, diagnosis and treatment (review). Mol Med Rep. (2024) 29:43. doi: 10.3892/mmr.2024.13167 117 ParkKBKimEYChinHYoonDJJunK-H. Leptin stimulates migration and invasion and maintains cancer stem-like properties in gastric cancer cells. Oncol Rep. (2022) 48:1–10. doi: 10.3892/or.2022.8377 118 MonaciSCoppolaFFilippiIFalsiniACarraroFNaldiniA. Targeting hypoxia signaling pathways in angiogenesis. Front Physiol. (2024) 15:1408750. doi: 10.3389/fphys.2024.1408750 119 YooJ-YKuBJKimTHIl AhnJAhnJYYangWSet al. β-catenin activates TGF-β-induced epithelial–mesenchymal transition in adenomyosis. Exp Mol Med. (2020) 52:1754–65. doi: 10.1038/s12276-020-00514-6 120 QiQLiuXZhangQGuoS-W. Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells. Sci Rep. (2020) 10:1281. doi: 10.1038/s41598-020-57997-6 121 GuoQJinYChenXYeXShenXLinMet al. NF-κB in biology and targeted therapy: new insights and translational implications. Sig Transduct Target Ther. (2024) 9:53. doi: 10.1038/s41392-024-01757-9 122 Bora-SinghalNSahaBMohankumarDPadmanabhanJCoppolaDChellappanS. A novel PHD2/VHL-mediated regulation of YAP1 contributes to VEGF expression and angiogenesis. Cancer Res Commun. (2022) 2:624–38. doi: 10.1158/2767-9764.CRC-21-0084 123 LinS-CLiW-NLinS-CHouH-TTsaiY-CLinT-Cet al. Targeting YAP1 ameliorates progesterone resistance in endometriosis. Hum Reprod. (2023) 38:1124–34. doi: 10.1093/humrep/dead071 124 WuLLanDSunBSuRPeiFKuangZet al. Luoshi Neiyi Prescription inhibits estradiol synthesis and inflammation in endometriosis through the HIF1A/EZH2/SF-1 pathway. J Ethnopharmacol. (2024) 335:118659. doi: 10.1016/j.jep.2024.118659 125 PejovicTCathcartAMAlwaqfiRBrooksMNKelsallRNezhatFR. Genetic links between endometriosis and endometriosis-associated ovarian cancer—a narrative review (Endometriosis-Associated Cancer). Life (Basel). (2024) 14:704. doi: 10.3390/life14060704 126 ZubrzyckaAZubrzyckiMPerdasEZubrzyckaM. Genetic, epigenetic, and steroidogenic modulation mechanisms in endometriosis. J Clin Med. (2020) 9:1309. doi: 10.3390/jcm9051309 127 LeapKYotovaIHorvathSMartinez-AgostoJA. Epigenetic age provides insight into tissue origin in endometriosis. Sci Rep. (2022) 12:21281. doi: 10.1038/s41598-022-25416-7 128 ZhangS-YZhangL-YWenRYangNZhangT-N. Histone deacetylases and their inhibitors in inflammatory diseases. BioMed Pharmacother. (2024) 179:117295. doi: 10.1016/j.biopha.2024.117295 129 SemenzaGL. Hypoxia-inducible factor 1: control of oxygen homeostasis in health and disease. Pediatr Res. (2001) 49:614–7. doi: 10.1203/00006450-200105000-00002 130 CevikECMamillapalliRSferruzzaGMamillapalliPTaylorHS. Epigenetic biomarkers of progestin-resistance in endometriosis. biomark Res. (2026) 14:32. doi: 10.1186/s40364-026-00907-1 131 HisrichBVYoungRBSansoneAMBowensZGreenLJLesseyBAet al. Role of human galectins in inflammation and cancers associated with endometriosis. Biomolecules. (2020) 10:230. doi: 10.3390/biom10020230 132 ChandrakanthAFirdousSVasantharekhaRSantoshWSeetharamanB. Exploring the effects of endocrine-disrupting chemicals and miRNA expression in the pathogenesis of endometriosis by unveiling the pathways: a systematic review. Reprod Sci. (2024) 31:932–41. doi: 10.1007/s43032-023-01412-8 133 SzubertMGabrielIRycerzAGolińskaMWilczyńskiJR. MicroRNA expression profile in endometriosis and endometriosis-associated ovarian cancer—systematic review. Cells. (2026) 15:374. doi: 10.3390/cells15040374 Summary

DNA methylation, endometriosis, epigenetics, hypoxia, non-coding RNA, post-translational modification, therapeutic targets Citation Zhang Y, Zhan Y, Wu H, Huang W and Du J (2026) The hypoxia-epigenetics-ncRNA axis in endometriosis: from molecular cascades to self-sustaining pathogenic circuits. Front. Endocrinol. 17:1873599. doi: 10.3389/fendo.2026.1873599 Received 06 May 2026 Revised 04 June 2026 Accepted 08 June 2026 Published 26 June 2026 Volume 17 - 2026 Edited by Sudhir Kumar, Emory University, United States Reviewed by Alok Kumar, University of Pittsburgh, United States Deepali Luthra, Stanford University, United States Updates Copyright © 2026 Zhang, Zhan, Wu, Huang and Du. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Juan Du, [email protected] †These authors have contributed equally to this work Disclaimer All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.