Cellular Phenotypic Changes in Endometriosis: Pathogenetic Mechanisms and Therapeutic Implications

Endometriosis is a common gynecological disorder characterized by extra-uterine growth of endometrial-like tissues, which causes chronic inflammation, pelvic pain and infertility and greatly impairs patients’ quality of life. Despite its high prevalence, the exact pathogenesis of endometriosis remains incompletely understood and clinical therapeutic options are still limited. This paper is a combined narrative-bibliometric review. It systematically summarizes the roles and molecular mechanisms of multiple cellular phenotypic alterations including hypoxic microenvironment, aberrant cell proliferation, dysregulated autophagy, pyroptosis, ferroptosis and epithelial-mesenchymal transition (EMT) in the pathogenesis of endometriosis. Bibliometric analyses were performed based on the Web of Science Core Collection for each sub-theme, with dozens to hundreds of English-language publications included to assist in identifying research hotspots. By integrating evidence from in-vitro cellular experiments, animal models and human tissue studies, this review illustrates the interconnections among these cellular phenotypes, provides theoretical references for understanding the pathophysiology of endometriosis, and discusses corresponding translational and therapeutic implications.

endometriosis, hypoxia, cell proliferation, autophagy, pyroptosis, ferroptosis, epithelial-mesenchymal transition

Endometriosis (EMS) is an estrogen-dependent chronic gynecological disorder prevalent among reproductive-age women. It is defined by the growth, invasion and cyclic bleeding of functional endometrial-like tissues outside the uterine cavity, which may result in pain and even infertility. Lesions are most frequently located in the ovaries and uterosacral ligaments but can invade multiple organs across the human body. Its prevalence ranges from 5%–15% among reproductive-age women globally, approximately 10% in Chinese reproductive-age women, and rises to 30%–45% among infertile women. It constitutes a chronic disease that severely impairs social, occupational and psychological well-being. Sampson’s retrograde menstruation hypothesis is widely accepted but cannot fully interpret the heterogeneous clinical manifestations of endometriosis. More than 90% of women experience retrograde menstruation during menstruation, yet only approximately 10% develop endometriosis, indicating that additional determinants govern disease progression. Academician Lang Jinghe proposed the “eutopic endometrium-determinant theory”: whether endometrial fragments from retrograde menstruation can adhere, invade and grow in ectopic sites is predominantly determined by the intrinsic properties of eutopic endometrium. Eutopic endometrium in patients with endometriosis exhibits ultrastructural hyperactivity, enhanced angiogenic potential and invasive capacity. Retrograde menstruation merely delivers these endometrial fragments to the pelvic cavity. Immune responses are secondary factors that contribute to ectopic tissue acceptance. This hypothesis revises Sampson’s planting theory and better explains why only a subset of women with retrograde menstruation develop endometriosis. After reaching the pelvic cavity, endometrial fragments go through three key pathological and molecular steps for lesion establishment: attachment, aggression and angiogenesis, known as the “3A model”. Although endometriosis is histologically benign, it displays cancer-like biological behaviors including progressive invasive growth, estrogen-dependent progression, recurrence and metastatic tendency. Such malignant-like characteristics are largely driven by interactive cellular phenotypic reprogramming, including hypoxic microenvironment, aberrant cell proliferation, dysregulated autophagy, pyroptosis, ferroptosis and epithelial-mesenchymal transition (EMT). Deeply deciphering these mechanisms may provide potential biomarkers for early diagnosis and lay a theoretical foundation for developing targeted therapies. Therefore, this review aims to elaborate the pathogenesis of endometriosis from the perspective of cellular phenotypes and construct a conceptual framework for pathological progression of ectopic lesions. This review focuses on six core cellular phenotypes: hypoxia, aberrant proliferation, autophagy dysregulation, pyroptosis, ferroptosis and EMT (Figure 1), which are repeatedly reported as key drivers of lesion progression in recent mechanistic studies. We acknowledge that immune disturbance, fibrosis, angiogenesis, stem-cell-related effects, epigenetic modification and progesterone resistance are also clinically relevant but fall outside the primary scope of this manuscript. The cancer-like invasive and recurrent features of endometriotic lesions are largely mediated by the above-mentioned cellular phenotypic reprogramming. This review intends to integrate pre-clinical and human-derived evidence and discuss potential therapeutic implications. Bibliometric analyses are only used to visualize research hotspots in each subsection; this is neither a systematic review nor a meta-analysis. Bibliometric Methods Bibliometric analyses were independently performed for each cellular-phenotype sub-theme based on the Web of Science Core Collection. Six sets of topic-search (TS) queries were constructed for hypoxia, cell proliferation, autophagy, pyroptosis, ferroptosis and EMT, respectively. Multi-word fixed-phrase terms were enclosed in double quotation marks to avoid word-splitting retrieval. Uniform filtering thresholds were applied for all six datasets: publication time span from January 1, 2005 to August 31, 2025; document types limited to original articles and reviews; language restricted to English only. It should be emphasized that bibliometric outputs in this manuscript serve merely as an auxiliary navigational tool for mapping research hotspots. Publication counts, citation metrics and institutional/author productivity cannot be fully equated with the quality or causal evidence strength of individual studies. No further meta-analytical synthesis was performed on bibliometric datasets. The full search strings are presented below: - Hypoxia:TS=(Endometriosis) AND (Hypoxia OR “Oxygen Deficiency” OR “Oxygen Deficiencies” OR Hypoxemia OR Anoxia) - Proliferation:TS=(Endometriosis) AND (Proliferation OR “Cellular Proliferation” OR “Cell Multiplication”) - Autophagy: TS=(Endometriosis) AND (Autophagy OR Autophagocytosis OR “Cellular Autophagy” OR Lipophagy OR Ribophagy OR Reticulophagy OR “ER-phagy” OR Nucleophagy) - Ferroptosis: TS=(Endometriosis) AND Ferroptosis - Pyroptosis:TS=(Endometriosis) AND (Pyroptosis OR Pyroptoses OR “Pyroptotic Cell Death” OR “Caspase-1-dependent cell death”) - Epithelial-mesenchymal transition: TS=(Endometriosis) AND (“Epithelial-Mesenchymal Transition” OR “Epithelial-Mesenchymal Transformation”) The Role of Hypoxia in Endometriosis Hypoxia refers to insufficient oxygen supply or excessive oxygen consumption that disturbs normal cellular function. In 2007, Wu et al first reported up-regulated HIF-1α mRNA and protein together with its transcriptional activity in regulating leptin expression in endometriotic lesions, which pioneered research concerning hypoxia in endometriosis pathogenesis. The uterus is highly vascularized and supplies sufficient oxygen for endometrial cells. After shedding endometrial tissues reach the pelvic cavity via retrograde menstruation, neovasculature has not been established and cells are subjected to persistent hypoxic stress. Transient physiological hypoxia participates in endometrial repair and prevents excessive menstrual bleeding. However, in patients with endometriosis, crosstalk between hypoxic microenvironment and ectopic endometrial cells facilitates cellular adaptation to low-oxygen conditions and confers survival advantages, ultimately promoting disease progression. This process is mainly mediated by hypoxia-inducible factor (HIF). HIF is a heterodimer composed of HIF-1α and HIF-1β. HIF-1β remains stable under both normoxia and hypoxia, while HIF-1α is stabilized only under hypoxic conditions and serves as the master regulator of hypoxia responses. When endometrial cells enter the pelvic cavity without adequate blood perfusion, accumulated HIF-1α initiates transcription of diverse downstream target genes and promotes endometriosis progression through multiple pathways. Hypoxia Modulates Apoptotic Pathways to Alter Ectopic Cell Survival Apoptosis is genetically-programmed cell death responsible for clearing senescent endometrial cells during menstruation and maintaining endometrial homeostasis. Suppressed apoptosis and enhanced survival represent critical survival advantages for ectopic endometrial cells, and hypoxia inhibits apoptosis via multiple signaling cascades. HIF-1α Over-Expression Mediates Anti-Apoptotic Effects In-vitro cellular experiments confirm that hypoxia stabilizes HIF-1α protein in endometriotic stromal cells and peritoneal mesothelial cells. According to in-vitro studies, nuclear-translocated HIF-1α binds hypoxia-response elements within promoter regions of VEGFA and its receptor genes, up-regulates VEGFA mRNA, elevates local VEGF levels, promotes angiogenesis and enhances cell survival while reducing apoptosis.1 In-vitro experiments by Lin et al demonstrated that hypoxia stimulates ESCs to secrete substantial TGF-β1, activates the TGF-β1/Smad signaling axis, up-regulates integrins and markedly strengthens the adhesive capacity of endometrial stromal cells.2 Furthermore, hypoxia elevates IL-6 expression and further activates STAT3 signaling, which produces anti-apoptotic effects on ectopic endometrial stromal cells in in-vitro models.3 Semaphorin 3A (Sema3A) exerts both neuro-regulatory and immunomodulatory functions. Mouse animal models revealed that hypoxia-driven HIF-1α up-regulates Sema3A mRNA and protein in ESCs. Sema3A contributes to local neural remodeling and pain generation, and also polarizes macrophages toward anti-inflammatory phenotypes to indirectly facilitate proliferation and migration of ectopic cells.4 Collectively, in-vitro and animal studies indicate that HIF-1α promotes endometriosis via multiple downstream axes, yet direct validations from large-scale human lesion tissues remain lacking. MicroRNAs participate in upstream and downstream regulation of HIF signaling: miR-199a, miR-17-92 cluster and miR-20b modulate HIF-1α under hypoxia; miR-23, miR-24, miR-26, miR-107, miR-210 and miR-373 are transcriptionally induced by HIF-1α.5,6 Among them, miR-210 is most robustly up-regulated under hypoxia in ectopic endometrial cells. In-vitro experiments suggest that miR-210 participates in cell proliferation, anti-apoptosis and angiogenesis via STAT3 signaling.7 It should be noted that most miRNA-related evidence comes from in-vitro cell experiments; validations in human tissue specimens are limited and inconsistent results exist among several studies. Hypoxia Drives Glycolytic Reprogramming and Suppresses Apoptosis Glycolysis generates lactate from glucose or glycogen under oxygen-deficient conditions and can serve as an energy-producing pathway even under aerobic circumstances. Tumor cells prefer glycolysis despite sufficient oxygen supply, known as the Warburg effect. In-vitro and histological observations indicate that endometriotic cells exhibit Warburg-like metabolic phenotypes. Peritoneal mesothelial cells adjacent to endometriotic lesions display higher glycolytic activity and increased lactate production compared with women without endometriosis.8 Under hypoxia, mitochondrial oxidative phosphorylation (OXPHOS) is suppressed. To satisfy biosynthetic and energetic demands, HIF shifts cellular metabolism toward glycolysis as an adaptive strategy for ectopic cells. In-vitro experiments show that HIF enhances glucose uptake by up-regulating GLUT1 (SLC2A1). Meanwhile, HIF-1 recognizes hypoxia-response elements and transcriptionally activates key glycolytic enzymes including HK1, HK2, PFK-1, PKM2 and LDHA to rapidly produce ATP for basic cellular survival.9 Although glycolysis yields less ATP per glucose molecule than OXPHOS, its high reaction velocity guarantees rapid energy supply. Apoptosis execution (caspase activation) is energy-consuming; sustained ATP production from glycolysis prevents necrosis caused by ATP depletion and supplies energy for damage repair and apoptosis resistance.10 Intermediate metabolites of glycolysis also provide precursors for biosynthesis of nucleotides, lipids and amino acids to support cell proliferation.11 Glycolysis-derived lactate acidifies the local microenvironment. Tumor-derived in-vitro co-culture models indicate that lactate-induced acidification suppresses cytotoxic functions of NK cells and T-lymphocytes. This mechanism is presumed to participate in shaping the endometriotic microenvironment, yet direct experimental evidence within endometriosis systems is still absent.12 Most glycolysis-associated findings are derived from cellular experiments; further clinical specimens are required to verify dynamic alterations of glycolytic enzymes and lactate concentrations in human lesions. Hypoxia-Mediated Autophagy Facilitates Endometriosis Progression Autophagy is a constitutive catabolic pathway that sequesters organelles and macromolecules for lysosomal degradation and metabolite recycling. It serves as a vital compensatory response to oxidative or hypoxic stress. Moderate autophagy supports cell survival, whereas excessive or insufficient autophagy disrupts cellular homeostasis. Immunohistochemical analyses based on human endometrial specimens demonstrated that autophagy marker LC3 and HIF-1α are significantly elevated in ectopic endometrium compared with eutopic and normal endometrium, and LC3 expression positively correlates with HIF-1α. These correlative findings imply that hypoxia-triggered oxidative stress modulates autophagy and aberrant autophagy promotes proliferation and invasion of ectopic cells.2 Further mechanistic insights are obtained from in-vitro cellular models: hypoxia up-regulates lncRNA MALAT1 and enhances autophagic activity in a time-dependent manner, elevates stromal cell anti-apoptotic capacity and promotes EMT to drive lesion migration and invasion. MALAT1 modulates stromal cell apoptosis via the miR-126-5p/CREB1 axis and activates the PI3K-AKT pathway.13 The canonical PI3K-AKT-mTOR autophagy pathway synergizes with MALAT1-mediated non-canonical autophagy. CircFOXO3 also contributes to this regulatory network. In-vitro experiments reveal that hypoxia-induced ADAR1 elevation represses circFOXO3, induces autophagy through inhibiting p53 protein degradation and participates in endometriosis progression.14 Human tissues only provide correlative phenotypic observations; causal molecular mechanisms are largely supported by in-vitro cell models, and causal validations in human samples remain lacking. Hypoxia Promotes Endometriosis via Hormonal Signaling Modulation Endometriosis is a hormone-dependent disease. Hypoxia modulates steroidogenic enzymes through multiple signaling axes with HIF-1α as the central mediator. Cyclooxygenase-2 (COX-2) is the rate-limiting enzyme for PGE2 synthesis and is overexpressed in ectopic lesions to drive PGE2 production. The COX-2/PGE2 cascade further up-regulates steroidogenic enzymes including StAR and aromatase and leads to local estrogen excess. Cellular experiments demonstrate that HIF-1α represses dual-specificity phosphatase 2 (DUSP2). DUSP2 de-phosphorylates ERK and p38 MAPK; DUSP2 down-regulation prolongs activation of ERK/p38 MAPK and increases COX-2 expression. In turn, ERK activation promotes nuclear accumulation of HIF-1α and forms a positive-feedback loop enhancing ectopic cell survival.15 Studies on normal endometrium indicate that transcriptional repressor COUP-TFII binds to the COX-2 promoter and inhibits its transcription and IL-1β-driven COX-2 elevation. After hypoxic treatment of ectopic endometrial cells, hypoxia impairs COUP-TFII function and relieves this transcriptional repression.16,17 Meanwhile, hypoxia activates YAP1, which further up-regulates StAR and COX-2.18 Collectively, in-vitro evidence demonstrates that hypoxia drives COX-2 over-expression from multiple routes, augments local estrogen synthesis, and activated estrogen further amplifies COX-2-PGE2-mediated inflammatory responses, forming a positive-feedback loop that aggravates endometriotic lesions. Evidence Synthesis and Therapeutic Implications Evidence supporting hypoxia-driven endometriosis progression originates from in-vitro cell experiments, animal models and limited correlative observations in human tissues. Human specimens can only demonstrate differential molecular expression in lesions but cannot directly prove causal relationships between hypoxia and downstream signaling. Most causal mechanistic evidence relies on pre-clinical cellular and animal models. Therefore, caution should be exercised when translating pre-clinical findings directly into clinical practice. Several mechanisms remain controversial and await validation using more clinical samples and further experiments. From a therapeutic perspective, targeting HIF-1α, glycolytic reprogramming and downstream hypoxia-related signaling pathways holds potential intervention value. Nevertheless, extensive crosstalk exists between hypoxia-associated cascades and other cellular phenotype pathways including proliferation, autophagy and cell-death signaling. Single-target interventions are unlikely to achieve satisfactory efficacy. Future translational research should further explore multi-target combinatorial strategies. Of note, therapeutic strategies targeting these molecular targets remain at pre-clinical stage; no completed clinical trials for endometriosis are currently available. Relevant research hot-spots derived from bibliometric analysis are provided in Supplementary Figures S1–S5. Cell Proliferation and Endometriosis Cell proliferation constitutes a fundamental biological process for organismal growth, development, reproduction and inheritance. Aberrant cell proliferation in endometriosis (EMS) is orchestrated by complex multi-layered molecular networks. Multiple key molecules regulating proliferation of ectopic cells have been identified, providing potential targets for disease-directed intervention. PFKFB3 is up-regulated in EMS tissues and promotes cell proliferation via modulating epithelial-mesenchymal transition (EMT). In-vitro cellular experiments show that PFKFB3 binds and stabilizes β-catenin protein, activates Wnt-driven proliferative programs and accelerates cell-cycle progression.19 In addition, non-receptor tyrosine kinase PYK2 phosphorylates Snail1, up-regulates EMT-associated genes and markedly enhances proliferation, migration and invasion of EMS cells.20 Another study reported that lactate accumulated in lesion microenvironment triggers histone H3 lysine-18 lactoylation (H3K18lac), up-regulates HMGB1 and activates AKT phosphorylation to drive aberrant proliferation of ectopic cells.21 These studies reveal regulatory cascades including PFKFB3-β-catenin, PYK2-Snail1 and lactate-HMGB1-AKT and supply molecular clues for targeted therapy. However, most of these results are derived from in-vitro cellular models and sufficient causal validations in human tissues are still lacking. Aberrant cell proliferation serves as a major driver for lesion formation. Glycolytic enzyme PGK1 is highly expressed in EMS and facilitates lesion growth by promoting nuclear translocation and transcriptional activity of DDIT4. Animal-model experiments confirmed that PGK1 inhibitor NG52 significantly suppresses cell proliferation within ectopic lesions.22 Bone-marrow-derived mesenchymal stem cells (BM-MSCs) accelerate colonization and expansion of ectopic endometrial tissues via paracrine activation of CDK1-positive cell populations in-vivo.23 Activation of EMT cascades such as the Snail1/PYK2 axis enhances migratory capacity while accelerating lesion progression through synergistic proliferation-invasion effects.24 Proliferation marker PCNA exhibits elevated expression in EMS tissues and positively correlates with lesion invasiveness. This observation originates from correlative immunohistochemistry on human specimens and only reflects association rather than causality.21 Collectively, targeting pathways such as PFKFB3-β-catenin, PYK2-Snail1 and PGK1-DDIT4 holds promise for suppressing lesion development. Non-coding RNAs also participate in proliferation regulation. In-vitro experiments indicate that miR-2861 is down-regulated in EMS tissues and promotes disease progression by de-repressing STAT3 and MMP2.25 lncRNA IGF2-AS activates the PI3K/AKT/mTOR axis through the IGF2/miR-370-3p cascade and drives ectopic endometrial cell growth.26 LINC01116 promotes proliferation and migration of endometrial stromal cells via the miR-9-5p/FOXP1 axis.27 Most non-coding-RNA-related mechanistic evidence comes from in-vitro cellular experiments; functional validations in clinical lesion samples remain limited. Evidence Synthesis and Therapeutic Implications Mechanistic evidence regarding aberrant cell proliferation is derived from three sources: in-vitro cell experiments, animal-model studies and correlative expression analyses of human tissues. Human specimens can only reveal differential molecular expression and cannot confirm causal regulatory relationships. Many potential therapeutic targets remain at the pre-clinical research stage. From a therapeutic perspective, molecules such as PFKFB3, PYK2 and PGK1 represent candidate intervention targets. Nevertheless, proliferative signaling extensively crosstalks with hypoxia, autophagy, EMT and other phenotypic pathways, and single-target inhibition may produce limited efficacy. Future translational work should prioritize multi-target combinatorial strategies, and more clinical specimens plus in-vivo animal experiments are needed to further validate target efficacy and safety. Of note, therapeutic strategies targeting these molecular targets remain at pre-clinical stage; no completed clinical trials for endometriosis are currently available. Relevant research hot-spots derived from bibliometric analysis are provided in Supplementary Figures S6–S10. Dual Roles of Autophagy in Endometriosis Apart from hypoxia-induced autophagy described above, accumulating studies demonstrate that autophagy exerts dual functions in endometriosis: it can support cell survival under certain circumstances while triggering cell death under other conditions. Transcription factor EB (TFEB) is over-expressed in ectopic EMS endometrium. Human-derived endometrial specimens together with in-vitro cellular experiments show that TFEB promotes autophagy and inhibits apoptosis in human endometrial stromal cells (HESCs) via activating autophagy marker LC3. TFEB over-expression enhances migratory and invasive capacities of HESCs and facilitates lesion growth through autophagy-dependent mechanisms.28 DIRAS3 is significantly up-regulated in epithelial cells of EMS lesions and induces autophagy to promote cell survival; DIRAS3 knockdown reduces cell proliferation and elevates apoptotic rates.29 Several in-vitro studies suggest that in secretory-phase ectopic endometrium, estrogen and progesterone synergistically suppress autophagic activity via the CXCL12/CXCR4-driven over-activation of NF-κB/FADD-Caspase and PI3K signaling. Suppressed autophagy is reflected by decreased Beclin1, impaired LC3 conversion and accumulated p62. Autophagy inhibition enables ectopic cells to evade immune clearance and supports lesion colonization.30–32 Collectively, existing evidence indicates that autophagy predominantly facilitates lesion survival under most pathological contexts, though excessive autophagy may conversely trigger cell death. Evidence Synthesis and Therapeutic Implications Evidence in this section consists of correlative expression data from human tissues and in-vitro cellular experiments. Human samples only permit observation of molecular expression differences. The switching mechanisms determining whether autophagy promotes survival or cell death under in-vivo conditions lack sufficient human functional validations. Many conclusions rely on in-vitro cell models, and triggering thresholds for autophagy-mediated dual effects under physiological in-vivo settings remain unclear. From a therapeutic perspective, modulating autophagy holds intervention potential. However, autophagy exhibits dual “double-edged-sword” properties; either pharmacological activation or inhibition of autophagy may bring undesired off-target outcomes. Future translational studies need to fully consider such duality, explore tissue-specific regulatory strategies and combine interventions targeting other cellular phenotypic pathways. Of note, therapeutic strategies targeting these molecular targets remain at pre-clinical stage; no completed clinical trials for endometriosis are currently available. Relevant research hot-spots derived from bibliometric analysis are provided in Supplementary Figures S11–13. Molecular Mechanisms of Pyroptosis and Its Roles in EMS Pyroptosis represents a subtype of programmed cell death. It was originally defined in 2001 by Cookson and Brennan as caspase-1-dependent inflammatory cell death. In 2018, the Nomenclature Committee on Cell Death (NCCD) updated its definition: pyroptosis is a regulated form of cell death mediated by gasdermin-family pore formation on plasma membranes, frequently but not invariably accompanied by inflammatory caspase activation.33 NLRP3 belongs to the NOD-like receptor family and constitutes the core component of the NLRP3 inflammasome, which plays central roles in innate-immune responses. Histological observations demonstrate that NLRP3 is barely detectable in endometrial tissues from healthy women, whereas NLRP3 inflammasome activity is markedly elevated in ectopic lesions from EMS patients. Inflammasome activation in ectopic tissues triggers pyroptosis via Gasdermin D (GSDMD) / Gasdermin E (GSDME), promotes IL-1β release and activates TGF-β1 signaling to drive fibrotic alterations within lesions.34 Elevated PGE2 in inflamed ectopic endometrium promotes inflammatory-cell migration and infiltration through the NLRP3/caspase-1 cascade. TRIM24 acts as a negative inflammatory regulator and is down-regulated in ectopic endometrium. Reduced TRIM24 increases levels of pyroptosis-related markers including NLRP3, procaspase-1, activated caspase-1, pro-IL-1β and mature IL-1β, and augments secretion of IL-1β and IL-18 in hESCs. These findings imply that NLRP3/caspase-1/IL-1β-axis-mediated pyroptosis participates in EMS pathological progression.35 Non-coding RNAs also regulate pyroptosis. In-vitro cellular experiments indicate that lnc-MALAT1, highly expressed in EMS, competitively sponges miR-141-3p, relieves its repression of NLRP3, thereby activating the NLRP3 inflammasome and inducing pyroptosis.36 Integrative bioinformatic analysis based on GEO datasets combined with cellular experiments confirm that lncRNA NEAT1 sponges miR-141-3p to up-regulate HTRA1 and further activate NLRP3 inflammasome-driven pyroptosis.37,38 Taken together, pyroptosis sustains persistent local inflammation and contributes to fibrosis remodeling and immune-microenvironment alteration in endometriosis. Evidence Synthesis and Therapeutic Implications Existing pyroptosis-related research includes correlative expression testing on human tissues, while most mechanistic evidence originates from in-vitro cellular experiments. Human samples only demonstrate molecular expression changes. Real-time dynamics of pyroptosis within lesions and the respective contributions of different cell populations (stromal, epithelial, immune cells) still require more functional validations using primary human tissues. Therapeutically, inhibiting the NLRP3 inflammasome-pyroptosis cascade may ameliorate inflammation and fibrosis in ectopic lesions. Nevertheless, pyroptosis serves an essential host-defense function; systemic inhibition carries potential immune-related risks. Future research should prioritize strategies targeting lesions locally. Of note, therapeutic strategies targeting these molecular targets remain at pre-clinical stage; no completed clinical trials for endometriosis are currently available. Relevant research hot-spots derived from bibliometric analysis are provided in Supplementary Figures S14. Metabolic Features of Ferroptosis Ferroptosis is an iron-dependent regulated cell-death modality first described by Dixon et al in 2012. It is characterized by intracellular redox imbalance and massive lipid-peroxide accumulation, which disrupt phospholipid bilayer integrity and trigger necrotic-like cell death.39 Repeated hemorrhage and inflammation within endometriotic lesions cause iron overload and accumulation of ROS and free radicals in local microenvironment. Ferrous iron mediates the Fenton reaction and generates highly-toxic hydroxyl radicals that damage biological macromolecules. Iron overload exists in peritoneal fluid and ectopic lesions of EMS patients and produces dual biological outcomes. On one hand, ectopic endometrial cells can up-regulate molecules such as BECN1 and ATF4, activate the xCT cystine transporter and mevalonate-cholesterol biosynthetic pathways to enhance antioxidant capacity, resist ferroptosis and support survival and proliferation. However, such evidence is mainly derived from in-vitro and bioinformatic analyses, and actual strength of these compensatory pathways in human lesions awaits further confirmation.40–43 On the other hand, iron overload in peritoneal fluid up-regulates HMOX1, induces ferroptosis in ovarian granulosa cells and early embryos, contributes to follicular atresia and impaired embryonic development associated with EMS-related infertility. Ferroptosis inhibitors such as Fer-1 can alleviate such embryotoxicity in animal models.43–45 Animal and in-vitro models reveal that iron overload triggers macrophage ferroptosis, impairs phagocytic capacity and augments secretion of pro-angiogenic factors, further accelerating lesion progression.46 Multiple non-coding RNAs mediate bidirectional regulation of ferroptosis. In-vitro experiments show that miR-21-3p antagonizes ferroptosis by suppressing p53 and activating SLC7A11. MALAT1 silencing promotes ferroptosis via the miR-145-5p/MUC1 axis.46,47 lncRNA ADAMTS9-AS1 is up-regulated in patient specimens and animal models; it represses ferroptosis and promotes cell migration through the miR-6516-5p/GPX4 axis and is regarded as a potential therapeutic target.48 Evidence Synthesis and Therapeutic Implications Ferroptosis-related human-sample research is largely restricted to iron-content and molecular-expression correlative measurements. Mechanistic insights are mostly obtained from cellular and animal models. Direct detection of real-world ferroptosis levels among different cell types (stromal, immune, reproductive cells) within human lesions remains technically challenging, and in-vivo contributions of many molecular pathways still need verification. Ferroptosis participates in both ectopic-cell survival and infertility-associated damage. Any intervention strategy must balance these dual effects. Targeting key ferroptosis molecules such as GPX4 and SLC7A11 possesses potential value, yet differential effects on lesion cells vs reproductive cells should be carefully considered to avoid reproductive toxic risks. Of note, therapeutic strategies targeting these molecular targets remain at pre-clinical stage; no completed clinical trials for endometriosis are currently available. Relevant research hot-spots derived from bibliometric analysis are provided in Supplementary Figures S15. Epithelial-Mesenchymal Transition (EMT) and Aggressiveness in Endometriosis Epithelial-mesenchymal transition (EMT) refers to biological reprogramming through which epithelial cells gradually lose epithelial properties and acquire mesenchymal phenotypes. In EMS, representative EMT markers include Twist, Snail, Slug, ZEB1/2, E-cadherin, N-cadherin, keratins and tight-junction proteins.49 In-vitro cellular experiments suggest that estrogen elevates RhoA/ROCK activity via the ERα/ERK axis to promote EMT and cell proliferation. Meanwhile, TGF-β1 cooperates with ROS and other stimuli to induce IL-33 release. IL-33 activates the Wnt/β-catenin pathway through ST2-receptor-mediated phosphorylation and further drives EMT progression.50 Receptor tyrosine kinase RON mediates EMT through Akt and MAPK cascades and enhances migratory and invasive phenotypes of endometrial epithelial cells.51 EGFR-driven MMP-7 up-regulation promotes EMT in ovarian endometriosis via the ERK1-AP1 axis.52 Non-coding RNAs also participate in multi-layered EMT regulation. Linc-ROR acts as a molecular sponge for miR-204-5p and de-represses SMAD4 to establish the Linc-ROR/miR-204-5p/SMAD4 regulatory axis facilitating EMT.53 circATRNL1 sponges miR-141-3p and miR-200a-3p to de-inhibit YAP1 and drives EMT-associated malignant phenotypes. hsa_circ_0005991 cooperatively promotes EMT progression through the miR-30b-3p/Cdc42EP1 axis.54,55 Collectively, in-vitro studies demonstrate multiple regulatory networks governing EMT in EMS and provide candidate directions for targeted intervention. Evidence Synthesis and Therapeutic Implications Most mechanistic evidence for EMT originates from in-vitro cellular models. Human lesion tissues display altered expression of EMT markers. Nevertheless, direct in-vivo evidence for complete EMT of epithelial cells within ectopic lesions remains limited. Several scholars argue that partial phenotypic conversion rather than full EMT may predominate. Therefore, regulatory pathways observed in-vitro cannot be simply equated to authentic pathological processes inside human patients. Therapeutically, inhibiting EMT-related signaling may weaken migratory and invasive capacities of ectopic lesions. Considering extensive crosstalk between EMT and hypoxia, proliferation and cell-death pathways, single-target strategies may achieve limited efficacy. Future translational research should further explore combinatorial interventions targeting multiple cellular phenotypes. Of note, therapeutic strategies targeting these molecular targets remain at pre-clinical stage; no completed clinical trials for endometriosis are currently available. Relevant research hot-spots derived from bibliometric analysis are provided in Supplementary Figures S16–S19. Crosstalk Among Diverse Cellular Phenotypic Alterations Individual cellular phenotypes including hypoxia-driven signaling, aberrant proliferation, autophagy, pyroptosis, ferroptosis and EMT do not operate in isolation within endometriotic lesions. Complex reciprocal crosstalk forms an interconnected regulatory network that jointly shapes the survival, migration and invasive capacity of ectopic endometrial cells. Hypoxia functions as an upstream master trigger for multiple downstream phenotypic reprogramming. HIF-1α-dependent hypoxic signaling can simultaneously promote EMT reprogramming, modulate autophagic flux, alter glycolytic metabolism, and change cellular susceptibility to regulated cell death including pyroptosis and ferroptosis. For instance, hypoxia-induced autophagy may exert dual-edged effects: it can either support cell survival via adaptive metabolic recycling, or conversely sensitize cells toward ferroptosis under severe oxidative stress. EMT activation further amplifies proliferative potential and changes cell vulnerability to cell-death stimuli. Epithelial-mesenchymal transition renders endometrial cells more resistant to apoptotic stimuli, while also reshaping iron-metabolic homeostasis to modify the threshold of ferroptosis. In turn, ferroptosis and pyroptosis, as inflammatory forms of cell death, release abundant inflammatory mediators and damage-associated molecular patterns (DAMPs) into the lesion microenvironment; these inflammatory products can feedback-activate HIF-1α signaling, boost proliferative signalling cascades and further sustain EMT activity, establishing self-reinforcing positive-feedback loops within lesions. Autophagy occupies a central nodal position linking metabolism, iron homeostasis and cell-death programs. Autophagy-related pathways can modulate ferritin degradation (ferritinophagy) to alter intracellular iron pools, which directly influences the occurrence of ferroptosis. Meanwhile, autophagy may either restrict or promote pyroptosis depending on stimulus intensity and cellular context. It should be emphasized that most of the above-described crosstalk relationships are primarily supported by in-vitro cellular and animal-model evidence. Robust functional validations of these interactive networks in human primary ectopic lesion tissues remain limited. In-vivo spatiotemporal dynamics of how these phenotypes regulate one another in different lesion compartments are still poorly characterized. Research Gaps Despite accumulating mechanistic knowledge regarding cellular phenotypic alterations in endometriosis, several prominent research gaps remain to be addressed. First, the majority of mechanistic conclusions are derived from in-vitro cell experiments and animal-model studies. Human-tissue-based evidence is largely restricted to correlative expression profiling (immunohistochemistry, transcriptomics). Direct functional experiments using fresh primary human ectopic lesion samples are scarce; therefore, causal relationships observed in pre-clinical models cannot be simply extrapolated to real-world human pathological processes. Second, most existing mechanistic studies do not stratify patients according to clinical endometriosis subtypes (ovarian endometrioma, peritoneal endometriosis, deep-infiltrating endometriosis). Whether hypoxia, proliferation, autophagy and regulated cell-death pathways exert distinct contributions across different lesion subtypes remains unclear. Lesion heterogeneity has not been sufficiently considered in most published experimental designs. Third, current animal models cannot fully recapitulate the full spectrum of human endometriosis pathological features, hormone cycles and lesion microenvironment. Results obtained from rodent models require cautious interpretation when translated to human disease. Fourth, nearly all identified molecular targets associated with these cellular phenotypes remain at the pre-clinical research stage. Large clinical cohorts, well-validated circulating or tissue-based biomarkers, and completed clinical trials targeting these pathways for endometriosis therapy are still absent. Fifth, the spatiotemporal sequence and dynamic balance of crosstalk among multiple cellular phenotypes inside living human lesions are largely unknown. It remains unclear which phenotype acts as the primary driver and which acts as secondary downstream consequence during different disease progression stages. Collectively, these gaps highlight that further multi-omics human-tissue investigations, improved disease models, and translational clinical studies are urgently required to move basic mechanistic discoveries toward diagnostic and therapeutic applications.

Endometriosis (EMS) represents a complex gynecological disease whose pathogenesis involves dynamic alterations of multiple cellular phenotypes, including hypoxia, aberrant cell proliferation, autophagy, pyroptosis, ferroptosis and EMT. Additional factors such as epigenetic regulation (DNA methylation, histone modification, non-coding RNAs) also contribute to disease development. These phenotypes do not function independently but interact via intricate molecular networks to jointly drive EMS progression. Although partial mechanisms have been preliminarily uncovered, multiple controversies and unresolved questions persist. For instance, whether hypoxia universally acts as a dominant driver across all EMS subtypes remains debatable. The relative contributions of distinct regulated cell-death modalities (pyroptosis, ferroptosis) to pathological progression still require further experimental and clinical validation. From a therapeutic standpoint, interventions targeting single phenotypic pathways may yield limited outcomes. Multi-target combinatorial therapies represent promising future directions. For example, simultaneous modulation of autophagy and EMT may suppress invasiveness of ectopic lesions. Individualized precision therapy also deserves attention, because EMS in different patients may be predominated by distinct cellular phenotypes, and therapeutic regimens should be adjusted according to molecular profiles. Future research priorities include: (i) deciphering spatiotemporal dynamics of crosstalk among various cellular phenotypes; (ii) developing novel multi-target therapeutic agents with synergistic effects; (iii) establishing biomarker-based clinical-stratification systems. Through multidisciplinary translational efforts focusing on these cellular phenotypic alterations, improved diagnostic and therapeutic strategies for endometriosis are expected, ultimately enhancing long-term clinical outcomes and quality of life for affected patients. Abbreviations BM-MSCs, bone marrow mesenchymal stem cells; CeRNA, competitive endogenous RNA; COUP-TFII, chicken ovalbumin upstream promoter–transcription factor II; COX-2, Cyclooxygenase 2; DDIT4, DNA damage-inducible transcript 4; DUSP2, dual-specificity phosphatase 2; EMS, endometriosis; EMT, epithelial–mesenchymal transition; ERK, extracellular signal-regulated kinase; ESCs, endometrial stromal cells; GEO, Gene Expression Omnibus; GSDMD, Gasdermin D; GSDME, Gasdermin E; H3K18lac, histone H3 lysine 18; HESCs, human endometrial stromal cells; HIF-1α, hypoxia-inducible factor-1α; HK1, hexokinase 1; HK2, hexokinase 2; HMGB1, high-mobility group box 1; HREs, hypoxia response elements; IGF2-AS, Insulin-like growth factor 2 antisense RNA; IL-1β, interleukin-1β; IL-8, interleukin-8; LDHA, lactate dehydrogenase A; LncRNAs, long non-coding RNAs; MMP2, matrix metalloproteinase 2; NCCD, Nomenclature Committee on Cell Death; NLR, the NOD-like receptor; OXPHOS, oxidative phosphorylation; p38 MAPK, p38 mitogen-activated protein kinase; PCNA, proliferating cell nuclear antigen; PFK-1, phosphofructokinase-1; PFKFB3, 6-phosphofructo-kinase-2/fructose diphosphatase-2 isoenzyme 3; PGE2, prostaglandin E2; PGK1, Phosphoglycerate kinase 1; PKM2, pyruvate kinase M2; PYK2, proline-rich tyrosine kinase 2; ROS, reactive oxygen species; StAR, steroidogenic acute regulatory protein; TFEB, transcription factor EB; TGF-β1, transforming growth factor-β1; VEGF-A,vascular endothelial growth factor A; YAP1, Yes-associated protein 1. Data Sharing Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Acknowledgments All the authors wish to express their gratitude to the participants who volunteered for this study. Author Contributions All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Funding Yinchuan science and Technology Bureau project. 2022 Ningxia Hui Autonomous Region Science and Technology Leading Talent Training Project (2022GKLRLX010). Disclosure The authors declare no competing financial interests.

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