The pathogenesis of AM-related infertility begins with structural anomalies that disrupt the physiological architecture of the reproductive tract. Structural assessments through hysterosalpingography reveal significantly higher uterine cavity distortion rates in patients with AM compared with controls: 78% in diffuse AM and 54% in focal AM vs. 37% in non-AM populations (6). Anatomical distortion of the uterine wall, characterized by myometrial hypertrophy and endometrial invagination into the myometrium, not only destroys the spatial integrity required for embryo implantation but also exerts mechanical traction on the fallopian tubes, impairing their transport dynamics (11). Using T2-weighted MRI and hysterosalpingoscintigraphy, Kissler et al (12) demonstrated a significantly higher incidence of impaired tubal transport in patients with diffuse AM compared with those with focal AM and healthy controls. This tubal dysfunction compromises the timely meeting of gametes and the subsequent transport of embryos to the uterine cavity, directly hindering fertilization. Concurrently, the structural derangement of the uterus exacerbates functional impairments: Aberrant myometrial contractility patterns (marked by increased frequency and uncoordinated contractions) disrupt embryo positioning within the uterus and reduce blood perfusion to the junctional zone (JZ), a critical region for implantation (13). Additionally, reduced ovarian responsiveness in patients with AM is closely linked to local and systemic inflammatory cytokines [such as tumor necrosis factor-α (TNF-α) and IL-6], which interfere with granulosa cell function and folliculogenesis, diminishing oocyte quality and quantity (11).

Underpinning these structural and functional abnormalities is molecular and immunological dysregulation, with the persistent inflammatory microenvironment acting as a central driver. Spatial transcriptomic analyses have revealed that during ectopic endometrial invasion in AM, SFRP5⁺ epithelial cells promote endometrial proliferation and angiogenesis through activation of the Indian hedgehog signaling molecule signaling pathway, initiating basal layer invagination, while ESR1⁺ smooth muscle cells (SMCs) facilitate invasive tract formation via collagen degradation (13). These processes not only reinforce uterine structural distortion but also sustain inflammation, which further suppresses implantation-related molecular pathways. Specifically, elevated levels of pro-inflammatory cytokines (such as IL-6 and TNF-α) and oxidative stress markers in the adenomyotic microenvironment downregulate key implantation genes such as Homeobox (HOX)A10, HOXA11 and leukemia inhibitory factor (LIF), compromising ER and inhibiting decidualization (6). A genomic study has further confirmed the dysregulation of 34 fertility-associated genes during the implantation window, including imbalances in the matrix metalloproteinases (MMPs)/tissue inhibitors (TIMPs) system, an essential regulator of decidualization and trophoblast invasion (14).

Notably, these pathological processes are mutually reinforcing; structural distortion amplifies inflammatory signaling by disrupting tissue integrity, while inflammation exacerbates structural and functional damage through fibrosis (driven by CNN1⁺ stromal fibroblasts) and sustained tissue injury (13). This loop ultimately creates an intrauterine environment hostile to embryo survival and implantation.

Clinical data consistently validate the link between the pathological features of AM and poor reproductive outcomes, with severity-dependent effects clearly observed. In terms of ART outcomes, meta-analysis data has revealed that patients with AM have a clinical pregnancy rate of 40.5% following in vitro fertilization (IVF)/intracytoplasmic sperm injection compared with 49.8% in controls [risk ratio (RR), 0.72; 95% confidence interval (CI), 0.55-0.95], coupled with significantly elevated miscarriage rates (31.9 vs. 14.1%; RR, 2.12; 95% CI 1.20-3.75) (15). Further supporting this severity-dependent effect, a prospective multicenter study by Mavrelos et al (16) demonstrated a stepwise decline in clinical pregnancy rates: 42.7% (95% CI, 37.1-48.3) in women without sonographic AM features, 22.9% (95% CI, 13.4-32.6) in those with four features and further to 13.0% (95% CI, 2.2-23.9) in those with all seven features, indicating a strong association between disease severity and reduced fertility. Epidemiological data further highlight the role of AM in reproductive failure: The prevalence of AM is 24.4% among infertile populations, rising to 38.2% in recurrent miscarriage cohorts and 34.7% in recurrent implantation failure (RIF) groups (17), a finding consistent with the notion that persistent inflammatory and molecular dysregulation disproportionately affects women with repeated reproductive losses. Even in oocyte recipient cycles, AM independently increases early miscarriage risk and lowers term pregnancy rates, likely due to JZ dysfunction impairing trophoblast development and early placentation (18). Collectively, this confirms that intrauterine pathological changes (rather than ovarian factors alone) drive poor reproductive outcomes (11).

Synthesizing the aforementioned mechanisms and clinical evidence, we consider that while anatomical derangements and myometrial dysfunction represent relatively fixed pathological endpoints, the aberrant inflammatory milieu (functioning as the core mediator of the pathological loop) constitutes a tractable therapeutic target. Elucidating the key signaling pathways and immunomodulatory networks underlying inflammation-driven damage could inform the development of novel interventional strategies to disrupt this pathological loop, restore ER and ultimately improve fertility outcomes in patients with AM. This framework also directs future translational research toward validating these targets in clinical trials.

IL-6, predominantly secreted by activated macrophages (19), exhibits elevated expression in endometrial stromal cells (ESCs) in macrophage co-culture systems (20). Spatial transcriptomics analysis has identified an IL-6-centered protein-protein interaction subnetwork within adenomyotic lesions, forming a synergistic pro-inflammatory axis with cytokines such as CXCL8 and TNF-α, which activates local inflammatory cascades via the Toll-like receptor (TLR)4/NF-κB signaling pathway (21). Mechanistically, canonical IL-6 signaling involves complex formation with the soluble IL-6 receptor and gp130 co-receptor (22), triggering Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 pathway activation characterized by STAT3 phosphorylation and nuclear translocation (23). Dysregulation of the IL-6/JAK2/STAT3 pathway has been implicated in the pathogenesis of autoimmune diseases, chronic inflammation and certain malignancies (24). In AM, endometrial cell-derived exosomes have been shown to activate this signaling pathway, thereby promoting ESC proliferation, migration and cell cycle progression. Tocilizumab, an IL-6 receptor inhibitor, was able to effectively reverse these effects (25). Moreover, IL-6 trans-signaling activates the PI3K/AKT/mTOR pathway, which suppresses the autophagic death of ectopic endometrial cells, thereby promoting lesion establishment (26). Concurrently, activation of the RAS/RAF/MEK/ERK pathway enhances cellular motility, accelerating disease progression in AM (27).

In reproductive physiology, IL-6 plays key regulatory roles in embryo implantation, fetal development and other pregnancy-associated processes (28). Experimental evidence demonstrates that blastocyst development is impaired in IL-6 knockout mice, thereby adversely affecting pregnancy outcomes. IL-6 not only induces the secretion of monocyte chemoattractant protein-1 (MCP-1) by decidual stromal cells, promoting macrophage recruitment and the formation of a localized inflammatory response that impairs embryo implantation (20), but also disrupts ER and affects embryo implantation through activation of the JAK/STAT3 signaling pathway (29). Furthermore, IL-6 mediates vascular and immune dysregulation at the maternal-fetal interface (placenta/decidua) and has been proposed as a potential diagnostic or biomarker candidate for endometriosis (EMs)-associated infertility (30).

As a key member of the α-chemokine family, CXCL8 mediates neutrophil chemotaxis and activation via specific interactions with cognate receptors CXCR1 and CXCR2. In patients with AM, CXCL8 mRNA and protein expression are markedly upregulated in both ectopic lesions and the eutopic endometrium (31), paralleled by proliferative-phase upregulation of CXCR1/CXCR2 receptors on endometrial epithelial cells (32). Through paracrine signaling, the CXCL8-CXCR1 axis is activated, thereby promoting the invasive growth of ectopic endometrial tissue (33).

Physiologically, CXCL8 expression in normal endometrium peaks during the late secretory phase, facilitating neutrophil recruitment and stromal proliferation to prepare for menstruation (32). However, in AM pathophysiology, loss of CXCL8 cyclical rhythmicity results in defective postmenstrual repair and pathological angiogenesis within the eutopic endometrium. Activation of the TLR4/p38/ERK pathway can induce CXCR1 expression and promote CXCL8 secretion (34). Clinical analyses reveal diminished CXCL8 concentrations in the cervical mucus of patients with AM-associated infertility (35), while elevated serum CXCL8 levels and autoantibody positivity highlight its potential as a diagnostic biomarker for immune-mediated infertility (36). Singh et al (37) demonstrated inverse correlations between CXCL8 levels and both oocyte maturity and embryo quality. A further study has confirmed the dual role of CXCL8 in regulating early pregnancy outcomes through endometrial paracrine signaling and mediating embryo implantation via CXCR1 binding in patients with AM (38).

IL1B, a prototypical pro-inflammatory cytokine, initiates biological responses through binding to IL-1 receptor type I (IL-1R1) and recruiting IL-1 receptor accessory protein (IL-1RAcP) to form a high-affinity receptor complex (39). IL1B undergoes canonical activation by lipopolysaccharide (LPS) binding to TLRs. This binding event induces TLRs to recruit the adaptor protein MyD88 via their intracellular Toll/IL-1 receptor domain, culminating in IL1B transcriptional activation (40). Elevated IL1B expression is consistently observed in the eutopic and ectopic endometrium of patients with AM (19), where it serves as a critical initiator of pathological inflammatory cascades. MyD88 can also activates IRAK kinases and the IκB kinase (IKK) complex, leading to inhibitor of NF-κB (IκB) degradation and NF-κB nuclear translocation (41), thereby initiating downstream inflammatory cascades via the classical NF-κB pathway.

Furthermore, upregulation of IL1B has been implicated in disrupting the T helper cell 17 (Th17)/regulatory T cells (Treg) balance, leading to immune intolerance at the maternal-fetal interface, which is a key mechanism underlying implantation failure (42). The function of regulatory factors involved in embryo-maternal communication, such as IL-1RAcP and IL-1R antagonist (IL-1RA), may also be impaired. The ratio of IL-1RA to IL1B has been proposed as a potential predictive marker for adverse pregnancy outcomes in patients with AM (43).

In addition, Wang et al (44) demonstrated a significant positive correlation between IL1B expression and serum levels of estradiol (E2), progesterone and endometrial thickness (P<0.05), suggesting that IL1B may synergize with E2 and progesterone to improve ER and could serve as a predictive indicator of pregnancy outcomes. Lastly, IL1B has been reported to impair sperm binding to the zona pellucida in EMs (45), suggesting that this mechanism may also contribute to infertility in patients with AM.

As a representative anti-inflammatory cytokine, IL-10 exerts its effects by forming a functional heterodimeric receptor complex composed of IL-10 receptor 1 and IL-10 receptor 2 (46). On one hand, IL-10 suppresses immune responses by inhibiting Th1 cell activity and disrupting the Th1/Th2 balance; on the other hand, it can also enhance immune responses by stimulating the functions of CD8⁺ T cells, NK cells and B cells (47).

Multiple studies have confirmed that IL-10 expression is significantly elevated in both the eutopic and ectopic endometrial epithelial tissues of patients with AM compared with normal endometrium (48-50). Mechanistically, ectopic endometrial tissues in AM exhibit tumor-like invasive and immune escape properties as they must evade host immune surveillance to colonize and proliferate within the myometrium (51). This process is highly consistent with the immunosuppressive function of IL10. In tumor cells, IL-10 has been shown to inhibit antigen-presenting cell function and T cell activation by inducing the expression of human leukocyte antigen-G (HLA-G) and downregulating the levels of classical MHC class I and II antigens, thereby reducing pro-inflammatory cytokine production and achieving immune escape (52). This suggests that IL-10 may play a similar role in AM, promoting immune escape and enabling ectopic endometrial cells to invade the myometrium and establish local immune tolerance (53).

At the maternal-fetal interface, IL-10 critically maintains immune tolerance through STAT3/HOXA10-mediated regulation of ER (54). During the implantation window, IL-10 contributes to the establishment of a tolerogenic immune microenvironment by reducing the proportion and functional activity of uterine NK (uNK) cells at the decidual-placental interface. Abnormally low IL-10 levels in the endometrium or placental tissues have been observed in pregnancy-related complications such as recurrent miscarriage and preeclampsia (55). During the implantation window, significantly reduced local endometrial IL-10 levels have been observed in patients with AM, which may represent a key factor contributing to their lower embryo implantation rates compared with women with normal endometrium (20).

COX-2 is a key enzyme involved in the conversion of arachidonic acid into various endogenous prostaglandins. While typically undetectable in normal tissues, COX-2 can be induced by inflammatory stimuli, earning it the label of a 'stress gene' (56). In AM, elevated COX-2 expression has been observed in both the eutopic and ectopic endometrium; it contributes to disease pathogenesis by regulating inflammatory pathways linked to cell proliferation, angiogenesis and immune suppression (57). Moreover, COX-2 has been proposed as a potential molecular biomarker or therapeutic target for dysmenorrhea in patients with early-stage AM (58). An in vitro study has shown that COX-2 inhibitors significantly suppress the migration and invasion of endometrial mesenchymal stem cells (59), supporting its potential as a novel therapeutic target in AM.

COX-2 exacerbates AM-associated infertility through multiple mechanisms. First, its upregulation increases prostaglandin E2 (PGE2) production, driving chronic inflammation that leads to ovarian apoptosis, pelvic adhesions, fallopian tube dysfunction and luteal phase defects. Second, COX-2-derived PGE2 activates aromatase, boosting local estrogen biosynthesis and creating a positive feedback loop between estrogen and inflammation that accelerates ectopic lesion growth. In addition, the COX-2/PGE2 signaling pathway downregulates progesterone receptor (PR) expression, inducing progesterone resistance and impairing endometrial decidualization (60). Furthermore, COX-2 may disrupt the function of stromal telocytes, compromising structural integrity at the utero-tubal junction and affecting gamete transport and the embryo implantation microenvironment (61). Through these coordinated effects on hormonal balance, tissue structure and immune-endocrine crosstalk, COX-2 acts as a central regulator of reproductive dysfunction in AM.

NF-κB serves as a central regulator of inflammatory responses. Upon stimulation by pro-inflammatory factors such as LPS, TNF-α or IL-1, IKKβ mediates the phosphorylation of IκB, leading to the release of the active p50/p65 heterodimer. This complex translocates into the nucleus and initiates the transcription of pro-inflammatory cytokines such as IL-6, TNF-α and CXCL8, as well as COX-2 (62). A preclinical study has validated the pathogenic role of NF-κB in AM, where endometrial microenvironmental aberrations sustain NF-κB activation, generating cytotoxic inflammation that impairs embryonic viability and endometrial epithelial integrity, ultimately diminishing implantation rates, effects reversible through NF-κB inhibition in murine AM models (63).

In terms of pregnancy, the TLR4/NF-κB pathway regulates maternal-fetal immune tolerance by modulating the Th17/Treg cell ratio. This balance is crucial for proper trophoblast invasion and angiogenesis at the placental interface, which are essential for ensuring adequate fetal blood supply, nutrient delivery and successful pregnancy outcomes (64). Furthermore, NF-κB engages in reciprocal crosstalk with PR isoforms: Chronic inflammatory signaling induces constitutive NF-κB activation that selectively downregulates PR-B expression, fostering progesterone resistance. This molecular disruption impairs endometrial decidualization and creates a non-receptive implantation milieu. Fig. 1 illustrates the regulatory networks of multiple inflammation-related cytokines (including IL-1, IL-6, IL-8 and IL-10) and their downstream signaling pathways (such as NF-κB and STAT3) involved in the aforementioned processes (65).

Immune cells serve as the primary source of inflammatory cytokines, and their dysregulated activation and crosstalk disrupt the endometrial immune microenvironment and maternal-fetal interface homeostasis, ultimately contributing to AM-associated infertility.

Macrophages are critical regulators of tissue inflammation and repair, and their phenotypic and functional abnormalities are closely linked to AM pathogenesis. Studies consistently demonstrate significantly elevated macrophage density in both the eutopic and ectopic endometrial tissues of patients with AM compared with normal endometrium (66,67), with a phenotypic shift: Pro-inflammatory M1 macrophages decrease, while anti-inflammatory M2 macrophages increase, this shift creates an immunosuppressive microenvironment that favors ectopic lesion survival.

The pathogenic effects of M2 macrophages in AM are multifaceted: First, excessive M2-derived cytokines (such as IL-10 and TGF-β) promote angiogenesis, accelerate ectopic endometrial cell proliferation and induce pathological tissue fibrosis. Second, M2 macrophages activate the STAT3 signaling pathway in ectopic endometrial cells, further enhancing their growth and invasive capacity (68), Third, the accumulation of M2 macrophages alters myometrial contractility, disrupting embryo transport through the fallopian tube and impairing the stability of the implantation microenvironment (69).

Mechanistically, an in vitro study has confirmed that AM-derived ESCs secrete chemokine CCL2, which recruits monocytes via the estrogen receptor β (ERβ)/NF-κB signaling pathway (70); these recruited monocytes then undergo excessive M2 polarization under the influence of the CCL2-CCR2 axis. In addition, ESCs release exosomal microRNA (miRNA/miR)-301a-3p, which mediates M2 polarization via the PTEN/PI3K pathway (71), forming a vicious cycle. Upregulated Legumain pseudogene 1 not only promotes M2 polarization but also serves as a non-invasive biomarker for predicting lesion recurrence (72). The resultant M1/M2 disequilibrium disrupts implantation-phase inflammatory homeostasis at the maternal-fetal interface, impairing embryo attachment competence (73).

uNK cells are the most abundant lymphocyte subset in the endometrium, accounting for 30-50% of endometrial lymphocytes and 70% of decidual lymphocytes. Under physiological conditions, uNK cells play indispensable roles in regulating ER, trophoblast invasion and placental vascular remodeling, functions mediated by their secretion of cytokines such as TNF-α, IL-10, IL-1β and LIF (74). The number and function of uNK cells exhibit dynamic changes throughout the menstrual cycle: Their counts remain low during the proliferative phase, increase significantly after ovulation and peak during early pregnancy (75). In the secretory phase, uNK cells participate in spiral artery remodeling; after embryo implantation, they promote early placental development by facilitating trophoblast invasion and optimizing spiral artery dilation, thereby ensuring efficient maternal-fetal exchange of nutrients and oxygen (76). Additionally, uNK cells eliminate infected maternal decidual cells during early pregnancy, maintaining local immune surveillance without damaging the embryo (77). Abnormal uNK cell function has been implicated in multiple reproductive disorders, including recurrent miscarriage and repeated implantation failure, highlighting their critical role in reproductive success (78).

Although current studies have not confirmed significant differences in NK cell expression in women with AM, one key study has reported increased uNK cell counts in the eutopic endometrium of patients with severe AM (diffuse or adenomyoma type). More notably, regardless of quantity, the functional defect of uNK cells in AM [specifically, reduced expression of killer immunoglobulin-like receptors (KIRs)] is a major factor impairing embryo implantation (79). Furthermore, uNK cells collaborate with other endometrial/decidual immune cells to establish a Th2-dominant immune environment, a hallmark of maternal-fetal immune tolerance. In AM, abnormal uNK cell subsets or dysregulated uNK-derived cytokine networks disrupt this Th2-dominant state, increasing the risk of maternal immune rejection of the embryo and impeding successful pregnancy (80).

Aberrant activation of immune cells such as mast cells and T cells adversely affects reproductive function by modulating the inflammatory microenvironment. Table SI summarizes the key immune cell subsets (including mast cells, T cells and other relevant populations), their associated pro-inflammatory/profibrotic mediators and downstream pathological effects on the endometrium and reproductive outcomes. Specifically, activated mast cells release profibrotic mediators such as TGF-β1 and fibroblast growth factor (FGF), which accelerate endometrial fibrosis (81); this not only distorts the endometrial structure (compromising ER) but also enhances the invasive capacity of ectopic lesions. Moreover, mast cell-derived inflammatory mediators (such as histamine and prostaglandins) disrupt endometrial epithelial integrity and alter local blood flow, creating an unfavorable microenvironment for embryo implantation (82).

T cell subsets (particularly Th17 cells and Treg cells) play a central role in maintaining immune homeostasis at the maternal-fetal interface. In AM, this balance is severely disrupted: The number of pro-inflammatory Th17 cells increases, while the number and functional activity of immunosuppressive Treg cells decrease (83), This Th17/Treg imbalance intensifies local endometrial inflammation (such as elevated IL-17 secretion) and impairs maternal-fetal immune tolerance.

The tumor microenvironment, often referred to as the 'soil' for malignant tumor growth, plays a critical role in coordinating tumor invasion and immune evasion through inflammatory mediators, immune cell infiltration, angiogenesis and matrix remodeling. Notably, a highly analogous dynamic system exists in AM. Although considered a benign condition, AM lesions exhibit several hallmarks of malignancy. Specifically, ectopic endometrial cells are capable of degrading the basement membrane via MMP-2 and MMP-9, infiltrating the myometrium in an asymmetric pattern, disrupting the vascular and lymphatic systems and facilitating the implantation of endometrial tissue within the myometrial layer, processes that closely resemble the local invasion behavior of malignant tumors (84). Furthermore, lesion cells can evade apoptosis by upregulating the anti-apoptotic protein Bcl-2 through the activation of NF-κB signaling (85). In addition, persistent activation of hypoxia-inducible factor-1α (HIF-1α) drives a shift toward glycolytic metabolic reprogramming, resulting in excessive lactate production. This not only supports cellular energy homeostasis but also creates an acidic microenvironment similar to that observed in tumors, thus establishing a vicious cycle that confers survival advantages (86). Notably, chronic inflammatory stimulation has been shown to induce the expression of epithelial-mesenchymal transition (EMT) markers such as Snail and vimentin, which enhances the invasive potential of lesion cells and significantly increases the risk of malignant transformation of ectopic endometrial lesions (87).

The immune dysregulation associated with AM markedly contributes to infertility; it impairs ovulatory function, induces tubal dysfunction or adhesions and disrupts the transport of sperm and embryos (88). Additionally, the immunosuppressive microenvironment, characterized by the secretion of immunoinhibitory factors, interferes with the immune support required for normal embryo development, leading to pregnancy failure (Fig. 2) (89). Some patients may also produce autoantibodies against endometrial tissue or embryos (such as antiphospholipid antibodies and anti-endometrial antibodies), directly damaging the endometrium or targeting the embryo, thereby impairing implantation (90). Moreover, abnormal expression of chemokines and adhesion molecules may disrupt embryo-endometrial signaling, reducing ER. A recent single-cell RNA sequencing study has revealed altered intercellular communication among epithelial cells, stromal cells, perivascular cells, endothelial cells and immune cells within ectopic lesions. These alterations lead to changes in pathways associated with cell proliferation, angiogenesis and immune responses, underscoring the dynamic remodeling of the AM microenvironment. This spatiotemporal dysregulation ultimately impairs embryo implantation (91).

Under physiological conditions, the JZ (a transitional region between the endometrium and myometrium) serves two core functions; it exhibits periodic contractile patterns to regulate menstrual shedding, gamete transport and embryo implantation (92), while also acting as a physiological immune regulatory barrier that maintains genital tract microbial homeostasis and optimizes the embryo implantation microenvironment via immune cells (such as macrophages and NK cells) and cytokine networks (93).

In MRI diagnostics, JZ thickening (>12 mm) is explicitly a pathognomonic feature of AM (94). Maubon et al (95) confirmed a threshold-dependent association between JZ thickness and implantation rate: Implantation rates of 45% when JZ thickness is <10 mm, a sharp decline to 16% at 10-12 mm, and a further reduction to 5% in cases with JZ thickness >12 mm. They further summarized that MRI-quantified JZ thickness is the primary negative predictor of implantation failure; specifically, beyond the critical threshold of 7 mm, the risk of implantation failure increases exponentially (95). This inverse thickness-implantation relationship persists across diagnostic modalities. Notably, Tellum et al (96) emphasized that JZ morphological heterogeneity, particularly focal asymmetric thickening secondary to myometrial cysts or adenomyoma formation, should be incorporated into the differential diagnostic criteria for AM.

JZ dysfunction in patients with AM impairs placentation. Impaired decidual transformation leads to trophoblast retention within the JZ, hindering spiral artery remodeling and causing defective deep placentation (17). Single-cell RNA sequencing has further confirmed a reduced number of uNK cells and an insufficient secretion of angiogenic factors in JZ-thickened regions, which directly limits the depth of trophoblast invasion and exacerbates defective deep placentation (16). Therefore, the abnormally thickened JZ observed in AM may hinder embryo transport and preimplantation positioning, while also disrupting the microenvironmental homeostasis at the endometrial-myometrial junction (EMJ) during decidualization (12).

Physiologically, uterine peristalsis exhibits phase-specific dynamics. Antegrade peristaltic waves mediate menstrual shedding during the proliferative phase, retrograde contractions facilitate sperm migration during the ovulatory window and quiescent contractions in the luteal phase create a favorable microenvironment for embryo implantation (97). Thus, physiological uterine peristalsis is indispensable for coordinating intrauterine sperm and embryo translocation. In patients with AM, speckle-tracking transvaginal ultrasonography reveals characteristic pathological contractile patterns, including a disorganized contractile direction during the ovulatory phase and hypercontractility in the luteal phase (98). The core mechanism underlying this pathological contractility is linked to the excessive local production of prostaglandin F2α (PGF2α) and IL-6 in the JZ (99). These factors collectively drive luteal-phase uterine hyperperistalsis, impairing embryo positioning and adhesion. Chronic hypercontractility further exacerbates JZ microtrauma, sustains inflammatory cascades and establishes an 'inflammation-estrogen' feedforward loop that accelerates AM pathogenesis. Clinically, these dysregulations manifest as obstetric sequelae, including uterine atony, retained placenta and postpartum hemorrhage, highlighting the central role of JZ dysfunction in both the pathological mechanisms and clinical consequences of AM (100).

The TIAR hypothesis is a central framework for explaining AM pathogenesis, as it highlights inflammation and immune dysregulation as key drivers of disease initiation and progression, with elevated inflammatory mediators and a disrupted endometrial immune niche ultimately impairing embryo implantation (101). This subsection systematically elaborates on the triggers of TIAR, its mediated pathological cascades and the subsequent amplifying loops that sustain AM development.

TIAR activation in AM arises from two primary sources of mechanical stress. Endogenously, supraphysiological uterine peristalsis and increased intrauterine pressure (a hallmark of AM) directly damage myocytes and fibroblasts within the JZ, a critical physical barrier between the endometrium and myometrium (102), and this mechanical damage initiates the TIAR cascade. Exogenously, iatrogenic injuries (such as curettage, childbirth, induced abortion and cesarean section) impose supraphysiological mechanical strain on the uterus, directly inducing COX-2 and CXCL8 expression in fibroblasts (4). Even mild mechanical stretching of cultured fibroblasts has been shown to activate COX-2, promote PGE2 and CXCL8 production and thereby trigger TIAR (4). Notably, iatrogenic damage often impairs the JZ (103); as the JZ serves as a barrier to prevent endometrial invasion, its disruption further facilitates endometrial penetration into the myometrium and increases AM risk following intrauterine procedures (104).

Once triggered, the TIAR cascade drives AM progression through a sequential pathological process. First, TIAR-induced microtrauma leads to myometrial fissures, enabling the ectopic displacement of endometrial fragments (105). These ectopic fragments are recognized by the immune system as damaged tissue-initiating lesion-specific inflammatory priming characterized by IL1B/IL-6 upregulation, platelet aggregation and HIF-1α stabilization, which propagates local-to-systemic inflammatory cascades (102). At the molecular level, IL1B plays a central role in amplifying inflammation; it activates COX-2 transcription via a mitogen-activated protein kinase (MAPK)-dependent pathway, which enhances COX-2 binding to the cAMP response element, recruiting immune cells and further amplifying the inflammatory cascade (106), and it activates the ERK1/2 and NF-κB signaling pathways to induce COX-2 expression; elevated COX-2 then promotes PGE2 synthesis (9), which in turn upregulates IL-6 and CXCL8 expression, creating a positive feedback loop to sustain inflammation.

Beyond inflammatory amplification, the TIAR-mediated response interacts with estrogen metabolism to form a vicious cycle that accelerates AM chronicity. PGE2 upregulates the expression of steroidogenic acute regulatory protein and CYP19A1 to enhance local E2 biosynthesis (67); E2 further activates estrogen receptors (ERα/ERβ) to promote cell proliferation while simultaneously trans-activating the COX-2 gene, thus increasing PGE2 production and perpetuating inflammation. Notably, ectopic lesions (predominantly localized to the anterior/posterior uterine walls and fundal-cornual regions with concentrated mechanical stress) exacerbate uterine hyperperistalsis, which reinforces this TIAR-inflammation-estrogen loop and in turn drives disease progression (107).

EMT is a biological process in which epithelial cells lose polarity and intercellular junctions, gaining mesenchymal characteristics, including enhanced motility and invasiveness (108). Hallmarks of EMT include downregulation of E-cadherin and upregulation of N-cadherin and vimentin, resulting in the loss of epithelial polarity and increased invasive potential. In AM, EMT serves as a key driver of ectopic lesion formation by enabling endometrial cells to traverse the EMJ and establish adenomyotic lesions (67), while also exacerbating disease progression by promoting fibrosis and uterine dysfunction.

Multiple cytokines and signaling pathways orchestrate EMT in AM. CXCL8 activates the FAK/PI3K/AKT pathway to enhance the proliferation, migration and invasiveness of eutopic ESCs (34), supporting their survival in ectopic environments (59). Macrophage-induced IL-6 overactivation in human endometrial cells suppresses E-cadherin promoter activity and upregulates N-cadherin/vimentin via the JAK2/STAT3 pathway, directly inducing EMT (67). IL1B activates the Wnt/β-catenin pathway, a key regulator of EMT, with COX-2 further amplifying this effect to drive AM progression (109,110). Hypoxic conditions in the ectopic microenvironment also induce HIF-1α expression, which upregulates IL-6, CXCL8 and CXCL12. CXCL12 promotes angiogenesis via its receptor CXCR4, while IL-6 and CXCL8 amplify inflammatory and pro-fibrotic signals (103).

Additionally, Notch1 is upregulated in ectopic endometrium and indirectly promotes EMT by modulating pathways such as NF-κB, leading to N-cadherin/Snail/Slug upregulation and E-cadherin loss; downregulation of Numb, a negative regulator of Notch, may further exacerbate EMT-driven fibrosis and lesion invasion (111). Although the direct role of IL-10 in AM-associated EMT remains unstudied, its EMT-promoting effects in cancer and renal cells suggest potential relevance (112); notably, thymus-expressed chemokine derived from embryonic stem cells and macrophages upregulates Tregs in the ectopic microenvironment, promoting IL-10/TGF-β1 secretion that suppresses NK cell cytotoxicity and Th1-type immunity, creating an immunosuppressive niche that protects ectopic endometrial cells from clearance (113). Beyond driving ectopic lesions, EMT collaborates with fibrosis to worsen AM pathogenesis, as fibrosis in AM arises from dysregulated wound healing. Unlike the regenerative phase of normal tissue repair (where injured cells are replaced without scarring), AM is characterized by a fibrotic phase in which parenchymal tissue is replaced by fibrotic connective tissue, accompanied by excessive extracellular matrix (ECM) deposition and remodeling imbalance (114).

EMT and FMT are central to this process, driving lesion stabilization and myometrial thickening (115), while ectopic ESCs directly interact with the myometrium to induce SMC fusion and abnormal expansion, altering uterine morphology and function. As key fibrotic regulators, macrophages orchestrate EMT, FMT and SMC modulation via M1-M2 polarization and activation of the canonical TGF-β/Smad3 pathway, synergistically promoting ECM collagen synthesis; during phagocytic clearance of cellular debris, they also regulate ECM turnover via the dynamic balance between MMPs and their TIMPs, mediating the degradation-deposition cycle of ECM reconstruction (84,116), a pathway that further cross-talks with PI3K/AKT and MAPK signaling to amplify pro-fibrotic effects. Under TIAR mechanisms, ectopic endometrial cells undergo cyclic hemorrhage-induced chronic inflammation, triggering EMT, FMT and SMC modulation to form fibrotic scars, with fibrosis markers such as α-smooth muscle actin and type I collagen positively correlating with uterine volume, linking fibrosis severity to disease progression (114).

From a reproductive perspective, EMT and fibrosis disrupt AM-associated reproductive function via multiple pathways: They cause structural disruption at the EMJ, interfering with embryo implantation and placental development; induce uterine hyperperistalsis, impairing embryo and gamete transport (117); and promote excessive scar formation that increases intrauterine adhesion risk, ultimately contributing to infertility (118). The integrated regulatory network linking these key pathogenic processes (inflammatory cytokine signaling, TIAR cascades, EMT, FMT and fibrosis) to AM-related reproductive dysfunction is systematically summarized in Fig. 3.

In AM, aberrantly elevated pro-angiogenic factors, such as VEGF and FGF, and reduced anti-angiogenic activity drive excessive neovascularization. This not only provides nutritional support for ectopic lesions [facilitates their invasion, survival and proliferation to form a vicious cycle (119)] but also causes structural abnormalities in neovessels. These fragile vessels are prone to rupture, leading to abnormal uterine bleeding, disrupted endometrial homeostasis and impaired ER (120). The aberrant vascular network further interferes with embryo positioning and adhesion, contributing to implantation failure.

Pathological angiogenesis in AM is primarily triggered by TIAR, closely linked to vascular damage from cyclical endometrial bleeding (121). Under physiological conditions, endometrial repair follows a four-phase process: Hemostasis, inflammation, proliferation and remodeling (122). This ordered process ensures proper tissue recovery without persistent damage. However, in pathological states, this repair process is disrupted. The disorganized repair leads to vascular structures, which in turn exacerbate local inflammation and fibrosis and perpetuate a vicious cycle of tissue injury and dysregulated repair.

In the initial phase of repair, activated platelets drive hemostasis (123) and release bioactive molecules [such as thromboxane A2, 5-hydroxytryptamine, PDGF and epidermal growth factor (EGF)] that upregulate pro-inflammatory genes including VEGF, COX-2 and MMP-9, thereby creating a pro-angiogenic microenvironment (124). Notably, VEGF, a key specific marker of angiogenesis, not only directly promotes endothelial cell proliferation but is also elevated in the follicular fluid of patients with EMs, and clinically increased VEGF levels are significantly associated with poor ovarian response, reduced oocyte maturation rates and higher miscarriage risk (125).

Moreover, platelets secrete platelet-derived growth factor, EGF and FGF to directly stimulate endothelial proliferation and recruit macrophages and neutrophils to the lesion site; these immune cells subsequently release inflammatory cytokines (such as IL-6, IL-10, CXCL8, TGF-β, IL-22 and NF-κB) to amplify the local inflammatory response (Fig. 4) (126,127). Platelets also upregulate tissue factor, which binds to circulating factor VIIa to activate the coagulation cascade. The resultant thrombin generation promotes sustained platelet activation, forming a 'coagulation-inflammation' positive feedback loop (128). Salim et al (129) confirmed the upregulation of these angiogenesis- and inflammation-related factors in adenomyotic lesions, supporting increased pathological neovascularization. Growing evidence indicates that platelets are not merely hemostatic cells but also key immunoregulatory agents (130) whose interaction with ectopic lesions fosters a microenvironment supporting lesion progression and fibrosis (131).

The interplay between angiogenesis, immune cells and inflammation is well-recognized (132). Angiogenesis is modulated by immune cells and inflammatory mediators (133-135) and reciprocally influences immune responses. Wei et al (136) demonstrated that IL-6 promotes pathological angiogenesis by upregulating VEGF via activating the STAT3 signaling pathway. Clinical data reveal a strong positive correlation between serum IL-6 levels and lesion microvessel density, indicating the potential of IL-6 as a biomarker for disease progression (137). Thymic stromal lymphopoietin (TSLP) induces CXCL8 secretion in cervical cancer cells via the ERK1/2 pathway to stimulate human umbilical vein endothelial cell proliferation and angiogenesis, and this mechanism appears to be recapitulated in the ectopic endometrium of AM, suggesting TSLP as a potential therapeutic target (138,139). IL1B enhances CXCL8 and VEGF expression to promote invasive migration of ESCs and facilitate immune cell extravasation by upregulating ICAM-1 and VCAM-1, thereby driving tissue remodeling (140). Silencing the COX-2 gene significantly reduces VEGF and MMP-9 expression in ectopic endometrium, underscoring the pivotal role of COX-2 as an upstream regulator in AM (141). Additionally, clinical specimens show a strong correlation between COX-2 positivity, dysmenorrhea severity and lesion volume (58). As a central transcription factor, NF-κB directly regulates COX-2, VEGF, MMPs and the plasminogen activator system (142,143), and mediates endothelial inflammation induced by IL1B and TNF-α (144), highlighting the central role of the COX-2/NF-κB axis.

Compared with normal endometrium, IL-10 expression in adenomyotic tissues is reduced by 62%, which impairs its regulatory effect on COX-2, MMP-2 and MMP-9 and contributes to uncontrolled angiogenesis (145); this dysregulation is closely associated with impaired ER due to an abnormal IL-10/IL-6 ratio during the implantation window. IL-22, a member of the IL-10 cytokine family, enhances stromal cell invasiveness by upregulating VEGF, IL-6 and CXCL8 expression (146), and clinical data show that serum IL-22 levels are significantly elevated in infertile patients and inversely correlated with embryo implantation rates during IVF cycles (147). Fischer et al (148) confirmed by immunohistochemistry that eutopic endometrial cells in AM exhibit heightened sensitivity to IL-1, with increased expression of CXCL8, CXCL8 receptor and VEGF, indicating that excessive neovascularization impairs ER. The expression of angiogenic markers in both eutopic and ectopic endometrium suggests that angiogenesis not only facilitates invasion of normal endometrial tissue but also supports the maintenance of ectopic lesions, thereby serving as a critical factor in implantation failure (128).

Furthermore, tissue injury-induced vascular hyperpermeability, extravasation of blood components and increased interstitial fluid volume (149) may contribute to common clinical symptoms in patients with AM such as abnormal uterine bleeding and infertility (150). Perfusion loss and subsequent hypoxia from vascular injury activate the HIF-1α/NF-κB pathway, which robustly upregulates VEGF expression (151) and drives the COX-2-PGE2-P450 aromatase positive feedback loop, leading to abnormal uterine peristalsis; clinical data show a strong correlation between COX-2 and VEGF expression (152). During this process, upregulated PGE2 activates P450 aromatase to promote local estrogen synthesis, which in turn induces EMT and increases vascular permeability, driving ectopic endometrial cells into a pro-angiogenic state (67,153). Additionally, extravasated platelets may provide a protective barrier for ectopic stromal cells, shielding them from physical clearance and immune surveillance (133).

NSAIDs exert therapeutic effects in AM primarily by inhibiting COX activity and subsequently reducing prostaglandin synthesis (201). Studies have demonstrated that NSAIDs can decrease the depth of endometrial infiltration into the myometrium, inhibit the migration and invasion of ESCs and induce apoptosis (202,203). In addition, NSAIDs suppress key pathological processes such as fibrosis, angiogenesis and EMT (204). Therefore, NSAIDs are considered promising pharmacological candidates for the clinical management of AM.

Celecoxib, a highly selective COX-2 inhibitor, significantly reduces inflammatory responses and the depth of lesion infiltration in EMs by suppressing the expression of pro-inflammatory cytokines such as IL1B, IL-6 and TNF-α, as well as the transcription factor NF-κB (205). Studies have suggested that in ART, localized inflammatory responses may impair embryo implantation by inducing abnormal uterine contractility and reducing ER via prostaglandin-mediated mechanisms (10,206). Theoretically, NSAIDs may improve ART outcomes by mitigating the detrimental effects of prostaglandins; however, this hypothesis requires further experimental validation (207).