Hippo pathway in endometriosis pathogenesis: from cellular dysregulation to therapeutic opportunities

Endometriosis is a chronic, heterogeneous gynaecological disorder characterised by the presence of endometrial-like tissue outside the uterine cavity and is associated with pain, infertility, and reduced quality of life. Emerging evidence suggests that dysregulation of the Hippo signalling pathway—a central regulator of cell proliferation, survival, mechanotransduction, and tissue homeostasis—may contribute to several pathogenic processes involved in endometriosis. This narrative review synthesises direct evidence from endometriosis studies and clearly identified mechanistic evidence from related disease models. Aberrant Hippo pathway activity and sustained activation of the transcriptional co-activator YAP1 have been linked to enhanced cellular proliferation, invasive behaviour, apoptosis resistance, altered autophagy, ferroptosis resistance, fibrosis, and progesterone resistance. Hippo signalling integrates mechanical, metabolic, inflammatory, and hormonal cues within the endometriotic microenvironment and interacts with other disease-relevant pathways, including the mechanistic target of rapamycin (mTOR), estrogen and progesterone signalling, epigenetic regulation, and immune modulation. Preclinical and experimental findings suggest that components of the Hippo pathway and its regulatory network may represent potential non-hormonal therapeutic targets. However, no Hippo pathway-targeting strategy has been clinically validated for endometriosis, and the physiological roles of YAP/TAZ in tissue homeostasis and regeneration require careful consideration. Further subtype-resolved mechanistic studies, robust preclinical validation, and clinical safety assessment are, therefore, required before these approaches can be translated into practice. 1 Endometriosis Endometriosis is a chronic and debilitating gynaecological disorder characterised by endometrial-like tissue outside the uterine cavity, commonly involving the ovaries, pelvic peritoneum, and other pelvic structures. Based on anatomical location and pathological features, the disease is conventionally classified into three major subtypes: superficial peritoneal endometriosis (SPE), the most prevalent form; ovarian endometrioma (OE), commonly referred to as an endometrioma or “chocolate cyst”; and deep infiltrating endometriosis (DE). These subtypes may represent biologically distinct entities with differences in inflammatory activity, fibrosis, hormonal responsiveness, and invasive behaviour (Nisolle and Donnez, 1997). Although the precise etiology of endometriosis remains incompletely understood, the disease is widely considered to arise from a complex interplay of genetic susceptibility, environmental influences, hormonal dysregulation, and altered immune responses. Retrograde menstruation remains the most widely accepted initiating mechanism; however, only a subset of women develop endometriosis, suggesting that additional molecular, inflammatory, and microenvironmental factors contribute to lesion establishment and persistence (Habiba et al., 2023). In severe cases, endometriosis may result in infertility (Ozkan et al., 2008). Several risk factors have been associated with endometriosis, including early menarche, shorter menstrual cycle length, low body mass index (BMI), nulliparity, and congenital obstructive Müllerian anomalies (As-Sanie et al., 2025). Recent evidence further characterises endometriosis as a chronic inflammatory and fibrotic disorder associated with altered immune responses, extracellular matrix remodelling, progesterone resistance, and aberrant tissue repair, potentially reflecting the repeated microinjury and repair processes proposed in the tissue injury and repair (TIAR) theory (Chapron et al., 2019). Given the established role of Hippo-YAP signalling in mechanosensing and fibrotic tissue remodelling, dysregulation of this pathway may contribute to lesion establishment, persistence, and fibrosis (Liu et al., 2015). Direct comparisons among SPE, OE, and DE are currently lacking; therefore, the possibility of greater Hippo pathway activation in highly fibrotic or invasive lesions, particularly DE, should be regarded as a testable hypothesis rather than an established subtype-specific mechanism (Table 1). TABLE 1 | Component | Category | Function in the Hippo pathway | Relevance to endometriosis | Key reference | |---|---|---|---|---| | MST1/2 (STK4/STK3) | Ser/Thr kinases | Initiate Hippo kinase cascade | Reduced activity has been associated with increased YAP activation in ectopic lesions | Boggiano et al. (2011), Callus et al. (2006), Harvey et al. (2013) | | SAV1 | Scaffold protein | Stabilizes MST1/2–LATS complex | Downregulated in ectopic tissue | Callus et al. (2006), Cui et al. (2020) | | MOB1A/B | Adaptor proteins | Required for LATS activation | Decreased phosphorylation in ectopic endometrium | Praskova et al. (2008), Cui et al. (2020) | | LATS1/2 | Tumour suppressor kinases | Phosphorylate YAP/TAZ | Reduced activity may facilitate nuclear YAP accumulation | (Meng et al. (2015), Harvey et al. (2013), Cui et al. (2020) | | YAP1 | Transcriptional co-activator | Drives TEAD-dependent transcription | Reported to be overexpressed and transcriptionally active in ectopic lesions | Song et al. (2016), Pei et al. (2019) | | TAZ (WWTR1) | Transcriptional co-activator | Functional paralog of YAP | Elevated expression in lesions | Song et al. (2016), Boddeti et al. (2025) | | TEAD1–4 | Transcription factors | Bind YAP/TAZ | Mediate fibrotic and invasive programs | Zhao et al. (2008), Zhu et al. (2017) | Core components of the Hippo signalling pathway and their functions. Endometriosis presents with a broad spectrum of clinical manifestations, among which pelvic pain is the most frequently reported symptom and affects approximately 80% of patients with endometriosis (Maddern et al., 2020). This pain commonly manifests as dysmenorrhea, dyspareunia, dyschezia, or pain during urination (dysuria). Endometriosis-associated pain is multifactorial and arises from the interaction of central and peripheral pain mechanisms, driven by lesion-specific pathophysiological processes. These include elevated levels of cytokines, growth factors, prostaglandins, and other inflammatory mediators within the lesion microenvironment, as well as neuroangiogenesis, fibrosis, aberrant tissue remodelling, and altered immune cell activity, all of which contribute to lesion persistence and chronic pain development. Studies have demonstrated that endometriotic lesions and the surrounding peritoneal microenvironment differ fundamentally from eutopic endometrium in terms of inflammatory signalling, steroid hormone responsiveness, neurovascular density, and immune cell composition, particularly involving macrophage-related pathways (Table 2). Collectively, these features link lesion biology to pain pathways and lesion persistence, providing mechanistic insight into disease symptoms while also highlighting potential targets for disease-modifying therapies (Saunders and Horne, 2025). Persistent peripheral inflammation may additionally promote central sensitisation, thereby contributing to chronic pelvic pain in endometriosis (Maddern et al., 2020). TABLE 2 | Biological process | Hippo/YAP involvement | Pathological consequence | Key reference | |---|---|---|---| | Cell proliferation | Nuclear YAP-TEAD activation | Lesion growth | Song et al. (2016), Cui et al. (2020) | | Apoptosis | Suppression of pro-apoptotic genes | Lesion survival | Vetvicka et al. (2016), Song et al. (2016) | | Autophagy | YAP-mTOR activation | Impaired decidualisation | Pei et al. (2019), Pei et al. (2022) | | Ferritinophagy | Reduced USP33–LATS1 activity and impaired NCOA4-mediated ferritinophagy | Reduced ferroptotic sensitivity and lesion survival | Santana-Codina et al. (2021), Li L. et al. (2026) | | Ferroptosis | Antioxidant reprogramming | Ferroptosis resistance | Ni and Li (2024), Sun and Chi (2021), Xiang et al. (2023) | | Fibrosis | YAP-driven connective tissue growth factor (CTGF)/extracellular matrix (ECM) induction | Tissue stiffening | (Liu et al. (2015), Zhu et al. (2017) | | EMT and invasion | YAP-driven transcription | Enhanced invasive behaviour; possible relevance to fibrotic or deep lesions | Konno et al. (2020), Feng et al. (2025) | | Angiogenesis | Hypoxia-YAP signalling | Sustained vascularization | Wu et al. (2019), Lin et al. (2017) | Hippo-YAP-dependent cellular processes dysregulated in endometriosis. Additional clinical manifestations include heavy or irregular menstrual bleeding, such as intermenstrual bleeding, menorrhagia, or prolonged menstrual periods, as well as infertility, often presenting as difficulty in achieving or maintaining a successful pregnancy. Gastrointestinal symptoms are also common and may include bloating (frequently referred to as “endo belly”), nausea, diarrhea, constipation, or abdominal pain (Velho et al., 2023). Systemic symptoms such as persistent fatigue may occur even after adequate rest. Some patients experience painful ovulation or mid-cycle pain, while others report localised tenderness or pruritus in surgical scars following endometriosis-related procedures. Psychological comorbidities, including anxiety and depression, are frequently reported and substantially impair quality of life (Saunders and Horne, 2021). Collectively, these diverse clinical manifestations reflect the complex inflammatory, neuroimmune, and fibrotic nature of endometriosis. The severity of symptoms varies widely among patients, and a significant proportion of women remain asymptomatic. The diagnosis of endometriosis typically relies on a combination of detailed medical history, physical examination, and imaging modalities. Ultrasonography and magnetic resonance imaging (MRI) are recommended in several clinical guidelines for the detection of OE and DE. However, these modalities have limited sensitivity for SPE and extrapelvic lesions. Emerging evidence suggests that molecular imaging approaches targeting fibrotic components of endometriotic lesions may improve diagnostic sensitivity and disease characterisation. In this context, radiolabeled molecular targets, such as fibroblast activation protein-α (FAP), which is highly expressed in fibrotic tissue, have emerged as promising alternative diagnostic tools. Furthermore, advanced imaging techniques, including positron emission tomography–computed tomography (PET–CT) combined with specific radiotracers, show potential for the detection of fibrotic endometriotic lesions. However, these approaches remain largely investigational and require further clinical validation before routine implementation. Nevertheless, the diagnostic utility of fluorodeoxyglucose (FDG) is limited by physiological uptake in the endometrium and ovaries of premenopausal women, complicating image interpretation (Saunders and Horne, 2025). In selected cases, diagnostic laparoscopy remains necessary to confirm endometriosis, allowing direct visualisation and surgical excision of ectopic lesions (Ozkan and Arici, 2009). According to the Revised American Society for Reproductive Medicine (rASRM) classification system, endometriosis is staged from I to IV based on lesion location, depth of invasion, extent, morphology, and subtype (Author Anonymous, 1997). However, mounting evidence indicates that the correlation between rASRM stage and pain severity is weak and inconsistent, underscoring that pain intensity does not reliably reflect disease stage (Vercellini et al., 2007). Despite its high prevalence, endometriosis is frequently misdiagnosed or remains undetected for prolonged periods, largely due to limited disease awareness and symptom overlap with other conditions such as irritable bowel syndrome, pelvic inflammatory disease, and bladder pain syndrome. Consequently, patients often consult multiple specialists and receive symptomatic treatment, resulting in repeated healthcare visits and substantial diagnostic delays (Melgaard et al., 2025) (Table 3). Current management strategies remain largely focused on symptom control and suppression of lesion growth; however, these approaches do not adequately address the underlying molecular mechanisms associated with lesion persistence, chronic inflammation, fibrosis and disease recurrence (Saunders and Horne, 2021; Kalaitzopoulos et al., 2021; Bora and Yaba, 2021). This limitation has driven increasing interest in molecular pathways involved in endometriosis pathogenesis, including pathways associated with inflammation, mechanotransduction, fibrosis and aberrant cellular survival signalling. Based on evidence derived from both endometriosis-specific studies and broader mechanobiology research, the Hippo pathway has emerged as a potential regulator linking these processes. TABLE 3 | Hormonal pathway | Interaction with YAP | Clinical implication | Key reference | |---|---|---|---| | Progesterone receptor (PGR) | YAP induces miR-21-5p | Progesterone resistance | Patel et al. (2017), Lin et al. (2023) | | Decidualisation | YAP suppresses autophagy | Implantation failure | Pei et al. (2019), Lin et al. (2023) | | Estrogen receptor β (ESR2) | YAP–ESR2 crosstalk | Enhanced invasiveness | Zeng et al. (2020) | | Progestin therapy | In vitro YAP inhibition increased progestin responsiveness | Potential restoration of sensitivity; not clinically validated | Lin et al. (2023) | Hippo-YAP signalling and hormonal resistance in endometriosis. Conventional therapeutic approaches primarily include hormonal suppression, analgesics, and surgical excision of lesions (Huntington and Gilmour, 2005). Non-steroidal anti-inflammatory drugs are commonly used for pain management, although the supporting evidence is limited (Brown et al., 2017). Hormonal therapies suppress disease activity but may be limited by adverse effects, contraindications, and symptom recurrence after discontinuation (Petraglia et al., 2025). Laparoscopic excision may reduce pain and improve fertility outcomes in selected patients, although recurrence remains common (Vercellini et al., 2009). In addition to conventional therapies, lifestyle and complementary interventions have been investigated as supportive approaches to symptom management. Dietary modification, physical activity, and stress-reduction strategies may improve pain perception or quality of life in some patients, although the evidence is heterogeneous (Nirgianakis et al., 2022). A systematic review has examined physical exercise in endometriosis (Bonocher et al., 2014), while more recent work has evaluated broader self-management strategies (Mardon et al., 2023). Acupuncture has also been assessed in a systematic review and meta-analysis (Giese et al., 2023). Natural bioactive compounds and herbal medicines are under experimental investigation for anti-inflammatory, antifibrotic, and signalling-modulatory effects (Elbanna et al., 2025). These findings remain preliminary and do not establish clinical efficacy or Hippo pathway specificity. Although substantial progress has been made in defining the inflammatory, hormonal, and fibrotic biology of endometriosis, important mechanistic and therapeutic gaps remain. This review, therefore, examines evidence linking Hippo pathway dysregulation to lesion establishment, persistence, and clinical phenotypes while explicitly distinguishing direct endometriosis data from mechanistic evidence extrapolated from related models. It also evaluates experimental therapeutic strategies and the limitations that must be addressed before clinical translation. 2 Literature search strategy PubMed was the sole bibliographic database used for this narrative review. The search covered database inception to 31 July 2026, with no publication-year restriction. English-language, peer-reviewed original studies, translational or clinical investigations, and selected reviews with accessible abstracts and full texts relevant to the review scope were considered. The principal search strategy combined the disease term with pathway and process terms as follows: (“endometriosis” [Title/Abstract]) AND (“Hippo signalling” [Title/Abstract] OR “Hippo pathway” [Title/Abstract] OR YAP [Title/Abstract] OR TAZ [Title/Abstract] OR mechanotransduction [Title/Abstract] OR fibrosis [Title/Abstract] OR autophagy [Title/Abstract] OR ferroptosis [Title/Abstract] OR “progesterone resistance” [Title/Abstract] OR SOX18 [Title/Abstract] OR OTUB1 [Title/Abstract] OR USP33 [Title/Abstract] OR circRNA [Title/Abstract] OR m6A [Title/Abstract]). Additional targeted combinations were used for immune regulation, lesion subtype, and experimental therapeutic strategies (Table 4). TABLE 4 | Regulator | Mechanism | Effect on YAP | Functional outcome | Key reference | |---|---|---|---|---| | ECM stiffness | Actin remodelling | YAP activation | Fibrosis-driven persistence | Aragona et al. (2013), Liu et al. (2015) | | Hypoxia | LATS1 suppression | Nuclear YAP accumulation | Angiogenesis, inflammation | Wu et al. (2019), Lin et al. (2017) | | SOX18 | OTUB1 induction | YAP stabilization | Invasion and fibrosis | Feng et al. (2025) | | OTUB1 | Deubiquitination | Prevents YAP degradation | Sustained YAP signalling | Feng et al. (2025), Ling et al. (2022) | | USP33 | LATS1 stabilization through reduced ubiquitination | Indirect YAP inhibition | Restored ferritinophagy and ferroptotic sensitivity in one endometriosis study | Li J. et al. (2026), Li L. et al. (2026) | | ANTXR2 | Promotes nuclear YAP | Transcriptional activation | Lesion progression | Bell et al. (2001), Scobie et al. (2003), Liu et al. (2009), Lin et al. (2019) | | circRNAs | miRNA sponging | YAP derepression | EMT induction | Zhang et al. (2018), Wang et al. (2020) | | m6A modification | Reduced METTL3/METTL14 expression and global m6A hypomethylation | Association with Hippo-related transcript networks; direct causality unconfirmed | Enhanced proliferation and invasion after METTL3/METTL14 co-silencing | Wu et al. (2023), Li et al. (2019), Li et al. (2022), Shen et al. (2023) | Upstream regulators of Hippo–YAP signalling in endometriosis. Titles and abstracts were screened for relevance, followed by full-text evaluation. Studies directly investigating Hippo signalling in endometriosis were prioritised. Mechanistically relevant studies from other gynaecological, oncological, or fibrotic models were included only when direct endometriosis evidence was unavailable and are identified as indirect evidence in the text. Conference abstracts, editorials, duplicate reports, non-peer-reviewed material, and studies without a relevant Hippo-endometriosis or mechanistic link were excluded. Reference lists of eligible articles were also screened manually. Because the work was designed as a narrative review, duplicate removal and PRISMA-style numerical tracking were not prospectively recorded, and no formal risk-of-bias assessment was performed. The final synthesis contains 94 cited publications. This limitation is stated explicitly to avoid presenting the review as a systematic review. 3 Hippo signalling pathway The Hippo signalling pathway, also referred to as the Salvador–Warts–Hippo (SWH) pathway, is an evolutionarily conserved regulatory network that governs tissue homeostasis by controlling cell proliferation, apoptosis, and organ size. Initially characterised in Drosophila melanogaster, the pathway was shown to restrict tissue overgrowth by coordinating cell-cycle progression and programmed cell death. Beyond its classical role in growth control, the Hippo signalling functions as a mechanosensitive network that integrates biochemical, inflammatory, and biomechanical cues from the cellular microenvironment. In mammals, the core Hippo pathway consists of mammalian STE20-like kinases 1 and 2 (MST1/2), the scaffold protein Salvador homolog 1 (SAV1), MOB kinase activator 1A/B (MOB1A/B), large tumour suppressor kinases 1 and 2 (LATS1/2), the transcriptional co-activator Yes-associated protein 1 (YAP), and the transcriptional co-activator with PDZ-binding motif (TAZ; also known as WWTR1). In the canonical Hippo pathway, activation of MST1/2 and LATS1/2 results in phosphorylation-dependent inhibition of YAP and TAZ, promoting their cytoplasmic retention and degradation. Conversely, suppression or dysregulation of Hippo kinase activity permits nuclear accumulation of YAP/TAZ, where they interact primarily with TEAD transcription factors to regulate genes involved in proliferation, survival, fibrosis, mechanotransduction, cellular plasticity and tissue remodelling. The Hippo kinase cascade is initiated by thousand-and-one amino acid (TAO) kinases, a family of serine/threonine protein kinases comprising TAO1, TAO2, and TAO3, which phosphorylate and activate MST1/2 (Boggiano et al., 2011). Activated MST1/2, in complex with SAV1, subsequently recruit and phosphorylate LATS1/2 in association with MOB1A/B (Callus et al., 2006; Praskova et al., 2008). Activated LATS1/2 phosphorylate YAP and TAZ, promoting their cytoplasmic retention and functional inhibition. In parallel, members of the MAP4K family (MAP4K1/2/3/5) can activate LATS1/2 independently of MST1/2, providing regulatory redundancy (Meng et al., 2015). Collectively, these kinase networks constrain YAP/TAZ activity and preserve tissue homeostasis under physiological conditions. Additional upstream regulatory mechanisms further modulate Hippo pathway activity. Among these, the striatin-interacting phosphatase and kinase (STRIPAK) complex negatively regulates both MST1/2 and MAP4Ks, thereby suppressing Hippo signalling (Seo et al., 2020). Simultaneous depletion of MST1/2 and MAP4Ks results in profound impairment of downstream Hippo pathway activity, highlighting the importance of coordinated upstream regulation. Beyond canonical kinase-dependent regulation, YAP/TAZ activity responds to cell density, substrate stiffness, cellular tension, extracellular matrix (ECM) composition, soluble factors, and G protein-coupled receptor signalling (Gaspar and Tapon, 2014). YAP accumulates in the nucleus of sparsely populated cells but is sequestered in the cytoplasm at high cell density (Zhao et al., 2007). Increased ECM rigidity and mechanical stress enhance YAP/TAZ activity through actin-cytoskeleton remodelling, particularly F-actin assembly (Aragona et al., 2013). Mechanical inputs can also regulate YAP/TAZ independently of the core Hippo kinases. Cellular stressors, including hypoxia, osmotic imbalance, heat shock, and energy deprivation, further influence Hippo signalling (Fu et al., 2022). In endometriosis, chronic inflammation, fibrosis, hypoxia, and ECM remodelling may, therefore, create a permissive environment for aberrant YAP/TAZ activation. During menstruation, these mechanosensitive responses may intersect with hypoxia-inducible factor 1-alpha (HIF-1α)/YAP signalling and influence endometrial repair or ectopic lesion establishment (Zhang et al., 2022). Given its central role in cell fate and tissue growth, Hippo pathway dysregulation has been extensively studied in cancer and fibrotic diseases. Aberrant Hippo signalling can enhance proliferation, disrupt polarity, suppress apoptosis, and sustain YAP/TAZ–TEAD-dependent survival programmes (Yeung et al., 2019). Persistent YAP/TAZ activation has also been associated with fibrotic progression in the liver, kidney, lung, heart, and female reproductive tissues. In experimental fibrotic models, sustained YAP activation is linked to increased tissue stiffness and progressive fibrosis (Liu et al., 2015). YAP/TAZ activity has additionally been associated with treatment resistance and enhanced survival in several cancer models (Bartucci et al., 2015). These findings provide mechanistic context but should not be considered direct evidence in endometriosis. Although mutations in core Hippo pathway components are relatively uncommon in human cancers, functional pathway dysregulation is frequent. Mouse and Drosophila models show that loss of MST1/2 or LATS1/2, or constitutive YAP/TAZ activation, can drive tissue overgrowth and tumour formation. In human malignancies, altered upstream regulation—rather than direct mutation of core components—often underlies Hippo dysfunction (Harvey et al., 2013). Sustained YAP/TAZ activity can promote stem-like properties, metastatic potential, and chemoresistance (Zanconato et al., 2016). These observations support investigation of the pathway in other proliferative and fibrotic disorders while also underscoring the need to separate cross-disease mechanistic inference from endometriosis-specific evidence. 4 Hippo signalling dysregulation in endometriosis Aberrant regulation of cell proliferation, survival, apoptosis, and tissue remodelling is a defining feature of endometriosis, although the responsible molecular networks remain incompletely understood (Vetvicka et al., 2016). The Hippo pathway is a central regulator of tissue homeostasis, but its contribution to endometriosis has only recently been investigated (Ehmer and Sage, 2016). Available studies implicate altered Hippo-YAP signalling in lesion establishment, persistence, and progression and identify the pathway as a candidate experimental target rather than an established therapy (Song et al., 2016; Boddeti et al., 2025). Unless a subtype is explicitly stated, the cited tissue studies analysed ectopic endometriotic tissue without distinguishing SPE, OE, and DE. Figure 1 summarises direct endometriosis evidence and mechanisms inferred from related models using distinct graphical conventions. FIGURE 1 Comparative analyses of ectopic endometrium (EC), eutopic endometrium (EU), and endometrium from women without endometriosis (NE) have demonstrated alterations in canonical Hippo pathway components. Cui et al. (2020) reported increased YAP and TAZ protein expression in EC, accompanied by reduced MOB1, phosphorylated MOB1, SAV1, LATS1, and LATS2. These findings are consistent with suppression of canonical Hippo signalling and increased YAP/TAZ activity in ectopic lesions (Table 5). However, the study did not provide a direct comparison among SPE, OE and DE, and the results should not be interpreted as subtype-specific. TABLE 5 | Strategy | Target | Mechanism | Therapeutic potential | Key reference | |---|---|---|---|---| | Verteporfin | YAP–TEAD | Transcriptional blockade | Preclinical candidate; non-selective and not clinically validated for endometriosis | Sun and Chi (2021), Lin et al. (2023) | | SOX18 inhibition | SOX18–OTUB1 | Reduced YAP stability | Hypothesis-generating antifibrotic strategy requiring independent validation | Feng et al. (2025) | | OTUB1 targeting | Deubiquitinase | Promotes YAP degradation | Hypothesis-generating strategy to reduce YAP-dependent lesion survival | Feng et al. (2025) | | USP33 activation | Ferritinophagy | Restores ferroptosis | Single-study preclinical strategy to restore ferroptotic sensitivity | Li L. et al. (2026) | | mTOR inhibitors | YAP downstream | Autophagy restoration | Preclinical strategy requiring evaluation of systemic mTOR effects | Pei et al. (2019), Pei et al. (2022) | | Combination therapy | YAP + progestins | Overcomes resistance | Experimental combination strategy; clinical benefit unproven | Lin et al. (2023) | | Hu-Po-San | Multi-pathway network modulation | Hippo, inflammatory and fibrotic pathway modulation | Single-study preclinical formulation with uncertain active constituents and target specificity | Huo et al. (2025) | Therapeutic strategies targeting Hippo signalling in endometriosis. Hippo-YAP signalling may also participate in physiological endometrial repair during menstruation. Mechanical changes in ECM stiffness, together with reactive oxygen species (ROS)/hypoxia-inducible factor 1-alpha (HIF-1α) signalling, regulate YAP activity during endometrial regeneration (Zhang et al., 2022). In endometriosis, persistent inflammatory and hypoxic conditions may dysregulate these repair-associated responses and enhance ectopic cell survival. Endometriosis-specific experimental studies support a role for hypoxia-mediated YAP1 nuclear translocation in lesion progression (Lin et al., 2017). Within the TIAR framework, repeated tissue breakdown and repair may therefore create a permissive environment for aberrant YAP/TAZ activation after retrograde menstruation (Habiba et al., 2023). Findings in adenomyosis further suggest that suppression of canonical Hippo signalling can accompany epithelial–mesenchymal transition (EMT), proliferation and apoptosis resistance, but this represents supportive evidence from a related gynaecological disorder rather than direct evidence in endometriosis (Jin et al., 2023). Endometriosis is increasingly recognised as a disorder characterised by disrupted crosstalk between autophagy and apoptosis, which may support ectopic cell survival under adverse microenvironmental conditions (Kobayashi et al., 2024). The Hippo–YAP axis can regulate autophagy through the mechanistic target of rapamycin (mTOR). In vitro studies showed that YAP overexpression reduced autophagic flux, decreased the LC3-II/LC3-I ratio, and increased mTOR expression (Pei et al., 2019). YAP, TEAD1, and mTOR transcripts were also elevated in eutopic endometrial stromal cells (ESCs) from women with endometriosis. Rapamycin promoted decidualisation in vitro, whereas verteporfin did not reproduce this effect, indicating that the YAP–mTOR relationship and decidualisation phenotype require cautious interpretation (Pei et al., 2019). Transcriptomic analyses identified YAP-centred interaction networks associated with autophagy regulation in eutopic ESCs (Pei et al., 2022). Collectively, these findings support a possible YAP–mTOR–autophagy link, but the evidence remains predominantly cell-based. Beyond global autophagy, selective autophagic processes such as ferritinophagy may link Hippo signalling to iron-dependent cell death (Pei et al., 2022). Ferritinophagy is mediated primarily by nuclear receptor coactivator 4 (NCOA4) and contributes to iron homeostasis and ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation (Santana-Codina et al., 2021; Dixon et al., 2012). Despite recurrent haemorrhage and iron accumulation, endometriotic lesions can display reduced ferroptotic sensitivity (Ni and Li, 2024). The broader proposal that YAP/TAZ reprogramme antioxidant defences and limit lipid peroxidation is supported mainly by cancer and other disease models (Sun and Chi, 2021). Likewise, the E-cadherin–NF2–LATS–YAP/TAZ axis has been linked to density-dependent ferroptosis in non-endometriosis systems (Xiang et al., 2023). These mechanisms provide a biologically plausible framework but should not be presented as fully established in endometriosis. Direct endometriosis evidence has recently implicated ubiquitin-specific peptidase 33 (USP33) in the regulation of ferritinophagy and ferroptosis. Patient-derived tissue and mechanistic experiments showed that reduced USP33 was associated with increased LATS1 ubiquitination, enhanced YAP activity, impaired ferritinophagy and reduced ferroptotic cell death. Restoration of USP33 stabilised LATS1, reactivated Hippo signalling, and increased ferroptotic sensitivity (Li J. et al., 2026). This study identifies a potential USP33–LATS1–YAP axis in endometriosis; however, it currently represents a single recent report and requires independent replication. Broader conclusions regarding YAP/TAZ-mediated ferroptosis should therefore remain explicitly distinguished from this direct but still limited endometriosis evidence. Additional regulators of YAP activity contribute to endometriosis-associated invasive phenotypes. Apoptosis-stimulating protein of p53-2 (ASPP2), a tumour suppressor involved in p53-dependent apoptosis and epithelial polarity via PAR3 interaction (Sottocornola et al., 2010; Vives et al., 2006), has been implicated in YAP-dependent cell migration and invasion. Experimental suppression of ASPP2 reduces lipolysis-stimulated lipoprotein receptor (LSR) expression and induces YAP1 activation, promoting migratory and invasive behaviour in endometrial cells. Conversely, YAP1 knockdown restores ASPP2 function, indicating that ASPP2-mediated effects on cell motility are YAP-dependent (Konno et al., 2020). SRY-box transcription factor 18 (SOX18) has emerged as an upstream regulator of YAP signalling. SOX18 has physiological roles in development and tissue homeostasis (Saitoh and Katoh, 2002; Downes and Koopman, 2001), whereas pathological overexpression can promote proliferation, migration, invasion, and ECM remodelling in other disease contexts (Chen et al., 2024; Chen et al., 2020; Yin et al., 2017). Patient-derived lesion analyses and functional experiments reported increased SOX18 expression in ectopic endometriotic tissues and showed that SOX18 increased OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1), thereby stabilising YAP1 and promoting invasive and fibrotic programmes (Feng et al., 2025). Stabilised YAP1 can interact with TEAD transcription factors and induce fibrotic and invasive gene programmes (Zhao et al., 2008; Zhu et al., 2017). The proposed SOX18–OTUB1–YAP1 circuit is therefore mechanistically compelling, but its reproducibility, subtype distribution and clinical relevance remain to be established. Hormonal dysregulation remains central to endometriosis pathophysiology, particularly estrogen dominance and progesterone resistance (Patel et al., 2017; Marquardt et al., 2019). YAP1 has been implicated in progesterone resistance through upregulation of microRNA-21-5p (miR-21-5p) and repression of progesterone receptor (PGR) expression. In vitro pharmacological experiments showed that verteporfin reduced miR-21-5p and increased progestin responsiveness, while dienogest also reduced YAP1 and miR-21-5p expression (Lin et al., 2023). These cell-based findings support a possible YAP1–miR-21-5p–PGR mechanism but do not yet establish clinical benefit from YAP1 inhibition. Complex interactions between YAP1 and estrogen signalling have also been reported. Patient-derived cell-based experimental studies in ovarian endometriosis have demonstrated that YAP1 negatively regulates estrogen receptor β (ESR2), thereby modulating the invasive behaviour of endometriotic stromal cells. Knockdown of YAP1 increases ESR2 expression, while combined suppression of YAP1 and ESR2 markedly reduces cellular invasion, indicating that YAP1 influences lesion invasiveness in part through ESR2-dependent mechanisms (Zeng et al., 2020). Adaptation to hypoxia is a hallmark of ectopic lesion survival. Hypoxic conditions can reduce LATS1 expression, activate YAP1 and induce programmes associated with angiogenesis, steroidogenesis, inflammation and proliferation. Experimental disruption of hypoxia-induced YAP1 signalling using small interfering RNA (siRNA) or pharmacological inhibitors reduced lesion-related phenotypes in preclinical models (Wu et al., 2019; Lin et al., 2017). These findings support a role for YAP1 in hypoxia-associated progression but do not establish a clinically validated intervention. Emerging evidence suggests that Hippo signalling may also influence the immune microenvironment of endometriosis. A recent study reported that endometriosis-derived exosomes contained reduced miR-196a-5p and that experimental restoration of exosomal miR-196a-5p activated Hippo signalling in macrophages, increased M1-associated markers, and suppressed M2 polarisation (Lu et al., 2025). Pharmacological inhibition of Hippo signalling attenuated these effects, supporting a miR-196a-5p–Hippo-dependent mechanism. Thus, loss of exosomal miR-196a-5p may contribute to a pro-lesional macrophage phenotype, whereas restoration appears protective in the reported experimental system. This conclusion is currently based on a single study and requires validation in independent cohorts, additional immune-cell populations and in vivo models. Post-transcriptional regulation further expands the Hippo network in endometriosis. Circular RNAs (circRNAs) can act as microRNA (miRNA) sponges and show tissue-specific expression patterns (Memczak et al., 2013; Conn et al., 2015). A transcriptomic study of ovarian endometriosis identified circ_101,102 and circ_103,470 among circRNAs associated with Hippo and mTOR-related networks and EMT-related bioinformatic predictions (Zhang et al., 2018). These associations were primarily transcriptomic and were not independently replicated. A separate patient-tissue and in vitro study reported that circular RNA ATRNL1 (circATRNL1) promoted EMT through YAP1 upregulation (Wang et al., 2020). Accordingly, circRNA-mediated Hippo regulation is supported by a small number of studies with different designs, and independent functional validation remains necessary. Anthrax toxin receptor 2 (ANTXR2), a transmembrane protein initially characterised in vascular biology and anthrax toxin signalling (Bell et al., 2001; Scobie et al., 2003; Liu et al., 2009), has been implicated in Hippo–YAP regulation in endometriosis (Lin et al., 2019). Patient-derived tissue analyses and experimental studies reported ANTXR2 overexpressed in endometriotic lesions and an association with increased nuclear YAP1. Hypoxia-mediated reduction of enhancer of zeste homolog 2 (EZH2) was proposed to increase ANTXR2 expression, linking epigenetic regulation, hypoxia, and Hippo signalling (Lin et al., 2019). These findings identify a potential ANTXR2–YAP axis, but replication and subtype-specific validation are still required. Epitranscriptomic regulation through N6-methyladenosine (m6A) may also contribute to endometriosis-associated signalling networks. The m6A writer complex includes methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14), which regulate RNA processing, stability, and translation (Fu et al., 2014; Wang et al., 2016; Huang and Chen, 2023). Studies in reproductive biology and related disease models show that altered m6A regulation can affect proliferation, invasion, and EMT (Wu et al., 2023; Li et al., 2019; Li et al., 2022). In endometriosis, Shen et al. (2023) reported reduced METTL3 and METTL14 expression and global m6A hypomethylation in ectopic endometrium; experimental co-silencing of METTL3 and METTL14 increased proliferative and invasive phenotypes. Pathway analysis linked hypomethylated transcripts to several signalling networks, including Hippo signalling, but a direct causal METTL3/METTL14–Hippo–YAP mechanism was not demonstrated. The evidence should therefore be considered preliminary and hypothesis-generating. 5 Experimental therapeutic opportunities and future directions Before Hippo pathway-directed strategies can be considered for clinical testing, their efficacy, safety, tissue specificity, and disease subtype dependence require robust preclinical evaluation. Aberrant YAP1 activity provides a rationale for translational research (Song et al., 2016; Cui et al., 2020), but currently available inhibitors are neither endometriosis-specific nor clinically validated. Verteporfin and related experimental YAP–TEAD-disrupting approaches should first be assessed in well-characterised cell, organoid and animal models for lesion burden, pain-related outcomes, recurrence, and systemic toxicity (Sun and Chi, 2021; Xiang et al., 2023). Combination approaches, including experimental YAP modulation with progestins, may be particularly relevant to progesterone-resistant phenotypes but remain supported mainly by cell-based evidence (Patel et al., 2017; Marquardt et al., 2019; Lin et al., 2023). Figure 2 maps the proposed intervention points and explicitly identifies their preclinical status. FIGURE 2 Experimental strategies may also target upstream regulators that stabilise or activate YAP1. SOX18 or OTUB1 inhibition could, in principle, destabilise YAP1, but these approaches remain hypothesis-generating and require independent validation (Feng et al., 2025). Restoration of USP33 may increase ferritinophagy and ferroptotic sensitivity through the LATS1–YAP axis; however, this proposal currently rests on a single endometriosis study (Li L. et al., 2026). The YAP–mTOR–autophagy relationship likewise provides a possible metabolic intervention point, although pathway complexity and the physiological functions of mTOR and YAP necessitate careful dose, timing, and tissue-specificity studies (Pei et al., 2019; Pei et al., 2022). Hu-Po-San (HPS) is a multi-component traditional Chinese herbal preparation composed of several herbal medicines rather than a single defined pharmacological compound; its precise formulation is study-specific and should be interpreted accordingly. In a rat model of endometriosis, multi-omics, network pharmacology and in vivo validation associated HPS treatment with activation of canonical Hippo signalling, reduced YAP-associated activity, reduced proliferation and angiogenesis, modulation of inflammatory pathways and increased apoptosis (Huo et al., 2025). The study reported reduced ectopic lesion growth and no detectable toxicity within the evaluated endpoints. Nevertheless, these findings derive from a single preclinical study; the active constituents and target specificity remain uncertain, and independent replication and human safety data are required. Several mechanistic priorities remain. Human studies should validate the SOX18–OTUB1–YAP1 axis across disease stages and lesion subtypes and determine whether its components correlate with fibrosis, severity, or progesterone resistance (Feng et al., 2025; Patel et al., 2017; Marquardt et al., 2019). The proposed ability of OTUB1 to stabilise both YAP1 and estrogen receptor alpha (ERα) also warrants direct investigation because it may connect Hippo-dependent programmes with hormonal signalling (Marquardt et al., 2019; Feng et al., 2025). Such studies should distinguish epithelial, stromal, immune, and fibrotic compartments and should avoid extrapolating subtype-specific conclusions from mixed ectopic tissue. Immune-cell and exosome-mediated regulation is another priority. In the available study, restoration of exosomal miR-196a-5p activated Hippo signalling and shifted macrophages away from an M2-like phenotype, whereas inhibition of Hippo signalling attenuated this effect (Lu et al., 2025). Future work should determine whether this mechanism is reproducible across lesion subtypes and whether other exosomal miRNAs exert opposing effects. More broadly, circRNA and miRNA networks should be evaluated using independent patient cohorts and functional models rather than inferred from pathway-enrichment analyses alone (Memczak et al., 2013; Conn et al., 2015; Zhang et al., 2018; Wang et al., 2020). Biomarker development also requires cautious validation. Circulating YAP/TAZ-regulated factors, including miR-21-5p, and tissue YAP1 expression are candidate biomarkers rather than established diagnostic or predictive tests. Large, prospectively characterised cohorts with lesion-subtype annotation, cycle-phase information, and treatment-response data are needed to assess analytical validity, clinical validity, and added value beyond current diagnostic methods (Lin et al., 2023; Zeng et al., 2020). 6 Challenges and limitations Several challenges currently limit clinical translation. Most evidence derives from in vitro experiments, patient-derived tissues, or animal models, and no Hippo-targeted intervention has been validated in clinical trials for endometriosis. Hippo signalling is also essential for normal tissue homeostasis, regeneration, wound healing, and stem-cell maintenance. Systemic inhibition of YAP/TAZ–TEAD activity may, therefore, produce both on-target physiological disruption and off-target toxicity. Tissue-selective delivery, exposure control, and long-term reproductive and systemic safety assessment are prerequisites for further development (Baroja et al., 2024; Paul et al., 2025). Verteporfin was developed as a photosensitiser for photodynamic therapy and is not a selective Hippo pathway inhibitor (Michels and Schmidt-Erfurth, 2001). Its reported YAP-related effects may therefore coexist with Hippo-independent mechanisms, and systemic administration requires evaluation of phototoxicity, tissue distribution, long-term safety, and interference with physiological regeneration. HPS poses different translational challenges because it is a complex formulation with uncertain active constituents, pharmacokinetics and target specificity, and its endometriosis evidence is limited to one preclinical study. These limitations preclude presenting either approach as an available non-hormonal treatment. Collectively, these limitations support a staged translational pathway: independent mechanistic replication, validation in subtype-resolved human models, pharmacokinetic and toxicological characterisation, tissue-selective delivery studies, and only then appropriately designed clinical investigation. Until these steps are completed, Hippo-directed strategies should be described as experimental or preclinical candidates. 7 Conclusion Current management of endometriosis relies primarily on hormonal suppression, analgesia, and surgery, which can reduce symptoms or lesion burden but do not directly target the molecular programmes that sustain chronic inflammation, fibrosis, and recurrence (Dunselman et al., 2014). This limitation, together with the chronic and heterogeneous nature of the disease (Falcone and Flyckt, 2018), supports the investigation of non-hormonal mechanisms. In this context, the emerging concept of endometriosis as an inflammatory–fibrotic disorder provides a strong rationale for examining mechanotransduction and Hippo signalling (Chapron et al., 2019). Importantly, the clinical relevance of lesion-directed interventions varies according to disease phenotype and the mechanisms underlying symptoms. For example, in superficial peritoneal endometriosis, the benefit of laparoscopic treatment for pain remains debated because pain is multifactorial and lesion-specific evidence is limited (Horne et al., 2019). Similarly, molecularly targeted approaches should be viewed as potential complements to, rather than replacements for, established management strategies. Endometriosis subtypes—including superficial peritoneal endometriosis (SPE), ovarian endometrioma (OE), and deep endometriosis (DE)—differ substantially in tissue architecture, fibrosis, invasiveness, and hormonal responsiveness, yet direct comparisons of Hippo pathway activity across these phenotypes remain scarce (Nisolle and Donnez, 1997; Habiba et al., 2023). Subtype-resolved analyses using patient tissues and physiologically relevant models will, therefore, be essential to determine whether YAP/TAZ activation represents a common pathogenic mechanism or is preferentially associated with fibrotic and invasive disease. Overall, current evidence supports Hippo pathway dysregulation as a plausible molecular axis integrating mechanotransduction, cell survival, fibrosis, immune regulation, and hormone resistance in endometriosis. However, the strength of evidence remains heterogeneous: while some associations are supported by patient-derived samples or endometriosis-specific experimental models, others are extrapolated from cancer and fibrotic diseases. No Hippo-targeted therapy or biomarker has yet been clinically validated in endometriosis. Thus, the Hippo pathway should presently be regarded as a compelling mechanistic and therapeutic research framework whose clinical relevance will depend on independent validation, subtype-specific investigation, and rigorous assessment of efficacy and safety. Statements Author contributions GK: Investigation, Validation, Visualization, Writing – original draft, Formal analysis, Software. AY: Investigation, Validation, Visualization, Writing – original draft, Conceptualization, Resources, Supervision, Writing – review and editing. Funding The author(s) declared that financial support was not received for this work and/or its publication. 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. If you identify any issues, please contact us. Publisher’s note 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. Glossary - ANTXR2 Anthrax toxin receptor 2 - ASPP2 Apoptosis-stimulating protein of p53-2 - BMI Body mass index - circRNA Circular RNA - circATRNL1 Circular RNA derived from ATRNL1 - CTGF Connective tissue growth factor - DE Deep infiltrating endometriosis - ECM Extracellular matrix - EMT Epithelial–mesenchymal transition - ERα Estrogen receptor alpha - ESR2 Estrogen receptor beta - ESCs Endometrial stromal cells - EZH2 Enhancer of zeste homolog 2 - FAP Fibroblast activation protein-alpha - FDG Fluorodeoxyglucose - HIF-1α Hypoxia-inducible factor 1-alpha - HPS Hu-Po-San - LATS1/2 Large tumour suppressor kinases 1 and 2 - MAP4Ks Mitogen-activated protein kinase kinase kinase kinases - METTL3 Methyltransferase-like 3 - METTL14 Methyltransferase-like 14 - m6A N6-methyladenosine - miRNA MicroRNA - MOB1A/B MOB kinase activator 1A/B - mTOR Mechanistic target of rapamycin - MRI Magnetic resonance imaging - MST1/2 Mammalian STE20-like kinases 1 and 2 - NCOA4 Nuclear receptor coactivator 4 - NE Normal endometrium - OE Ovarian endometrioma - OTUB1 OTU domain-containing ubiquitin aldehyde-binding protein 1 - PET-CT Positron emission tomography–computed tomography - PGR Progesterone receptor - ROS Reactive oxygen species - rASRM Revised American Society for Reproductive Medicine - SAV1 Salvador homolog 1 - siRNA Small interfering RNA - SOX18 SRY-box transcription factor 18 - SPE Superficial peritoneal endometriosis - STRIPAK Striatin-interacting phosphatase and kinase complex - TAO Thousand-and-one amino acid kinases - TAZ Transcriptional co-activator with PDZ-binding motif - TEAD TEA domain transcription factor - TIAR Tissue injury and repair - USP33 Ubiquitin-specific peptidase 33 - WWTR1 WW domain-containing transcription regulator 1 - YAP1 Yes-associated protein 1

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endometriosis, fibrosis, Hippo signalling pathway, non-hormonal therapy, progesterone resistance, YAP1 Citation Kara G and Yaba A (2026) Hippo pathway in endometriosis pathogenesis: from cellular dysregulation to therapeutic opportunities. Front. Pharmacol. 17:1897505. doi: 10.3389/fphar.2026.1897505 Received 01 June 2026 Revised 11 August 2026 Accepted 12 August 2026 Published 08 September 2026 Volume 17 - 2026 Edited by Krisztina Pohóczky, University of Pécs, Hungary Updates Copyright © 2026 Kara and Yaba. 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: Aylin Yaba, [email protected] ORCID: Aylin Yaba, orcid.org/0000-0001-6781-9983 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.