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.