Fibrosis and Mechanotransduction in Endometriosis: Linking ECM Remodeling and Tissue Stiffness to Pain

Endometriosis is characterized by pain symptoms, including dysmenorrhea, chronic pelvic pain, and dyspareunia, the severity of which does not necessarily correlate with the size or extent of lesions. Recent evidence suggests that, in addition to extracellular matrix (ECM) remodeling and tissue stiffening, neural remodeling and neuroimmune interactions may contribute to pain pathophysiology in endometriotic lesions. This review focuses on the relationship between fibrosis and mechanotransduction in endometriosis. We summarize their associations with inflammation, mechanical stimuli, intracellular signaling pathways, and pain, and examine the possibility that the biomechanical microenvironment of lesions may integrate these pathophysiological processes. Chronic inflammation may promote fibrotic responses, myofibroblast activation, and ECM accumulation. Subsequent ECM remodeling and tissue stiffening can alter cellular tension and activate mechanotransduction pathways. These mechanical signals may interact with inflammatory and neural pathways, potentially promoting neurotrophic factor signaling, sensory nerve remodeling, and nociceptor sensitization. Conversely, neuroimmune signaling may further modulate inflammatory and fibrotic responses, thereby establishing a self-reinforcing microenvironment. However, further investigation is required to determine how these pathophysiological processes differ according to lesion phenotype and anatomical location. In conclusion, pain associated with endometriosis may arise not simply from lesion burden but from dynamic interactions among endocrine, inflammatory, fibrotic, mechanical, and neural processes. The proposed "pain-fibrosis niche" model provides a conceptual framework for integrating these pathophysiological processes and may contribute to the development of mechanism-based and disease-modifying therapeutic strategies.