Exosomal miR-21-5p from ectopic endometrial stromal cells drives fibrosis progression in endometriosis through direct...

Ovarian endometriosis is a chronic inflammatory disease characterized by extensive tissue remodeling and fibrosis, which significantly impacts female reproductive health. This study demonstrates that ectopic endometrium (Ect) in patients with endometriosis exhibit pronounced fibrotic changes compared to normal (Norm) and eutopic endometrium (Eut), characterized by the upregulation of fibrosis-associated genes including α-SMA, Col-1α1, and CTGF. Using primary cell isolation and characterization, we identified that exosomes derived from ectopic endometrial stromal cells (EctESCs-exo) serve as critical mediators of this pathological process. Fluorescent tracking and functional assays revealed that EctESCs-exo are internalized by eutopic endometrial stromal cells (EutESCs), subsequently triggering a pro-fibrotic phenotype in vitro and promoting lesion growth and collagen deposition in a mouse model of endometriosis. Through bioinformatic and multi-cohort validation, miR-21-5p was found to be significantly enriched in both ectopic tissues and their secreted exosomes. Silencing miR-21-5p in donor ectopic endometrial stromal cells (EctESCs) effectively attenuated the fibrotic response in recipient cells, whereas miR-21-5p-enriched exosomes markedly accelerated disease progression and fibrosis in vivo. Mechanistically, dual-luciferase reporter assays and functional rescue experiments confirmed that miR-21-5p directly targets von Hippel-Lindau (VHL), a negative regulator of fibrosis that is downregulated in ectopic lesions. Collectively, our findings elucidate a novel mechanism of exosome-mediated intercellular communication where EctESCs drive fibrotic progression via the miR-21-5p/VHL axis, suggesting that targeting this pathway could offer a promising therapeutic strategy for endometriosis.