Targeting Piezo1 can improve endometrial fibrosis by inhibiting ferroptosis in endothelial cells

Intrauterine adhesion (IUA) is a fibrotic disorder characterized by excessive extracellular matrix deposition, leading to menstrual abnormalities, infertility, and recurrent miscarriage, for which effective treatments are lacking. Here, we employed single-cell RNA sequencing to analyze murine IUA models, revealing for the first time a significant reduction in endometrial endothelial cells accompanied by markedly upregulated <i>Piezo1</i> expression. Functional enrichment analysis demonstrated ferroptosis as the most prominently activated cell death pathway in IUA endometrial endothelial cells versus controls. Mechanistically, elevated matrix stiffness activates Piezo1 in endometrial endothelial cells, inducing iron overload, lipid peroxidation, and mitochondrial dysfunction, culminating in ferroptosis. Intrauterine administration of the Piezo1 inhibitor GsMTx4 attenuated stiffness-induced ferroptosis and significantly reduced endometrial fibrosis in murine IUA models. Collectively, matrix stiffness represents a therapeutic target for IUA, and targeting mechanotransduction pathways effectively counteracts endothelial ferroptosis to ameliorate endometrial fibrosis.