Zhang_2025_Biol.Sex.Differ_16_107

BACKGROUND: Polycystic ovary syndrome (PCOS) impairs endometrial receptivity, contributing to reproductive dysfunction. Our previous work identified ferroptosis-related dipeptidyl Peptidase 4 (DPP4) as a key regulator of endometrial receptivity in PCOS, though its mechanism remained unclear. OBJECTIVE: We aimed to explore the regulatory mechanism of DPP4 in the occurrence and tolerance of endometrial ferroptosis in PCOS. METHODS: Using high dose (HD) DHEA-induced rats and hormone-treated (E2 and HD DHEA) telomerase-immortalized human endometrial stromal cells (T-HESCs), we investigated DPP4's role in endometrial ferroptosis and receptivity. We evaluated the correlation of specific endometrial marker expression levels with reproductive outcomes. RESULTS: Phenotypic assessments revealed elevated endometrial Fe(2+) accumulation, antioxidant dysfunction, mitochondrial damage, and enhanced estrogen/androgen receptor expression in PCOS models. DPP4 inhibition via sitagliptin improved decidualization responses and receptivity markers in rats prior to pregnancy. In T-HESCs, downregulated DPP4 could suppress hormone receptor expression and ferroptosis markers. Functional validation using BeWo spheroid implantation assays demonstrated restored endometrial receptivity following DPP4 intervention. Mechanistically, DPP4-driven ferroptosis exacerbated PCOS-associated endometrial dysfunction, while its suppression would enhance stromal cell decidualization capacity and implantation potential. Consistent with these findings, evaluation of endometrial specimens from PCOS patients confirmed a marked reversal of ferroptosis-related markers following sitagliptin intervention, which was further associated with significantly improved reproductive outcomes, including higher clinical pregnancy and live birth rates. CONCLUSION: Reducing DPP4 expression not only inhibited ferroptosis but also improved the PCOS phenotype of the endometrium, ultimately influencing changes in endometrial receptivity, and indicating the ferroptosis-related protein DPP4 as a promising therapeutic target.