Exercise-induced irisin attenuates ferroptosis in polycystic ovary syndrome by modulating the NCOA4-FTH pathway

Hyperandrogenism is a central pathological feature of polycystic ovary syndrome (PCOS) that disrupts granulosa cell function. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, may contribute to ovarian injury. This study aimed to clarify the pathways of hyperandrogenic-induced granulosa cells ferroptosis, elucidating the molecular mechanism of exercise and its secretory factor, irisin, through the NCOA4-FTH pathway.

DHEA-induced PCOS model and in vitro granulosa cells were constructed to systematically evaluate the effects of exercise and irisin on ovarian function and ferroptosis. In vivo experiments included treadmill training in PCOS mice, assessment of estrous cycles, glucose/insulin tolerance, ovarian morphology, oxidative stress, ferroptosis, and NCOA4-FTH pathway proteins. In vitro, granulosa cells were treated with DHT and co-exposed to irisin or the ferroptosis inhibitor Ferrostatin-1 (Fer-1), with siRNA-mediated NCOA4 knockdown for functional verification.

DHEA-induced PCOS mice exhibited disrupted estrous cycles, abnormal follicular morphology, glucose intolerance, insulin resistance, and ferroptosis activation, characterized by oxidative stress, Fe²⁺ overload, and dysregulated ferroptosis-related proteins. Fer-1 reversed DHT-induced GPX4 downregulation, suggesting ferroptosis involvement. Eight-week aerobic exercise improved metabolic parameters and ovarian morphology, suppressed ferroptosis by modulating NCOA4 and GPX4 expression, and alleviated oxidative stress. Mechanistically, exercise-induced irisin inhibited ferritinophagy and restored iron metabolism via the NCOA4-FTH pathway. NCOA4 knockdown further validated its central role in regulating ferritinophagy.

Hyperandrogenism triggers granulosa cells ferroptosis in PCOS, while exercise and irisin protect ovarian function by regulating the NCOA4-FTH pathway, suggesting a potential therapeutic target for PCOS.