Canagliflozin alleviates hyperandrogen-induced granulosa cell ferroptosis in polycystic ovary syndrome mice by activating the AMPK/GSK3β/NRF2 pathway.

Abstract

Polycystic ovary syndrome (PCOS) is a common metabolic disorder affecting women of reproductive age. Clinical evidence suggests that the SGLT2 inhibitor canagliflozin has potential therapeutic effects in PCOS; however, its mechanisms remain unclear. The hyperandrogenic state in patients with PCOS leads to disrupted iron metabolism and oxidative stress. Herein, we aimed to investigate whether canagliflozin ameliorates PCOS symptoms by reducing oxidative stress and inhibiting granulosa cell ferroptosis, as well as to elucidate the underlying mechanisms. We found that canagliflozin treatment significantly restored the estrous cycle, improved polycystic ovarian morphology, reduced serum testosterone levels, and alleviated metabolic disorders, such as insulin resistance and dyslipidemia, in PCOS-like mice. Mechanistically, canagliflozin activated the AMPK/GSK3β pathway, promoted NRF2 nuclear translocation, upregulated GPX4, and ultimately inhibited lipid peroxidation and mitochondrial damage, thereby attenuating hyperandrogen-induced ferroptosis. These results reveal that canagliflozin exerts protective effects via the AMPK/GSK3β/NRF2 axis, thereby offering a potential alternative for PCOS treatment and identifying a promising drug target for clinical intervention.