Rescuing Fertility: C-Phycocyanin Prevents Ovarian Damage through NRF2-Mediated Ferroptosis Pathways in Polycystic Ovary Syndrome Models

Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with oxidative stress, though its pathogenesis is not fully understood. C-Phycocyanin (C-PC), a plant-derived antioxidant protein, shows potential for treating PCOS, but its mechanisms are unclear. This study investigates C-PC’s effects in both in vivo and in vitro models. Using a dehydroepiandrosterone (DHEA)-induced PCOS mouse model, oral C-PC administration improved estrous cycles, reduced cystic follicles, and normalized serum hormone levels, including testosterone, estradiol, progesterone, and luteinizing hormone (LH). In vitro, DHEA-treated human granulosa cells (KGN) demonstrated that C-PC activated the NRF2/xCT/GPX4 pathway, enhanced antioxidant activity, improved mitochondrial function, and suppressed ferroptosis. Molecular docking and cellular thermal shift assay (CETSA) further confirmed the interaction between C-PC and NRF2. In vivo, C-PC alleviated oxidative stress, inhibited ferroptosis, and increased GPX4 and xCT expression. The protective effects were reversed by ML385 (an NRF2 inhibitor) and AAV-sh-NRF2. Additionally, C-PC reduced DHEA-induced p-AMPK levels, and an AMPK activator attenuated its effects on GPX4 and xCT, abolishing its protection against granulosa cell ferroptosis. These findings suggest that C-PC alleviates PCOS by inhibiting granulosa cell ferroptosis and activating NRF2 and ROS/AMPK signaling pathways, highlighting its therapeutic potential for PCOS.