拯救女性生育力：C-藻蓝蛋白通过NRF2介导的铁死亡通路防止多囊卵巢综合征模型中的卵巢损伤

Polycystic ovary syndrome (PCOS), a common female endocrine disorder marked by disrupted folliculogenesis and hyperandrogenism, is increasingly linked to oxidative stress. Despite this association, the mechanistic basis remains poorly characterized. C-Phycocyanin (C-PC), a cyanobacteria-derived protein with potent antioxidant properties, has demonstrated therapeutic potential for treating PCOS, though the molecular pathways mediating its effects have yet to be delineated. This study employed both a dehydroepiandrosterone (DHEA)-induced murine model and DHEA-challenged human granulosa cells (KGN) to elucidate the regulatory role of C-PC. <i>In vivo</i>, oral administration of C-PC restored estrous cyclicity, reduced the prevalence of cystic follicles, and normalized circulating levels of testosterone, estradiol, progesterone, and luteinizing hormone (LH). <i>In vitro</i>, C-PC treatment activated the NRF2/xCT/GPX4 pathway, enhanced antioxidant activity, improved mitochondrial function, and suppressed ferroptotic death. Direct molecular interaction between C-PC and NRF2 was validated through molecular docking and cellular thermal shift assays (CETSA). Correspondingly, <i>in vivo</i> administration alleviated oxidative stress, inhibited ferroptosis, and increased GPX4 and xCT expression, effects reversed by pharmacological inhibition (ML385) and genetic silencing (AAV-sh-NRF2) of NRF2. C-PC also reduced DHEA-induced phosphorylation of AMPK, while co-treatment with an AMPK activator attenuated its effects on GPX4 and xCT, abolishing its anti-ferroptotic protection against granulosa cells. These findings suggest that C-PC mitigates PCOS pathology by repressing granulosa cell ferroptosis through coordinated activation of NRF2 and modulation of redox-sensitive AMPK signaling, highlighting its potential as a redox-targeted therapeutic strategy for PCOS.