Phoenixin‐14 Alleviates Premature Ovarian Failure by Inhibiting Ferroptosis Through SLC7A11/GPX4

Premature ovarian failure (POF) is a complex condition marked by early ovarian decline, reduced follicular reserve, and compromised oocyte quality. Oxidative stress (OS) and ferroptosis are critical drivers of POF progression. This study investigates the therapeutic potential of Phoenixin-14 (PNX-14) in alleviating POF in rats by modulating granulosa cell (GC) ferroptosis through the ATF4/SLC7A11/GPX4 signaling pathway. Cisplatin-induced POF rat models were used to evaluate PNX-14's effects on ovarian function, oxidative stress (MDA/SOD), and ferroptosis. Serum PNX-14 levels, GPR173 expression, body/ovarian weights, follicle development, and oxidative markers were analyzed. In cisplatin-induced POF rat models, serum PNX-14 levels and GPR173 expression were significantly downregulated, suggesting potential impairment of the PNX-14/GPR173 axis. PNX-14 administration improved body and ovarian weights, restored ovarian tissue structure, and reduced oxidative damage, as evidenced by reduced MDA levels and enhanced SOD activity. At the molecular level, PNX-14 suppressed ferroptosis in GCs by enhancing ATF4 expression, which in turn upregulated SLC7A11 and GPX4, critical components of cellular antioxidant defense. Caspase-3 assays suggested minimal apoptosis in cisplatin-treated cells. PNX-14 showed similar effectiveness to Fer-1 in reducing cisplatin-induced ferroptosis, evidenced by restored viability, lower Fe²⁺, and reduced MDA, without added benefit when combined. Silencing ATF4 reversed the beneficial effects of PNX-14 on GC viability and ferroptosis, confirming the pivotal role of ATF4 in mediating the protective effects of PNX-14. These results suggest that PNX-14 alleviates POF by inhibiting GC ferroptosis through the ATF4/SLC7A11/GPX4 axis, providing a potential therapeutic strategy for POF management.