The STING-OLA1-Keap1-Nrf2 axis regulates ferroptosis in premature ovarian failure

Premature ovarian failure (POF) is a serious reproductive disorder that deprives women of fertility and predisposes them to long-term metabolic, cardiovascular, and neuropsychological complications. Here we reveal that cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway driven ferroptosis is a key mechanism of granulosa-cell loss in POF. Mitochondrial stress releases cytosolic mtDNA, activating the cGAS-STING pathway. Activated STING was found to be a key upstream driver of ferroptosis by suppressing the Nrf2-mediated antioxidant defense system. Mechanistically, we identified Obg-like ATPase 1 (OLA1) as a novel STING-interacting protein. STING activation enhanced its binding to OLA1, disrupting the OLA1-Keap1 interactions, which in turn liberated Keap1 to promote Nrf2 degradation. Gene knockdown or pharmacologic inhibition of STING restored Nrf2 activity, limited ferroptosis in cellular models of POF and preserved follicular integrity in murine models of POF. Furthermore, we demonstrate that the natural flavonoid Icariin (ICA) binds directly to the His50/Asn131 pocket of STING, competitively displacing OLA1 and thereby enhancing OLA1-Keap1 interaction. This molecular realignment restores Nrf2 signaling, attenuates ferroptosis, and significantly preserves ovarian reserve in vivo. Collectively, our findings define the STING-OLA1-Keap1-Nrf2 axis as a pivotal driver of ferroptosis in POF and position ICA as a STING-targeting agent for this pathway. This mechanistic insight offers a substantial foundation for developing targeted ovarian-protective therapies, providing a mechanistic basis for exploring new therapeutic strategies for POF.