2. Academic Validation
  3. The STING-OLA1-Keap1-Nrf2 axis regulates ferroptosis in premature ovarian failure

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

  • Int J Biol Macromol. 2025 Dec 4;337(Pt 1):149424. doi: 10.1016/j.ijbiomac.2025.149424.
Nie Zhang 1,  Jiaoyu Li 2,  Ruixin Zhang 3,  Hongxu Chen 3,  Fang He 4,  Fangfang Li 5,  Zhuoying He 3,  Xiaoying Liu 2,  Linghui Cheng 6,  Fei Zhong 7,  Fengyu Zhu 8
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Department of Oncology, Fuyang Hospital of Anhui Medical University, Fuyang, 236000, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 218 Jixi Road, Hefei, 230022, Anhui, China.
  • 2 Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 218 Jixi Road, Hefei, 230022, Anhui, China.
  • 3 Department of Oncology, Fuyang Hospital of Anhui Medical University, Fuyang, 236000, China.
  • 4 Department of Ultrasound, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
  • 5 Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Department of Oncology, Fuyang Hospital of Anhui Medical University, Fuyang, 236000, China.
  • 6 Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 218 Jixi Road, Hefei, 230022, Anhui, China. Electronic address: [email protected].
  • 7 Department of Oncology, Fuyang Hospital of Anhui Medical University, Fuyang, 236000, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 218 Jixi Road, Hefei, 230022, Anhui, China. Electronic address: [email protected].
  • 8 Department of Obstetrics and Gynecology, NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, the First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei, 230022, Anhui, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 218 Jixi Road, Hefei, 230022, Anhui, China. Electronic address: [email protected].
PMID: 41352507 DOI: 10.1016/j.ijbiomac.2025.149424
Abstract

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.

Keywords

Ferroptosis; Premature ovarian failure; STING.

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