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  3. Estradiol alleviated chemotherapy-induced premature ovarian failure by blocking the ferroptosis via activating ESR2/Sirt1/Nrf2 pathway

Estradiol alleviated chemotherapy-induced premature ovarian failure by blocking the ferroptosis via activating ESR2/Sirt1/Nrf2 pathway

  • Biochem Pharmacol. 2025 Oct 29;243(Pt 1):117481. doi: 10.1016/j.bcp.2025.117481.
Fengyu Zhu 1,  Hongxu Chen 2,  Siyuan Wang 2,  Jiaoyu Li 3,  Ruixin Zhang 2,  Nie Zhang 2,  Zhuoying He 2,  Ke Han 4,  Linghui Cheng 3,  Fei Zhong 5
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022 Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230022 Anhui, China. Electronic address: zhufengyu@ahmu.edu.cn.
  • 2 Department of Oncology, Fuyang Hospital of Anhui Medical University, Fuyang 236000, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230022 Anhui, China.
  • 3 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022 Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230022 Anhui, China.
  • 4 Department of Oncology, Fuyang Hospital of Anhui Medical University, Fuyang 236000, China.
  • 5 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022 Anhui, China; Department of Oncology, Fuyang Hospital of Anhui Medical University, Fuyang 236000, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), No. 81 Meishan Road, Hefei 230022 Anhui, China. Electronic address: zhongfei@ahmu.edu.cn.
PMID: 41173058 DOI: 10.1016/j.bcp.2025.117481
Abstract

Premature ovarian failure (POF) is a clinical syndrome characterized by a decline in ovarian function in women before the age of 40. The aim of this study is to investigate the therapeutic effects of estradiol (E2) on POF induced by chemotherapy and elucidate its potential underlying mechanisms. The results showed that E2 treatment increased the ovary index and number of follicles in mice. E2 supplementation inhibited cisplatin induced Ferroptosis in mouse ovarian tissue and reversed the downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), solute carrier family 7 member 11 (SLC7A11), heme oxygenase 1 (HO-1) and Glutathione Peroxidase 4 (Gpx4) protein expression induced by cisplatin treatment. We also revealed that E2 alleviated cisplatin or RSL3-induced decreases in cell viability and increased lipid peroxidation (LPO) and Reactive Oxygen Species (ROS) levels in KGN and SVOG cells. Moreover, we found that E2 increases Nrf2, SLC7A11, HO-1, and Gpx4 protein levels in vitro. Further studies revealed that E2 activated SIRT1 both in vitro and in vivo. Treating KGN or SVOG cells with the SIRT1 Inhibitor EX527 prevented the ability of E2 to inhibit Ferroptosis and Nrf2 protein expression. We demonstrated that Estrogen receptor beta (ESR2) is involved in the positive regulation of SIRT1 expression. In summary, E2 supplementation alleviates chemotherapy-induced POF by inhibiting Ferroptosis through the ESR2/SIRT1/Nrf2pathway activation.

Keywords

Estradiol; Ferroptosis; Nrf2; Premature ovarian failure; Sirt1.

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