2. Academic Validation
  3. Indole-3-carbinol attenuates cisplatin-induced premature ovarian failure by activating Nrf2 through competitive binding of Keap1

Indole-3-carbinol attenuates cisplatin-induced premature ovarian failure by activating Nrf2 through competitive binding of Keap1

  • Phytomedicine. 2026 May:154:158040. doi: 10.1016/j.phymed.2026.158040.
Fengyu Zhu 1,  Ruixin Zhang 2,  Zhuoying He 2,  Nie Zhang 2,  Fangfang Li 3,  Jiaoyu Li 4,  Hongxu Chen 2,  Xiaoying Liu 4,  Linghui Cheng 5,  Fei Zhong 6
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, Anhui 230022, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Hefei, Anhui 230022, China. Electronic address: [email protected].
  • 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, Anhui 230022, China; Department of Oncology, Fuyang Hospital of Anhui Medical University, Fuyang 236000, China.
  • 3 Department of Oncology, Fuyang Hospital of Anhui Medical University, Fuyang 236000, China.
  • 4 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, Anhui 230022, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Hefei, Anhui 230022, 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, Anhui 230022, China; Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, Hefei, Anhui 230022, China. Electronic address: [email protected].
  • 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, Anhui 230022, China; Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China; Department of Oncology, Fuyang Hospital of Anhui Medical University, Fuyang 236000, China. Electronic address: [email protected].
PMID: 41818942 DOI: 10.1016/j.phymed.2026.158040
Abstract

Background: Premature ovarian failure (POF) leads to female infertility and significantly increases long-term health risks. However, available drugs that can reverse this condition are lacking.

Purpose: To elucidate the role of nuclear factor erythroid 2-related factor (Nrf2) in POF and the underlying molecular mechanism through which indole-3-carbinol (I3C) alleviates POF.

Methods: We established a POF model in wild type and Nrf2 knockout (Nrf2-KO) mice via cisplatin injection. ML385 and siRNA were used to inhibit and knockdown Nrf2 in vitro, respectively. Protein levels were detected by WB or IHC staining. Ovarian fibrosis was assessed by Masson and Sirius red staining. Cell viability, Lactate Dehydrogenase (LDH) levels, lipid peroxidation and ROS were determined to assess Ferroptosis.

Results: Nrf2-KO ovaries presented decreased levels of Glutathione Peroxidase 4 (Gpx4) and solute carrier family 7 member 11 (Slac7a11), along with elevated oxidative stress and fibrosis, resembling cisplatin-induced damage. Nrf2 overexpression or I3C treatment attenuated cisplatin-induced Ferroptosis in vitro, whereas Nrf2 knockdown or inhibition abolished the protective effect of I3C. Nrf2-KO mice exhibited POF phenotypes, and the protective effects of I3C were lost in these mice. Mechanistically, I3C activated Nrf2 by competitively binding to Keap1 residues Y334, S363, and R380. Further studies revealed that Nrf2 inhibits Ferroptosis by regulating NNT to maintain redox balance. NNT overexpression reversed oxidative damage caused by Nrf2 loss.

Conclusion: The core role and mechanism of Nrf2 in maintaining ovarian function and resisting cisplatin-induced POF were clarified. Moreover, a potential drug that alleviates ovarian damage by activating Nrf2 was identified.

Keywords

Ferroptosis; Indole-3-carbinol; Nrf2; Ovarian damage; Premature ovarian failure.

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