Targeting ferroptosis for the treatment of female reproductive system disorders

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a critical factor in female reproductive health and has been implicated in disorders such as polycystic ovary syndrome, premature ovarian insufficiency, endometriosis, and ovarian cancer. This review explores the intricate molecular mechanisms underlying ferroptosis, emphasizing its reliance on iron metabolism and oxidative stress, which disrupt key processes in reproductive tissues, including granulosa cell function, folliculogenesis, and embryo implantation. Increasing evidence linking ferroptosis to these conditions offers new therapeutic opportunities, with iron chelators, lipid peroxidation inhibitors, and antioxidants showing the potential to alleviate reproductive dysfunction by modulating ferroptotic pathways. In ovarian cancer, ferroptosis inducers combined with conventional cancer therapies, such as chemotherapy, provide promising strategies to overcome drug resistance. This review synthesizes current knowledge on ferroptosis and highlights its importance as a therapeutic target in reproductive health, emphasizing the need for further research to refine and expand treatment options, evaluate their applicability in clinical settings, and explore their role in fertility preservation. By advancing our understanding of ferroptosis regulation, these therapeutic approaches could lead to novel treatments for reproductive disorders and cancers, offering new hope for improving outcomes in women’s health and cancer therapy. Similar content being viewed by others Data availability Not applicable. Abbreviations - PCOS: - Polycystic ovary syndrome - POI: - Premature ovarian insufficiency - GPX4: - Glutathione peroxidase 4 - GSH: - Glutathione - LPCAT3: - Lysophosphatidylcholine acyltransferase 3 - NCOA4: - Nuclear receptor coactivator 4 - ACSL4: - Acyl-CoA synthetase long-chain family member 4 - TfR1: - Transferrin receptor 1 - FPN: - Ferroportin - PUFAs: - Polyunsaturated fatty acids - ROS: - Reactive oxygen species - ALOX15: - Arachidonate 15-lipoxygenase - LOX: - Lipoxygenase - LIP: - Labile iron pool - IREB2: - Iron-responsive element-binding protein 2 - Tf: - Transferrin - FTH1: - Ferritin heavy chain 1 - FSH: - Follicle-stimulating hormone - LH: - Luteinizing hormone - NCOA4: - Nuclear receptor coactivator 4 - FSP1: - Ferroptosis suppressor protein 1 - ACSL4: - Acyl-CoA synthetase long-chain family member 4 - SCD1: - Stearoyl-CoA desaturase 1 - CD44: - Cluster of differentiation 44 - HO-1: - Heme oxygenase-1 - NRF2: - Nuclear factor erythroid 2-related factor 2

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Front Genet Zuo Y, Zhang Y-F, Zhang R, Tian J, Lv X, Li R, Li S-P, Cheng M-D., Shan JL, Zhao Z et al (2022) Ferroptosis in cancer progression: role of noncoding RNAs. International Journal of Biological Sciences 2022. Funding This study was funded by Zhejiang Provincial Natural Science Foundation of China (No. QN25H270030 by YB. H), the Zhejiang Chinese Medical University (No. 2022JKZKTS26 by YB. H, 2022JKJNTZ16 by SL. C), the Zhejiang Province Traditional Chinese Medicine Science and Technology Project (No. 2024ZR015 by YB. H, 2023ZL056 by ZZ. Z), the Zhejiang Province Medical and Health Science and Technology Project (No. 2024KY1201 by YB. H, 2024KY1213 by ZZ. Z, 2025ZR123 by SL. C), the Hainan Province Health and Science & Technology Innovation Joint Project (No. WSJK2), the Hainan Province Natural Science Foundation Project (No. 823QN371 by JY. L), the Special Science and Technology Plan Project of Universities and Medical Institutions in Sanya City (No. 2021GXYL32 by JY. L), the Hainan Province Health Industry Scientific Research Project (No. 21A200333 by YL. L) and the Sanya University and Medical Institutions Special Science and Technology Project (No. 2021GXYL29 by YL. L). Author information Authors and Affiliations Contributions Rui Ye, Yi-min Mao, and Yi-ran Fei contributed equally to this work, sharing the first authorship. They were responsible for the conception, design, and drafting of the manuscript. Yue Shang, Ting Zhang, Jun-yu Li, Zhe-zhong Zhang, and Yong-lin Liu played key roles in information retrieval, drafting, and critically revising the manuscript. Shi-liang Chen and Yi-bo He supervised the project, provided critical feedback, and ensured the final approval of the manuscript for publication. All authors read and approved the final manuscript. Corresponding authors Ethics declarations Ethics approval and consent to participate Not applicable. Competing interests The authors declare no competing interests. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rui Ye, Yi-ming Mao, Yi-ran Fei have contributed equally to this work and share the first authorship. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Ye, R., Mao, Ym., Fei, Yr. et al. Targeting ferroptosis for the treatment of female reproductive system disorders. J Mol Med 103, 381–402 (2025). https://doi.org/10.1007/s00109-025-02528-x Received: Revised: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s00109-025-02528-x