Multiple oestradiol functions inhibit ferroptosis and acute kidney injury

• 成果类型: Article
• 署名作者: Tonnus, Wulf; Maremonti, Francesca; Gavali, Shubhangi; Schlecht, Marlena Nastassja; Gembardt, Florian; Belavgeni, Alexia; Leinung, Nadja; Flade, Karolin; Bethe, Natalie; Traikov, Sofia; Haag, Anne; Schilling, Danny; Penkov, Sider; Mallais, Melodie; Gaillet, Christine; Meyer, Claudia; Katebi, Melika; Ray, Anushka; Gerhardt, Louisa M. S.; Brucker, Anne; Becker, Jorunn Naila; Tmava, Mirela; Schlicker, Lisa; Schulze, Almut; Himmerkus, Nina; Shevchenko, Andrej; Peitzsch, Mirko; Barayeu, Uladzimir; Nasi, Sonia; Putz, Juliane; Korach, Kenneth S.; Neugarten, Joel; Golestaneh, Ladan; Hugo, Christian; Becker, Jan Ulrich; Weinberg, Joel M.; Lorenz, Svenja; Proneth, Bettina; Conrad, Marcus; Wolf, Eckhard; Plietker, Bernd; Rodriguez, Raphael; Pratt, Derek A.; Dick, Tobias P.; Fedorova, Maria; Bornstein, Stefan R.; Linkermann, Andreas
• 署名单位: Technische Universitat Dresden; Carl Gustav Carus University Hospital; Ruprecht Karls University Heidelberg; Technische Universitat Dresden; Carl Gustav Carus University Hospital; Max Planck Society; Technische Universitat Dresden; Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht Karls University Heidelberg; Technische Universitat Dresden; University of Ottawa; UNICANCER; Universite PSL; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Institut Curie; Helmholtz Association; German Cancer Research Center (DKFZ); University of Kiel; Max Planck Society; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); Technische Universitat Dresden; Carl Gustav Carus University Hospital; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS); Yeshiva University; Montefiore Medical Center; University of Cologne; University of Michigan System; University of Michigan; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; University of Munich; University of Munich; German Center for Diabetes Research (DZD); Technische Universitat Dresden; Carl Gustav Carus University Hospital; University of London; King's College London; Technische Universitat Dresden; Helmholtz Association; Technische Universitat Dresden; Helmholtz-Center Munich - German Research Center for Environmental Health; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09389-x
• 发表日期: 2025-09-25
• 页码: 410462
• 关键词: acute-renal-failure; lipid-peroxidation; susceptibility; CONSEQUENCES; mortality; RECOVERY; survival

摘要

Acute tubular necrosis mediates acute kidney injury (AKI) and nephron loss1, the hallmark of end-stage renal disease2, 3-4. For decades, it has been known that female kidneys are less sensitive to AKI5,6. Acute tubular necrosis involves dynamic cell death propagation by ferroptosis along the tubular compartment7,8. Here we demonstrate abrogated ferroptotic cell death propagation in female kidney tubules. 17 beta-oestradiol establishes an anti-ferroptotic state through non-genomic and genomic mechanisms. These include the potent direct inhibition of ferroptosis by hydroxyoestradiol derivatives, which function as radical trapping antioxidants, are present at high concentrations in kidney tubules and, when exogenously applied, protect male mice from AKI. In cells, the oxidized hydroxyoestradiols are recycled by FSP19,10, but FSP1-deficient female mice were not sensitive to AKI. At the genomic level, female ESR1-deficient kidney tubules partially lose their anti-ferroptotic capacity, similar to ovariectomized mice. While ESR1 promotes the anti-ferroptotic hydropersulfide system, male tubules express pro-ferroptotic proteins of the ether lipid pathway which are suppressed by ESR1 in female tissues until menopause. In summary, we identified non-genomic and genomic mechanisms that collectively explain ferroptosis resistance in female tubules and may function as therapeutic targets for male and postmenopausal female individuals.