Multiple oestradiol functions inhibit ferroptosis and acute kidney injury

Wulf Tonnus, Francesca Maremonti, Shubhangi Gavali, Marlena Nastassja Schlecht, Florian Gembardt, Alexia Belavgeni, Nadja Leinung, Karolin Flade, Natalie Bethe, Sofia Traikov, Anne Haag, Danny Schilling, Sider Penkov, Melodie Mallais, Christine Gaillet, Claudia Meyer, Melika Katebi, Anushka Ray, Louisa M. S. Gerhardt, Anne Brucker, Jorunn Naila Becker, Mirela Tmava, Lisa Schlicker, Almut Schulze, Nina Himmerkus, Andrej Shevchenko, Mirko Peitzsch, Uladzimir Barayeu, Sonia Nasi, Juliane Putz, Kenneth S. Korach, Joel Neugarten, Ladan Golestaneh, Christian Hugo, Jan Ulrich Becker, Joel M. Weinberg, Svenja Lorenz, Bettina Proneth, Marcus Conrad, Eckhard Wolf, Bernd Plietker, Raphaël Rodriguez, Derek A. Pratt, Tobias P. Dick, Maria Fedorova, Stefan R. Bornstein and Andreas Linkermann ()
Additional contact information
Wulf Tonnus: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Francesca Maremonti: University of Heidelberg
Shubhangi Gavali: University of Heidelberg
Marlena Nastassja Schlecht: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Florian Gembardt: University of Heidelberg
Alexia Belavgeni: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Nadja Leinung: University of Heidelberg
Karolin Flade: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Natalie Bethe: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Sofia Traikov: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Anne Haag: Technische Universität Dresden
Danny Schilling: DKFZ-ZMBH Alliance
Sider Penkov: Technische Universität Dresden
Melodie Mallais: University of Ottawa
Christine Gaillet: Equipe Labellisée Ligue Contre le Cancer, Institut Curie, CNRS, INSERM, PSL Research University
Claudia Meyer: University of Heidelberg
Melika Katebi: University of Heidelberg
Anushka Ray: University of Heidelberg
Louisa M. S. Gerhardt: University of Heidelberg
Anne Brucker: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Jorunn Naila Becker: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Mirela Tmava: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Lisa Schlicker: German Cancer Research Center (DKFZ)
Almut Schulze: German Cancer Research Center (DKFZ)
Nina Himmerkus: Christian-Albrecht-University Kiel
Andrej Shevchenko: Max Planck Institute of Molecular Cell Biology and Genetics
Mirko Peitzsch: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Uladzimir Barayeu: Max Planck Institute for Polymer Research
Sonia Nasi: University of Lausanne
Juliane Putz: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Kenneth S. Korach: National Institutes of Health
Joel Neugarten: Albert Einstein College of Medicine
Ladan Golestaneh: Albert Einstein College of Medicine
Christian Hugo: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Jan Ulrich Becker: University Hospital of Cologne
Joel M. Weinberg: University of Michigan Medical Center
Svenja Lorenz: Helmholtz Zentrum München
Bettina Proneth: Helmholtz Zentrum München
Marcus Conrad: Helmholtz Zentrum München
Eckhard Wolf: LMU Munich
Bernd Plietker: Technische Universität Dresden
Raphaël Rodriguez: Equipe Labellisée Ligue Contre le Cancer, Institut Curie, CNRS, INSERM, PSL Research University
Derek A. Pratt: University of Ottawa
Tobias P. Dick: DKFZ-ZMBH Alliance
Maria Fedorova: Technische Universität Dresden
Stefan R. Bornstein: University Hospital Carl Gustav Carus at the Technische Universität Dresden
Andreas Linkermann: University of Heidelberg

Nature, 2025, vol. 645, issue 8082, 1011-1019

Abstract: Abstract Acute tubular necrosis mediates acute kidney injury (AKI) and nephron loss1, the hallmark of end-stage renal disease2–4. 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. 17β-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.

Date: 2025
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DOI: 10.1038/s41586-025-09389-x

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