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Tonnus, W.* ; Maremonti, F.* ; Gavali, S.* ; Schlecht, M.N.* ; Gembardt, F.* ; Belavgeni, A.* ; Leinung, N.* ; Flade, K.* ; Bethe, N.* ; Traikov, S.* ; Haag, A.* ; Schilling, D.* ; Penkov, S.P.* ; Mallais, M.* ; Gaillet, C.* ; Meyer, C.* ; Katebi, M.* ; Ray, A.* ; Gerhardt, L.M.S.* ; Brucker, A.J.* ; Becker, J.N.* ; Tmava, M.* ; Schlicker, L.* ; Schulze, A.* ; Himmerkus, N.* ; Shevchenko, A.* ; Peitzsch, M.* ; Barayeu, U.* ; Nasi, S.* ; Putz, J.* ; Korach, K.S.* ; Neugarten, J.* ; Golestaneh, L.* ; Hugo, C.* ; Becker, J.U.* ; Weinberg, J.M.* ; Lorenz, S. ; Proneth, B. ; Conrad, M. ; Wolf, E.* ; Plietker, B.* ; Rodriguez, R.* ; Pratt, D.A.* ; Dick, T.P.* ; Fedorova, M.* ; Bornstein, S.R. ; Linkermann, A.*

Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.

Nature 645, 1011-1019 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Acute-renal-failure; Lipid-peroxidation; Susceptibility; Consequences; Mortality; Recovery; Survival
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Quellenangaben Band: 645, Heft: 8082, Seiten: 1011-1019 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
Institute of Pancreatic Islet Research (IPI)
POF Topic(s) 30203 - Molecular Targets and Therapies
90000 - German Center for Diabetes Research
Forschungsfeld(er) Genetics and Epidemiology
Helmholtz Diabetes Center
PSP-Element(e) G-506900-001
G-502600-007
Förderungen Deutsche Forschungsgemeinschaft (DFG)
TU Dresden/Kings College London transcampus initiative
ForTra GmbH fur Forschungstransfer
DFG-Sachbeihilfe
BMBF (FERROPath consortium)
International research training group
Heisenberg professorship

European Research Council
Saechsische Aufbaubank
Japan Society for the Promotion of Sciences
Sonderzuweisung zur Unterstuetzung profilbestimmender Struktureinheiten 2021 by the SMWK
Bundesministerium fuer Bildung und Forschung
Foundation Charles Defforey-Institut de France
Deutsche Forschungsgemeinschaft
European Research Council under the European Union's Horizon 2020 research and innovation programme
Saxon state parliament
Natural Sciences and Engineering Research Council of Canada
SMWK
European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme
BMBF program FERROPATH
German Research Foundation
DOI 10.1038/s41586-025-09389-x
WOS ID 001549673600001
Scopus ID 105013283984
PubMed ID 40804518
Erfassungsdatum 2025-10-10
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