TY  - JOUR
AU  - Tonnus, Wulf
AU  - Maremonti, Francesca
AU  - Gavali, Shubhangi
AU  - Schlecht, Marlena Nastassja
AU  - Gembardt, Florian
AU  - Belavgeni, Alexia
AU  - Leinung, Nadja
AU  - Flade, Karolin
AU  - Bethe, Natalie
AU  - Traikov, Sofia
AU  - Haag, Anne
AU  - Schilling, Danny
AU  - Penkov, Sider
AU  - Mallais, Melodie
AU  - Gaillet, Christine
AU  - Meyer, Claudia
AU  - Katebi, Melika
AU  - Ray, Anushka
AU  - Gerhardt, Louisa M S
AU  - Brucker, Anne
AU  - Becker, Jorunn Naila
AU  - Tmava, Mirela
AU  - Schlicker, Lisa
AU  - Schulze, Almut
AU  - Himmerkus, Nina
AU  - Shevchenko, Andrej
AU  - Peitzsch, Mirko
AU  - Barayeu, Uladzimir
AU  - Nasi, Sonia
AU  - Putz, Juliane
AU  - Korach, Kenneth S
AU  - Neugarten, Joel
AU  - Golestaneh, Ladan
AU  - Hugo, Christian
AU  - Becker, Jan Ulrich
AU  - Weinberg, Joel M
AU  - Lorenz, Svenja
AU  - Proneth, Bettina
AU  - Conrad, Marcus
AU  - Wolf, Eckhard
AU  - Plietker, Bernd
AU  - Rodriguez, Raphaël
AU  - Pratt, Derek A
AU  - Dick, Tobias P
AU  - Fedorova, Maria
AU  - Bornstein, Stefan R
AU  - Linkermann, Andreas
TI  - Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.
JO  - Nature
VL  - nn
SN  - 0028-0836
CY  - London [u.a.]
PB  - Nature Publ. Group
M1  - DKFZ-2025-01687
SP  - nn
PY  - 2025
N1  - DKFZ-ZMBH Alliance / epub
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40804518
DO  - DOI:10.1038/s41586-025-09389-x
UR  - https://inrepo02.dkfz.de/record/303496
ER  -