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Friedmann Angeli, J.P.F.* ; Schneider, M.* ; Proneth, B. ; Tyurina, Y.Y.* ; Tyurin, V.A.* ; Hammond, V.J.* ; Herbach, N.* ; Aichler, M. ; Walch, A.K. ; Eggenhofer, E.* ; Basavarajappa, D.* ; Rådmark, O.* ; Kobayashi, S. ; Seibt, T. ; Beck, H.* ; Neff, F. ; Esposito, I.* ; Wanke, R.* ; Förster, H. ; Yefremova, O. ; Heinrichmeyer, M. ; Bornkamm, G.W. ; Geissler, E.K.* ; Thomas, S.B.* ; Stockwell, B.R.* ; O'Donnell, V.B.* ; Kagan, V.E.* ; Schick, J. ; Conrad, M.

Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice.

Nat. Cell Biol. 16, 1180-1191 (2014)
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Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic RAS. Yet, its relevance in non-transformed cells and tissues is unexplored and remains enigmatic. Here, we provide direct genetic evidence that the knockout of glutathione peroxidase 4 (Gpx4) causes cell death in a pathologically relevant form of ferroptosis. Using inducible Gpx4(-/-) mice, we elucidate an essential role for the glutathione/Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. We furthermore systematically evaluated a library of small molecules for possible ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called Liproxstatin-1, which is able to suppress ferroptosis in cells, in Gpx4(-/-) mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. In sum, we demonstrate that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 1465-7392
e-ISSN 1476-4679
Quellenangaben Volume: 16, Issue: 12, Pages: 1180-1191 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Reviewing status Peer reviewed