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

Friedmann Angeli, Jose Pedro, Schneider, Manuela, Proneth, Bettina, Tyurina, Yulia Y., Tyurin, Vladimir A., Hammond, Victoria J., Herbach, Nadja, Aichler, Michaela, Walch, Axel, Eggenhofer, Elke, Basavarajappa, Devaraj, Rådmark, Olof, Kobayashi, Sho, Seibt, Tobias, Beck, Heike, Neff, Frauke, Esposito, Irene, Wanke, Rüdiger, Förster, Heidi, Yefremova, Olena, Heinrichmeyer, Marc, Bornkamm, Georg W., Geissler, Edward K., Thomas, Stephen B., Stockwell, Brent R., O'Donnell, Valerie B. ORCID: https://orcid.org/0000-0003-4089-8460, Kagan, Valerian E., Schick, Joel A. and Conrad, Marcus 2014. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature Cell Biology 16 , pp. 1180-1191. 10.1038/ncb3064

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Nature Publishing Group
ISSN:	1465-7392
Date of Acceptance:	14 October 2014
Last Modified:	31 Oct 2022 09:38
URI:	https://orca.cardiff.ac.uk/id/eprint/81871

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