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

Jose Pedro Friedmann Angeli, Manuela Schneider, Bettina Proneth, Yulia Y. Tyurina, Vladimir A. Tyurin, Victoria J. Hammond, Nadja Herbach, Michaela Aichler, Axel Walch, Elke Eggenhofer, Devaraj Basavarajappa, Olof Rådmark, Sho Kobayashi, Tobias Seibt, Heike Beck, Frauke Neff, Irene Esposito, Rüdiger Wanke, Heidi Förster, Olena Yefremova, Marc Heinrichmeyer, Georg W. Bornkamm, Edward K. Geissler, Stephen B. Thomas, Brent R. Stockwell, Valerie B. O’Donnell, Valerian E. Kagan, Joel A. Schick, Marcus Conrad

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.