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

Friedmann Angeli, Jose Pedro, JP; Schneider, Manuela, M; Proneth, Bettina, B; Tyurina, Yulia Y, YY; Tyurin, Vladimir A, VA; Hammond, Victoria J, VJ; Herbach, Nadja, N; Aichler, Michaela, M; Walch, Axel, A; Eggenhofer, Elke, E; Basavarajappa, Devaraj, D; Rådmark, Olof, O; Kobayashi, Sho, S; Seibt, Tobias, T; Beck, Heike, H; Neff, Frauke, F; Esposito, Irene, I; Wanke, Rüdiger, R; Förster, Heidi, H; Yefremova, Olena, O; Heinrichmeyer, Marc, M; Bornkamm, Georg W, GW; Geissler, Edward K, EK; Thomas, Stephen B, SB; Stockwell, Brent R, BR; O'Donnell, Valerie B, VB; Kagan, Valerian E, VE; Schick, Joel A, JA; Conrad, Marcus, M     «

Friedmann Angeli, Jose Pedro, JP; Schneider, Manuela, M; Proneth, Bettina, B; Tyurina, Yulia Y, YY; Tyurin, Vladimir A, VA; Hammond, Victoria J, VJ; Herbach, Nadja, N; Aichler, Michaela, M; Walch, Axel, A; Eggenhofer, Elke, E; Basavarajappa, Devaraj, D; Rådmark, Olof, O; Kobayashi, Sho, S; Seibt, Tobias, T; Beck, Heike, H; Neff, Frauke, F; Esposito, Irene, I; Wanke, Rüdiger, R; Förster, Heidi, H; Yefremova, Olena, O; Heinrichmeyer, Marc, M; Bornkamm, Georg W, GW; Geissler, Edward K, EK; Thomas,...     »

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.     «

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...     »