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

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