期刊
NATURE CELL BIOLOGY
卷 16, 期 12, 页码 1180-U120出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3064
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资金
- Deutsche Forschungsgemeinschaft (DFG) [CO 291/2-3]
- Alexander von Humboldt-Stiftung
- Japan Society for the Promotion of Science (JSPS)
- Human Frontier Science Program (HFSP) [RGP0013]
- m4 Award (Bavarian Ministry of Economic Affairs)
- NIH [HL114453]
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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