Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
この論文をさがす
説明
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.
収録刊行物
-
- Nature Cell Biology
-
Nature Cell Biology 16 (12), 1180-1191, 2014-11-17
Springer Science and Business Media LLC
- Tweet
キーワード
- Male
- Indoles
- Cardiolipins
- Apoptosis
- Arachidonate 12-Lipoxygenase
- Kidney
- Cell Line
- Mice
- Quinoxalines
- In Situ Nick-End Labeling
- Animals
- Arachidonate 15-Lipoxygenase
- Humans
- Spiro Compounds
- Mice, Knockout
- Glutathione Peroxidase
- Phosphatidylethanolamines
- Imidazoles
- Acute Kidney Injury
- Phospholipid Hydroperoxide Glutathione Peroxidase
- Mitochondria
- Mice, Inbred C57BL
- Peroxidases
- Reperfusion Injury
- Phosphatidylcholines
- Lipid Peroxidation
詳細情報 詳細情報について
-
- CRID
- 1362825895249196928
-
- DOI
- 10.1038/ncb3064
-
- ISSN
- 14764679
- 14657392
-
- PubMed
- 25402683
-
- データソース種別
-
- Crossref
- OpenAIRE