Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature cell biology, 2014-12, Vol.16 (12), p.1180-1191

Ort / Verlag

England

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.