Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice.
Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice.
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DOI：
10.1038/ncb3064
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发表时间：
2014-12
影响因子：
21.3
通讯作者：
Conrad M
中科院分区：
文献类型：
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作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
铁凋亡是一种非凋亡形式的细胞死亡诱导的小分子在特定的肿瘤类型，并在工程细胞过度表达致癌RAS。然而，它在非转化细胞和组织中的相关性尚未探索，仍然是个谜。在这里，我们提供了直接的遗传证据，谷胱甘肽过氧化物酶4（Gpx 4）的敲除导致细胞死亡的病理相关形式的铁凋亡。使用诱导型Gpx 4 −/−小鼠，我们阐明了谷胱甘肽/Gpx 4轴在预防脂质氧化诱导的急性肾衰竭和相关死亡中的重要作用。我们还系统地评估了一个可能的铁凋亡抑制剂的小分子库，发现了一种名为livestatin-1的强效螺喹胺衍生物，它能够抑制细胞中的铁凋亡，在Gpx 4 −/−小鼠中，以及在缺血/再灌注诱导的肝损伤的临床前模型中。总之，我们证明了铁凋亡是一种普遍的和动态的细胞死亡形式，当受到阻碍时，承诺实质性的细胞保护。
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.