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

By J. Angeli, Manuela Schneider, B. Proneth, Y. Tyurina, V. Tyurin, V. Hammond, N. Herbach, M. Aichler, A. Walch, E. Eggenhofer and 19 more. Nature Cell Biology, 2014

3,295 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/807e3779fb6ac00b98dc5e77fd499784b175ceb3

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Citations in the corpus

The Tumor Suppressor Protein p53 and the Ferroptosis Network (2018, neutral): “Genetic depletion of GPX4 can trigger ferroptosis in an iron-, MEK-, and ROS-dependent manner in vitro or in vivo [23,24,31].”
Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration (2017, methodology): “We also showed that Gpx4BIKO mice fed a diet deficient in vitamin E, a lipid soluble antioxidant with anti-ferroptosis activity, had an expedited rate of hippocampal neurodegeneration and behavior dysfunction, and that treatment with a small-molecule ferroptosis inhibitor ameliorated…”
Activation of the p62-Keap1-NRF2 Pathway Protects against Ferroptosis in Hepatocellular Carcinoma Cells (2015, background): “, ferrostatin and liproxstatin).(13,14) Therefore, understanding of the mechanisms of ROS-induced ferroptosis and how this process relates to tumorigenesis and cancer therapy could lead to the development of successful therapies.”
Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC. (2016, neutral): “As already suggested by Friedman Angeli et al. (Friedmann Angeli et al., 2014), our results also suggest that it AC C EP TE D M AN U SC R IP T may be possible to pharmacologically modulate the ferroptotic signaling cascade in vivo.”
Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. (2017, neutral): “Remarkably, liproxstatin-1 completely suppressed lipid peroxidation as previously reported forGpx4 / cells (Friedmann Angeli et al., 2014).”
Ferroptosis in infection, inflammation, and immunity (2021, background): “Ferroptosismediated sterile inflammation is also involved in the progression of IRI in various tissues, such as heart (Gao et al., 2015), liver (Friedmann Angeli et al., 2014), kidney (Linkermann et al., 2014), brain (Tuo et al., 2017), and gut (Li et al., 2019b).”