Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice.
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.
Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstr. 1 85764 Neuherberg, Germany.
Jose Pedro
JP
Friedmann Angeli
Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Marchioninistr. 15 81377 Munich, Germany.
Manuela
M
Schneider
Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstr. 1 85764 Neuherberg, Germany.
Bettina
B
Proneth
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
Yulia Y
YY
Tyurina
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
Vladimir A
VA
Tyurin
Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Heath Park Cardiff CF14 4XN, UK.
Victoria J
VJ
Hammond
Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, Ludwig-Maximilians-University Munich, Veterinaerstr. 13 80539 Munich, Germany.
Nadja
N
Herbach
Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstr. 1 85764 Neuherberg, Germany.
Michaela
M
Aichler
Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstr. 1 85764 Neuherberg, Germany.
Axel
A
Walch
Department of Surgery, University Medical Center of Regensburg, Franz-Josef-Strauss Allee 11 93053 Regensburg, Germany.
Elke
E
Eggenhofer
Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, S-17177 Stockholm, Sweden.
Devaraj
D
Basavarajappa
Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, S-17177 Stockholm, Sweden.
Olof
O
Rådmark
1] Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstr. 1 85764 Neuherberg, Germany [2] Department of Food and Applied Life Sciences, Faculty of Agriculture, Yamagata University, Tsuruoka, Yamagata 997-8555, Japan.
Sho
S
Kobayashi
Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstr. 1 85764 Neuherberg, Germany.
Tobias
T
Seibt
Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Ludwig-Maximilians-University, Marchioninistr. 15 81377 Munich, Germany.
Heike
H
Beck
Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstr. 1 85764 Neuherberg, Germany.
Frauke
F
Neff
Institute of Pathology, Technische Universität München, Ismaningerstr. 22 81675 Munich, Germany.
Irene
I
Esposito
Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, Ludwig-Maximilians-University Munich, Veterinaerstr. 13 80539 Munich, Germany.
Rüdiger
R
Wanke
Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstr. 1 85764 Neuherberg, Germany.
Heidi
H
Förster
Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstr. 1 85764 Neuherberg, Germany.
Olena
O
Yefremova
Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstr. 1 85764 Neuherberg, Germany.
Marc
M
Heinrichmeyer
Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, Marchioninistr. 25 81377 Munich, Germany.
Georg W
GW
Bornkamm
Department of Surgery, University Medical Center of Regensburg, Franz-Josef-Strauss Allee 11 93053 Regensburg, Germany.
Edward K
EK
Geissler
Department of Biological Sciences and Department of Chemistry, Howard Hughes Medical Institute, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846 New York, New York 10027, USA.
Stephen B
SB
Thomas
Department of Biological Sciences and Department of Chemistry, Howard Hughes Medical Institute, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846 New York, New York 10027, USA.
Brent R
BR
Stockwell
Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Heath Park Cardiff CF14 4XN, UK.
Valerie B
VB
O'Donnell
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
Valerian E
VE
Kagan
Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstr. 1 85764 Neuherberg, Germany.
Joel A
JA
Schick
Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstr. 1 85764 Neuherberg, Germany.
Marcus
M
Conrad
D058186:Acute Kidney Injury / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism; D002460:Cell Line; D005979:Glutathione Peroxidase / Q000235:genetics*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010544:Peroxidases / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D011810:Quinoxalines / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000473:pathology*; D013141:Spiro Compounds / Q000494:pharmacology*
D002308:Cardiolipins; D007093:Imidazoles; D007211:Indoles; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D011810:Quinoxalines; D013141:Spiro Compounds; C000595890:liproxstatin-1; C507699:necrostatin-1; C483858:phosphatidylethanolamine; D010544:Peroxidases; C032991:arachidonic acid peroxide peroxidase; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase