Ferroptosis: an iron-dependent form of nonapoptotic cell death.
Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration.
Department of Biological Sciences, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846, New York, NY 10027, USA.
Scott J
SJ
Dixon
Kathryn M
KM
Lemberg
Michael R
MR
Lamprecht
Rachid
R
Skouta
Eleina M
EM
Zaitsev
Caroline E
CE
Gleason
Darpan N
DN
Patel
Andras J
AJ
Bauer
Alexandra M
AM
Cantley
Wan Seok
WS
Yang
Barclay
B
Morrison
Brent R
BR
Stockwell
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003514:Cyclohexylamines / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism*; D050356:Lipid Metabolism; D009369:Neoplasms / Q000473:pathology; D010655:Phenylenediamines / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D003514:Cyclohexylamines; D010655:Phenylenediamines; D010879:Piperazines; D017382:Reactive Oxygen Species; C477224:erastin; C573944:ferrostatin-1; D018698:Glutamic Acid; D007501:Iron