Ferroptosis: an iron-dependent form of nonapoptotic cell death.


Dixon, Scott J; Lemberg, Kathryn M; Lamprecht, Michael R; Skouta, Rachid; Zaitsev, Eleina M; Gleason, Caroline E; Patel, Darpan N; Bauer, Andras J; Cantley, Alexandra M; Yang, Wan Seok; Morrison, Barclay; Stockwell, Brent R

Publication Year 1905
Journal Cell
Pages 1060-1072
Volume 149
Issue 5
PMID 22632970.0
PMCID PMC3367386
DOI 10.1016/j.cell.2012.03.042
URL http://dx.doi.org/10.1016/j.cell.2012.03.042

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. Copyright ? 2012 Elsevier Inc. All rights reserved.