Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

Abstract

Summary Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and that cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

p53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells

“…Human HT-1080 fibrosarcoma cells are a classic ferroptosis model that express wild-type p53 (Dixon et al, 2012; Stockwell et al, 2017; Tarunina and Jenkins, 1993). To characterize the effects of p53 expression on ferroptosis in these cells, we used CRISPR/Cas9 technology to isolate a clonal TP53 knockout ( TP53 KO ) cell line.…”

“…System x c − is a cystine/glutamate antiporter whose constitutive activity suppresses ferroptosis in many cell types (Dixon et al, 2012; Stockwell et al, 2017). System x c − -mediated cystine import is necessary for the synthesis of the antioxidant tripeptide (reduced) glutathione (GSH).…”

“…System x c − -mediated cystine import is necessary for the synthesis of the antioxidant tripeptide (reduced) glutathione (GSH). Depletion of cystine and/or GSH results in the iron-dependent accumulation of lethal lipid-reactive oxygen species (ROS), a process that is suppressed by lipophilic antioxidants such as ferrostatin-1 (Dixon et al, 2012; Stockwell et al, 2017). Here, we examined the relationship between wild-type p53 expression and ferroptosis sensitivity in response to system x c − inhibition.…”

Iron-dependent cleavage of ribosomal RNA during oxidative stress in the yeast Saccharomyces cerevisiae

“…In previous studies, ribosome degradation has been observed during apoptotic cell death (13,14,60). Recently, a form of programed cell death in mammalian cells termed ferroptosis (61) has been related to the induction of an excessive lipid damage via iron-dependent peroxidation (reviewed in (62). Understanding the role of iron in ferroptosis is far from complete (48).…”

Cell Death Pathways Drive Necroinflammation during Acute Kidney Injury

“…Ferroptosis Ferroptosis is an iron-dependent cell death pathway that involves specific lipid peroxidation patterns that are involved in plasma membrane rupture [9]. However, the precise mechanisms of how lipid peroxidation actually causes the membrane to disintegrate are elusive.…”