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

Brent R. Stockwell, José Pedro Friedmann Angeli, Hülya Bayir, Ashley I. Bush, Marcus Conrad, Scott J. Dixon, Simone Fulda, Sergio Gascón, Stavroula K. Hatzios, Valerian E. Kagan, Kay Noel, Xuejun Jiang, Andreas Linkermann, Maureen E. Murphy, Michael Overholtzer, Atsushi Oyagi, Gabriela C. Pagnussat, Jason Park, Qitao Ran, Craig S. RosenfeldKonstantin Salnikow, Daolin Tang, Frank M. Torti, Suzy V. Torti, Shinya Toyokuni, Keith Woerpel, Donna D. Zhang

Research output: Contribution to journalReview article

Abstract

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 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. 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 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.

Original languageEnglish (US)
Pages (from-to)273-285
Number of pages13
JournalCell
Volume171
Issue number2
DOIs
StatePublished - Oct 5 2017

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Cell death
Metabolism
Oxidation-Reduction
coenzyme Q10
Cell Death
Unsaturated Fatty Acids
Iron
Biological Phenomena
Mammals
Lipid Peroxides
Huntington Disease
Biosynthesis
Cerebral Hemorrhage
Reperfusion Injury
Brain Ischemia
NADP
Medicine
Glutathione
Parkinson Disease
Large scale systems

Keywords

  • cancer
  • cell death
  • ferroptosis
  • glutathione
  • iron
  • metabolism
  • neurodegeneration
  • peroxidation
  • PUFA
  • ROS

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., ... Zhang, D. D. (2017). Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell, 171(2), 273-285. https://doi.org/10.1016/j.cell.2017.09.021

Ferroptosis : A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. / Stockwell, Brent R.; Friedmann Angeli, José Pedro; Bayir, Hülya; Bush, Ashley I.; Conrad, Marcus; Dixon, Scott J.; Fulda, Simone; Gascón, Sergio; Hatzios, Stavroula K.; Kagan, Valerian E.; Noel, Kay; Jiang, Xuejun; Linkermann, Andreas; Murphy, Maureen E.; Overholtzer, Michael; Oyagi, Atsushi; Pagnussat, Gabriela C.; Park, Jason; Ran, Qitao; Rosenfeld, Craig S.; Salnikow, Konstantin; Tang, Daolin; Torti, Frank M.; Torti, Suzy V.; Toyokuni, Shinya; Woerpel, Keith; Zhang, Donna D.

In: Cell, Vol. 171, No. 2, 05.10.2017, p. 273-285.

Research output: Contribution to journalReview article

Stockwell, BR, Friedmann Angeli, JP, Bayir, H, Bush, AI, Conrad, M, Dixon, SJ, Fulda, S, Gascón, S, Hatzios, SK, Kagan, VE, Noel, K, Jiang, X, Linkermann, A, Murphy, ME, Overholtzer, M, Oyagi, A, Pagnussat, GC, Park, J, Ran, Q, Rosenfeld, CS, Salnikow, K, Tang, D, Torti, FM, Torti, SV, Toyokuni, S, Woerpel, K & Zhang, DD 2017, 'Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease', Cell, vol. 171, no. 2, pp. 273-285. https://doi.org/10.1016/j.cell.2017.09.021
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ et al. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell. 2017 Oct 5;171(2):273-285. https://doi.org/10.1016/j.cell.2017.09.021
Stockwell, Brent R. ; Friedmann Angeli, José Pedro ; Bayir, Hülya ; Bush, Ashley I. ; Conrad, Marcus ; Dixon, Scott J. ; Fulda, Simone ; Gascón, Sergio ; Hatzios, Stavroula K. ; Kagan, Valerian E. ; Noel, Kay ; Jiang, Xuejun ; Linkermann, Andreas ; Murphy, Maureen E. ; Overholtzer, Michael ; Oyagi, Atsushi ; Pagnussat, Gabriela C. ; Park, Jason ; Ran, Qitao ; Rosenfeld, Craig S. ; Salnikow, Konstantin ; Tang, Daolin ; Torti, Frank M. ; Torti, Suzy V. ; Toyokuni, Shinya ; Woerpel, Keith ; Zhang, Donna D. / Ferroptosis : A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. In: Cell. 2017 ; Vol. 171, No. 2. pp. 273-285.
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N2 - 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 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. 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 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.

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KW - cancer

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KW - iron

KW - metabolism

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KW - PUFA

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