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. Rosenfeld; Konstantin Salnikow; Daolin Tang; Frank M. Torti; Suzy V. Torti; Shinya Toyokuni; K. A. Woerpel; Donna D. Zhang

doi:10.1016/j.cell.2017.09.021

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, K. A. Woerpel, Donna D. Zhang

Research output: Contribution to journal › Review article › peer-review

3980 Scopus citations

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 language	English (US)
Pages (from-to)	273-285
Number of pages	13
Journal	Cell
Volume	171
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2017.09.021
State	Published - Oct 5 2017
Externally published	Yes

Keywords

PUFA
ROS
cancer
cell death
ferroptosis
glutathione
iron
metabolism
neurodegeneration
peroxidation

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2017.09.021

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Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., Fulda, S., Gascón, S., Hatzios, S. K., Kagan, V. E., Noel, K., Jiang, X., Linkermann, A., Murphy, M. E., Overholtzer, M., Oyagi, A., Pagnussat, G. C., Park, J., Ran, Q., ... 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

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, KA & 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

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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.",

keywords = "PUFA, ROS, cancer, cell death, ferroptosis, glutathione, iron, metabolism, neurodegeneration, peroxidation",

author = "Stockwell, {Brent R.} and {Friedmann Angeli}, {Jos{\'e} Pedro} and H{\"u}lya Bayir and Bush, {Ashley I.} and Marcus Conrad and Dixon, {Scott J.} and Simone Fulda and Sergio Gasc{\'o}n and Hatzios, {Stavroula K.} and Kagan, {Valerian E.} and Kay Noel and Xuejun Jiang and Andreas Linkermann and Murphy, {Maureen E.} and Michael Overholtzer and Atsushi Oyagi and Pagnussat, {Gabriela C.} and Jason Park and Qitao Ran and Rosenfeld, {Craig S.} and Konstantin Salnikow and Daolin Tang and Torti, {Frank M.} and Torti, {Suzy V.} and Shinya Toyokuni and Woerpel, {K. A.} and Zhang, {Donna D.}",

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

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doi = "10.1016/j.cell.2017.09.021",

language = "English (US)",

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T2 - A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

AU - Stockwell, Brent R.

AU - Friedmann Angeli, José Pedro

AU - Bayir, Hülya

AU - Bush, Ashley I.

AU - Conrad, Marcus

AU - Dixon, Scott J.

AU - Fulda, Simone

AU - Gascón, Sergio

AU - Hatzios, Stavroula K.

AU - Kagan, Valerian E.

AU - Noel, Kay

AU - Jiang, Xuejun

AU - Linkermann, Andreas

AU - Murphy, Maureen E.

AU - Overholtzer, Michael

AU - Oyagi, Atsushi

AU - Pagnussat, Gabriela C.

AU - Park, Jason

AU - Ran, Qitao

AU - Rosenfeld, Craig S.

AU - Salnikow, Konstantin

AU - Tang, Daolin

AU - Torti, Frank M.

AU - Torti, Suzy V.

AU - Toyokuni, Shinya

AU - Woerpel, K. A.

AU - Zhang, Donna D.

PY - 2017/10/5

Y1 - 2017/10/5

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.

AB - 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.

KW - PUFA

KW - ROS

KW - cancer

KW - cell death

KW - ferroptosis

KW - glutathione

KW - iron

KW - metabolism

KW - neurodegeneration

KW - peroxidation

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

Abstract

Keywords

ASJC Scopus subject areas

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