Review

. 2017 Oct 5;171(2):273-285.

doi: 10.1016/j.cell.2017.09.021.

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

Brent R Stockwell¹, José Pedro Friedmann Angeli², Hülya Bayir³, Ashley I Bush⁴, Marcus Conrad², Scott J Dixon⁵, Simone Fulda⁶, Sergio Gascón⁷, Stavroula K Hatzios⁸, Valerian E Kagan⁹, Kay Noel¹⁰, Xuejun Jiang¹¹, Andreas Linkermann¹², Maureen E Murphy¹³, Michael Overholtzer¹¹, Atsushi Oyagi¹⁴, Gabriela C Pagnussat¹⁵, Jason Park¹⁶, Qitao Ran¹⁷, Craig S Rosenfeld¹⁰, Konstantin Salnikow¹⁸, Daolin Tang¹⁹, Frank M Torti²⁰, Suzy V Torti²¹, Shinya Toyokuni²², K A Woerpel²³, Donna D Zhang²⁴

Affiliations

¹ Department of Biological Sciences, Columbia University, 550 West 120(th) Street, MC 4846, New York, NY 10027, USA; Department of Chemistry, Columbia University, 550 West 120(th) Street, MC 4846, New York, NY 10027, USA. Electronic address: [email protected].
² Institute of Developmental Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), München, Germany.
³ Department of Critical Care Medicine, Safar Center for Resuscitation Research and Center for Free Radical and Antioxidant Health, University of Pittsburgh and Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
⁴ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
⁵ Department of Biology, Stanford University, Stanford, CA, USA.
⁶ Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, German Cancer Consortium (DKTK), partner site Frankfurt, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷ Ludwig-Maximilians University of Munich, Physiological Genomics, Biomedical Center (BMC), Planegg-Martinsried, Germany; Institute for Stem Cell Research, Helmholtz Center Munich at the Biomedical Center (BMC), Grosshaderner Strasse 9, 82152 Planegg-Martinsried, Germany.
⁸ Department of Molecular, Cellular and Developmental Biology and Department of Chemistry, Yale University, New Haven, CT 06511, USA; Microbial Sciences Institute, Yale University, West Haven, CT 06516, USA.
⁹ Center for Free Radical and Antioxidant Health, Departments of Environmental Health, Pharmacology and Chemical Biology, Chemistry, Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁰ Collaborative Medicinal Development, LLC, Sausalito, CA, USA.
¹¹ Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹² Department of Internal Medicine III, Division of Nephrology, University Hospital Carl Gustav Carus at Technische Universität Dresden, Dresden, Germany.
¹³ Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA, USA.
¹⁴ Ono Pharma USA, Lawrenceville, NJ 08648, USA.
¹⁵ Instituto de Investigaciones Biológicas, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Mar del Plata, 7600 Mar del Plata, Argentina.
¹⁶ Flagship Pioneering, Cambridge, MA, USA.
¹⁷ Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA.
¹⁸ Division of Cancer Biology, National Cancer Institute, NIH, Rockville, MD 20850, USA.
¹⁹ The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
²⁰ Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA.
²¹ Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA.
²² Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.
²³ Department of Chemistry, New York University, New York, NY, USA.
²⁴ Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA.

PMID: 28985560
PMCID: PMC5685180
DOI: 10.1016/j.cell.2017.09.021

Review

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

Brent R Stockwell et al. Cell. 2017.

. 2017 Oct 5;171(2):273-285.

doi: 10.1016/j.cell.2017.09.021.

Authors

Affiliations

¹ Department of Biological Sciences, Columbia University, 550 West 120(th) Street, MC 4846, New York, NY 10027, USA; Department of Chemistry, Columbia University, 550 West 120(th) Street, MC 4846, New York, NY 10027, USA. Electronic address: [email protected].
² Institute of Developmental Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), München, Germany.
³ Department of Critical Care Medicine, Safar Center for Resuscitation Research and Center for Free Radical and Antioxidant Health, University of Pittsburgh and Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
⁴ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
⁵ Department of Biology, Stanford University, Stanford, CA, USA.
⁶ Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, German Cancer Consortium (DKTK), partner site Frankfurt, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷ Ludwig-Maximilians University of Munich, Physiological Genomics, Biomedical Center (BMC), Planegg-Martinsried, Germany; Institute for Stem Cell Research, Helmholtz Center Munich at the Biomedical Center (BMC), Grosshaderner Strasse 9, 82152 Planegg-Martinsried, Germany.
⁸ Department of Molecular, Cellular and Developmental Biology and Department of Chemistry, Yale University, New Haven, CT 06511, USA; Microbial Sciences Institute, Yale University, West Haven, CT 06516, USA.
⁹ Center for Free Radical and Antioxidant Health, Departments of Environmental Health, Pharmacology and Chemical Biology, Chemistry, Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁰ Collaborative Medicinal Development, LLC, Sausalito, CA, USA.
¹¹ Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹² Department of Internal Medicine III, Division of Nephrology, University Hospital Carl Gustav Carus at Technische Universität Dresden, Dresden, Germany.
¹³ Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA, USA.
¹⁴ Ono Pharma USA, Lawrenceville, NJ 08648, USA.
¹⁵ Instituto de Investigaciones Biológicas, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Mar del Plata, 7600 Mar del Plata, Argentina.
¹⁶ Flagship Pioneering, Cambridge, MA, USA.
¹⁷ Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA.
¹⁸ Division of Cancer Biology, National Cancer Institute, NIH, Rockville, MD 20850, USA.
¹⁹ The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
²⁰ Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA.
²¹ Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA.
²² Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan.
²³ Department of Chemistry, New York University, New York, NY, USA.
²⁴ Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA.

PMID: 28985560
PMCID: PMC5685180
DOI: 10.1016/j.cell.2017.09.021

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.

Keywords: PUFA; ROS; cancer; cell death; ferroptosis; glutathione; iron; metabolism; neurodegeneration; peroxidation.

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Figures

**Figure 1. GPX4 uses glutathione to eliminate lipid peroxides formed in phospholipids containing polyunsaturated fatty acids**
System x_c^- imports cystine, which is reduced to cysteine and used to synthesize glutathione, a necessary cofactor of GPX4 for eliminating lipid peroxides.

**Figure 2. Pathways controlling ferroptosis**
The indicated pathways regulate ferroptosis sensitivity.

See this image and copyright information in PMC

Comment in

Reply to "Ferroptosis in the colon epithelial cells as a therapeutic target for ulcerative colitis".
Yokote A, Imazu N, Umeno J, Kawasaki K, Fujioka S, Fuyuno Y, Matsuno Y, Moriyama T, Miyawaki K, Akashi K, Kitazono T, Torisu T. Yokote A, et al. J Gastroenterol. 2024 Jan;59(1):77-78. doi: 10.1007/s00535-023-02064-w. Epub 2023 Nov 27. J Gastroenterol. 2024. PMID: 38008824 No abstract available.

References

1. Abrams RP, Carroll WL, Woerpel KA. Five-Membered Ring Peroxide Selectively Initiates Ferroptosis in Cancer Cells. ACS Chem Biol. 2016;11:1305–1312. - PMC - PubMed
1. Angeli JPF, Shah R, Pratt DA, Conrad M. Ferroptosis Inhibition: Mechanisms and Opportunities. Trends Pharmacol Sci. 2017;38:489–498. - PubMed
1. Ayton S, Fazlollahi A, Bourgeat P, Raniga P, Ng A, Lim YY, Diouf I, Farquharson S, Fripp J, Ames D, et al. Cerebral quantitative susceptibility mapping predicts β-amyloid-related cognitive decline. Brain. 2017 in press. - PubMed
1. Bannai S, Tsukeda H, Okumura H. Effect of antioxidants on cultured human diploid fibroblasts exposed to cystine-free medium. Biochem Biophys Res Commun. 1977;74:1582–1588. - PubMed
1. Barelli H, Antonny B. Lipid unsaturation and organelle dynamics. Curr Opin Cell Biol. 2016;41:25–32. - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

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