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 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

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    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