Cited by 2,329Ferroptosis and cancer prognosisAntioxidant Activity and Oxidative StressSelenium in Biological Systems

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Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis

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Yang, Wan Seok, Kim, Katherine J., Gaschler, Michael M., Patel, Milesh, Shchepinov, Mikhail S., Stockwell, Brent R.·2016·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1603244113PMC PMC5003261

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Abstract

Significance: Ferroptosis is a regulated form of cell death induced by loss of glutathione peroxidase 4 (GPX4) phospholipid peroxidase activity and lethal accumulation of reactive oxygen species. Small-molecule inhibitors of GPX4 induce ferroptosis; however, the interaction between these inhibitors and GPX4 has remained elusive, as has the identity of the reactive oxygen species that drive execution of ferroptosis. We identified here a ligand-binding site on GPX4 and determined the specific lipids oxidized during ferroptosis. We further identified two key drivers of lipid peroxidation during ferroptosis: lipoxygenases and phosphorylase kinase G2. These findings reveal a previously enigmatic mechanism of ferroptotic lipid peroxide generation and suggest new strategies for pharmacological control of ferroptosis and diseases associated with this mode of cell death.

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Retracted

Authors: Yang, W. S., Kim, K. J., Gaschler, M. M., Patel, M., Shchepinov, M. S., & Stockwell, B. R.
Affiliations: St. John's University (US)
Columbia University (US)
New York University (US)
Retrotope (United States) (US)
ORCID: Yang, Wan Seok
Kim, Katherine J.
Shchepinov, Mikhail S.
Stockwell, Brent R.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2016-08-09
Volume: 113
Issue: 34
Pages: E4966-75
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1603244113
PMC: PMC5003261
OpenAlex: W2508296626
Cited by: 2,329
References: 60
Citations by year: 2026: 230 · 2025: 348 · 2024: 441 · 2023: 410 · 2022: 319 · 2021: 249 · 2020: 152 · 2019: 70 · 2018: 62 · 2017: 36 · 2016: 7
FWCI: 52.14
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.pnas.org/preview_site/misc/userlicense.xhtml (vor)
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (R01CA097061)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
Keywords: ferroptosis, lipid peroxidation, polyunsaturated fatty acids, lipoxygenase, GPX4, iron availability, selenocysteine, deuterated fatty acids, reactive oxygen species, non-apoptotic cell death
MeSH terms: Phospholipid Hydroperoxide Glutathione Peroxidase, Deuterium, Epithelial Cells, Fatty Acids, Unsaturated, Gene Expression Regulation, Glutathione Peroxidase, Humans, Iron, Lipid Peroxides, Phosphorylase Kinase, Recombinant Fusion Proteins, Lipid Peroxidation, Signal Transduction, Cell Death, Selenocysteine, Catalytic Domain, Protein Transport, Cell Line, Tumor, Green Fluorescent Proteins, Lipoxygenases

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Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis

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