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Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis
Open accessAbstract
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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“the ferroptosis-inhibiting effect of iron depletion by either chelators [539, 543, 548] or phosphorylase kinase catalytic subunit gamma 2 (PHKG2) knockdown [566]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [566]
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“In the context of ferroptosis, PUFA peroxidation seems to be mainly regulated by the mutually antagonistic activity of LOXs (which directly catalyze lipid peroxidation) and GPX4 (which indirectly inhibits it) [550, 566].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [566]
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Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691
Self-citationRegulation of Ferroptotic Cancer Cell Death by GPX4
Yang, W. S., SriRamaratnam, R., Welsch, M. E., Shimada, K., Skouta, R., Viswanathan, V. S., Cheah, J. H., Clemons, P. A., Shamji, A. F., Clish, C. B., et al. (2014) · Cell · doi:10.1016/j.cell.2013.12.010 · Cited by 7,713
Self-citationInactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
Friedmann Angeli, J. P., Schneider, M., Proneth, B., Tyurina, Y. Y., Tyurin, V. A., Hammond, V. J., Herbach, N., Aichler, M., Walch, A., Eggenhofer, E., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3064 · Cited by 3,732
Self-citationPrinciples of bioactive lipid signalling: lessons from sphingolipids
Hannun, Y. A., & Obeid, L. M. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2329 · Cited by 3,411
Ferroptosis as a p53-mediated activity during tumour suppression
Jiang, L., Kon, N., Li, T., Wang, S.-J., Su, T., Hibshoosh, H., Baer, R., & Gu, W. (2015) · Nature · doi:10.1038/nature14344 · Cited by 3,398
Dixon, S. J., Patel, D. N., Welsch, M., Skouta, R., Lee, E. D., Hayano, M., Thomas, A. G., Gleason, C. E., Tatonetti, N. P., Slusher, B. S., et al. (2014) · eLife · doi:10.7554/elife.02523 · Cited by 2,088
Self-citationYang, W. S., & Stockwell, B. R. (2008) · Chemistry & Biology · doi:10.1016/j.chembiol.2008.02.010 · Cited by 1,876
Self-citationA Lentiviral RNAi Library for Human and Mouse Genes Applied to an Arrayed Viral High-Content Screen
Moffat, J., Grueneberg, D. A., Yang, X., Kim, S. Y., Kloepfer, A. M., Hinkle, G., Piqani, B., Eisenhaure, T., Luo, B., Grenier, J. K., et al. (2006) · Cell · doi:10.1016/j.cell.2006.01.040 · Cited by 1,804
Self-citationRAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels
Yagoda, N., von Rechenberg, M., Zaganjor, E., Bauer, A. J., Yang, W. S., Fridman, D. J., Wolpaw, A. J., Smukste, I., Peltier, J. M., Boniface, J. J., et al. (2007) · Nature · doi:10.1038/nature05859 · Cited by 1,631
Self-citationLentivirus-delivered stable gene silencing by RNAi in primary cells.
Stewart, S. A., Dykxhoorn, D. M., Palliser, D., Mizuno, H., Yu, E. Y., An, D., Sabatini, D., Chen, I. S. Y., Hahn, W., Sharp, P., et al. (2003) · RNA: A publication of the RNA Society · doi:10.1261/rna.2192803 · Cited by 1,619
Seiler, A., Schneider, M., Förster, H., Roth, S., Wirth, E. K., Culmsee, C., Plesnila, N., Kremmer, E., Rådmark, O., Wurst, W., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.07.005 · Cited by 1,470
Dolma, S., Lessnick, S. L., Hahn, W. C., & Stockwell, B. R. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00050-3 · Cited by 1,446
Self-citationFerrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models
Skouta, R., Dixon, S. J., Wang, J., Dunn, D. E., Orman, M., Shimada, K., Rosenberg, P. A., Lo, D. C., Weinberg, J. M., Linkermann, A., et al. (2014) · Journal of the American Chemical Society · doi:10.1021/ja411006a · Cited by 1,146 · cited 1×
“Inhibition of ferroptosis is protective in models of Huntington’s disease (8), periventricular leukomalacia (8–10), and kidney dysfunction (8, 11, 12).”
BackgroundSelf-citationSynchronized renal tubular cell death involves ferroptosis
Linkermann, A., Skouta, R., Himmerkus, N., Mulay, S. R., Dewitz, C., De Zen, F., Prokai, A., Zuchtriegel, G., Krombach, F., Welz, P.-S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1415518111 · Cited by 1,126
Self-citationNeurobiology of Periventricular Leukomalacia in the Premature Infant
Volpe, J. J. (2001) · Pediatric Research · doi:10.1203/00006450-200111000-00003 · Cited by 945
Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease
Haeggström, J. Z., & Funk, C. D. (2011) · Chemical Reviews · doi:10.1021/cr200246d · Cited by 875
Yant, L. J., Ran, Q., Rao, L., Van Remmen, H., Shibatani, T., Belter, J. G., Motta, L., Richardson, A., & Prolla, T. A. (2003) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)01360-6 · Cited by 797
Signal transduction of stress via ceramide
Mathias, S., Peña, L. A., & Kolesnick, R. (1998) · Biochemical Journal · doi:10.1042/bj3350465 · Cited by 673
Iron‐dependent cell death of hepatocellular carcinoma cells exposed to sorafenib
Louandre, C., Ezzoukhry, Z., Godin, C., Barbare, J., Mazière, J., Chauffert, B., & Galmiche, A. (2013) · International Journal of Cancer · doi:10.1002/ijc.28159 · Cited by 602
Back, S. A., Gan, X., Li, Y., Rosenberg, P. A., & Volpe, J. J. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-16-06241.1998 · Cited by 586
A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion.
Li, Y., Maher, P., & Schubert, D. (1997) · Neuron · doi:10.1016/s0896-6273(00)80953-8 · Cited by 509
Zinoni, F., Birkmann, A., Stadtman, T. C., & Böck, A. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.13.4650 · Cited by 486
Early embryonic lethality caused by targeted disruption of the mouse PHGPx gene
Imai, H., Hirao, F., Sakamoto, T., Sekine, K., Mizukura, Y., Saito, M., Kitamoto, T., Hayasaka, M., Hanaoka, K., & Nakagawa, Y. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)00734-4 · Cited by 357
Jennis, M., Kung, C.-P., Basu, S., Budina-Kolomets, A., Leu, J. I.-J., Khaku, S., Scott, J. P., Cai, K. Q., Campbell, M. R., Porter, D. K., et al. (2016) · Genes & Development · doi:10.1101/gad.275891.115 · Cited by 357
Biosynthesis of Selenocysteine on Its tRNA in Eukaryotes
Xu, X.-M., Carlson, B. A., Mix, H., Zhang, Y., Saira, K., Glass, R. S., Berry, M. J., Gladyshev, V. N., & Hatfield, D. L. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0050004 · Cited by 303
Development of small-molecule probes that selectively kill cells induced to express mutant RAS
Weïwer, M., Bittker, J. A., Lewis, T. A., Shimada, K., Yang, W. S., MacPherson, L., Dandapani, S., Palmer, M., Stockwell, B. R., Schreiber, S. L., et al. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2011.09.047 · Cited by 237
Self-citationArnér, E. S. J., Sarioglu, H., Lottspeich, F., Holmgren, A., & Böck, A. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.3085 · Cited by 237
Strassburg, K., Huijbrechts, A. M. L., Kortekaas, K. A., Lindeman, J. H. N., Pedersen, T. L., Dane, A. D., Berger, R., Brenkman, A. B., Hankemeier, T., van Duynhoven, J., et al. (2012) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-012-6226-x · Cited by 237
Scheerer, P., Borchert, A., Krauß, N., Wessner, H., Gerth, C., Höhne, W. E., & Kühn, H. (2007) · Biochemistry · doi:10.1021/bi700840d · Cited by 179
Lipoxygenases and their involvement in programmed cell death
Maccarrone, M., Melino, G., & Finazzi‐Agrò, A. (2001) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400908 · Cited by 176
Brushia, R. (1999) · Frontiers in bioscience · doi:10.2741/brushia · Cited by 174
Molecular Basis of the Specific Subcellular Localization of the C2-like Domain of 5-Lipoxygenase
Kulkarni, S. S., Das, S., Funk, C. D., Murray, D., & Cho, W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112393200 · Cited by 162
Mechanism-Based Inhibition: Deriving KI and kinact Directly from Time-Dependent IC50 Values
Krippendorff, B., Neuhaus, R., Lienau, P., Reichel, A., & Huisinga, W. (2009) · SLAS DISCOVERY · doi:10.1177/1087057109336751 · Cited by 160
Cardiolipin oxidation sets cytochrome c free
Orrenius, S., & Zhivotovsky, B. (2005) · Nature Chemical Biology · doi:10.1038/nchembio0905-188 · Cited by 155
Mechanism-based therapeutic approaches to rhabdomyolysis-induced renal failure
Boutaud, O. G., & Roberts, L. J. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.10.704 · Cited by 140
Larraufie, M., Yang, W. S., Jiang, E., Thomas, A. G., Slusher, B. S., & Stockwell, B. R. (2015) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2015.07.018 · Cited by 135
Self-citationModulatory profiling identifies mechanisms of small molecule-induced cell death
Wolpaw, A. J., Shimada, K., Skouta, R., Welsch, M. E., Akavia, U. D., Pe'er, D., Shaik, F., Bulinski, J. C., & Stockwell, B. R. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1106149108 · Cited by 133
Self-citationLi, J., Wang, H., & Rosenberg, P. A. (2009) · Journal of Neuroscience Research · doi:10.1002/jnr.22029 · Cited by 132
Calcein as a Fluorescent Probe for Ferric Iron
Thomas, F., Serratrice, G., Beguin, C. G., Saint‐Aman, E., Pierre, J., Fontecave, M., & Pierre, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.19.13375 · Cited by 127
The N-terminal “β-Barrel” Domain of 5-Lipoxygenase Is Essential for Nuclear Membrane Translocation
Chen, X., & Funk, C. D. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008203200 · Cited by 122
Rousset, M., Zweibaum, A., & Fogh, J. (1981) · PubMed · Cited by 113
Small amounts of isotope-reinforced polyunsaturated fatty acids suppress lipid autoxidation
Hill, S. A., Lamberson, C. R., Xu, L., To, R., Tsui, H. S., Shmanai, V. V., Bekish, A. V., Awad, A. M., Marbois, B. N., Cantor, C. R., et al. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.06.004 · Cited by 109
Self-citationWang, H., Li, J., Follett, P. L., Zhang, Y., Cotanche, D. A., Jensen, F. E., Volpe, J. J., & Rosenberg, P. A. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03650.x · Cited by 97
Inhibition of casein kinase 1-epsilon induces cancer-cell-selective, PERIOD2-dependent growth arrest
Yang, W. S., & Stockwell, B. R. (2008) · Genome biology · doi:10.1186/gb-2008-9-6-r92 · Cited by 95
Self-citationCotticelli, M. G., Crabbe, A. M., Wilson, R. B., & Shchepinov, M. S. (2013) · Redox Biology · doi:10.1016/j.redox.2013.06.004 · Cited by 91
Self-citationRousset, M., Chevalier, G., Rousset, J., Dussaulx, E., & Zweibaum, A. (1979) · PubMed · Cited by 86
Shchepinov, M. S., Chou, V., Pollock, E. D., Langston, J. W., Cantor, C. R., Molinari, R. J., & Manning-Bog, A. (2011) · Toxicology Letters · doi:10.1016/j.toxlet.2011.07.020 · Cited by 81
Self-citationLysophosphatidylcholine-induced cellular injury in cultured fibroblasts involves oxidative events
Colles, S. M., & Chisolm, G. M. (2000) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33425-8 · Cited by 80
Acyl Ureas as Human Liver Glycogen Phosphorylase Inhibitors for the Treatment of Type 2 Diabetes
Klabunde, T., Wendt, K. U., Kadereit, D., Brachvogel, V., Burger, H.-J., Herling, A. W., Oikonomakos, N. G., Kosmopoulou, M. N., Schmoll, D., Sarubbi, E., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm049034y · Cited by 77
K252a is a potent and selective inhibitor of phosphorylase kinase
Elliott, L. H., Wilkinson, S. E., Sedgwick, A. D., Hill, C. H., Lawton, G., Davis, P. D., & Nixon, J. (1990) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(90)91369-4 · Cited by 64
Glutathione disulfide induces neural cell death via a 12-lipoxygenase pathway
Park, H., Khanna, S., Rink, C. L., Gnyawali, S. C., Roy, S., & Sen, C. K. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.37 · Cited by 60
Hagmann, W., Kagawa, D., Renaud, C., & Honn, K. V. (1993) · Prostaglandins · doi:10.1016/0090-6980(93)90066-g · Cited by 56
Shornick, L. P., & Holtzman, M. J. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)54160-0 · Cited by 55
Schnier, J. B., Nishi, K., Monks, A. P., Gorin, F. A., & Bradbury, E. M. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)01542-0 · Cited by 55
Takahashi, S., Satomi, A., Yano, K., Kawase, H., Tuji, Y., Murakami, S., Hirayama, R., & Tanimizu, T. (1999) · Journal of Gastroenterology · doi:10.1007/s005350050299 · Cited by 51
Mannes, A. M., Seiler, A., Bosello-Travain, V., Maiorino, M., & Conrad, M. (2011) · The FASEB Journal · doi:10.1096/fj.10-177147 · Cited by 51
Casañas‐Sánchez, V., Pérez, J. A. P., Fabelo, N., Herrera‐Herrera, A. V., Fernández, C., Marín, R., González-Montelongo, M. D. C., & Díaz, M. L. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12833 · Cited by 48
Arnér, E. S. J. (2002) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(02)47022-x · Cited by 47
Liu, J., Xian, G., Li, M., Zhang, Y., Yang, M., Yu, Y., Lv, H., Xuan, S., Lin, Y., & Gao, L. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.324 · Cited by 46
Schnurr, K., Borchert, A., Gerth, C., Anton, M., & Kühn, H. (2000) · Protein Expression and Purification · doi:10.1006/prep.2000.1262 · Cited by 12
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Metadata
- 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)
- 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
- 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
- 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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