Context-dependent regulation of ferroptosis sensitivity.

Leslie Magtanong, Grace D Mueller, Kevin J Williams, Maximilian Billmann, Katherine Chan, David A Armenta, Lauren E Pope, Jason Moffat, Charles Boone, Chad L Myers, James A Olzmann, Steven J Bensinger, Scott J Dixon

Journal: Cell chemical biology 2022;29(9):1409-1418.e6

PMID: 35809566

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Abstract

Ferroptosis is an important mediator of pathophysiological cell death and an emerging target for cancer therapy. Whether ferroptosis sensitivity is governed by a single regulatory mechanism is unclear. Here, based on the integration of 24 published chemical genetic screens combined with targeted follow-up experimentation, we find that the genetic regulation of ferroptosis sensitivity is highly variable and context-dependent. For example, the lipid metabolic gene acyl-coenzyme A (CoA) synthetase long chain family member 4 (ACSL4) appears far more essential for ferroptosis triggered by direct inhibition of the lipid hydroperoxidase glutathione peroxidase 4 (GPX4) than by cystine deprivation. Despite this, distinct pro-ferroptotic stimuli converge upon a common lethal effector mechanism: accumulation of lipid peroxides at the plasma membrane. These results indicate that distinct genetic mechanisms regulate ferroptosis sensitivity, with implications for the initiation and analysis of this process in vivo.

Address: Department of Biology, Stanford University, Stanford, CA 94305, USA.; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Lipidomics Laboratory, University of California, Los Angeles, Los Angeles, CA 90095, USA.; Department of Computer Science and Engineering, University of Minnesota-Twin Cities, 200 Union Street, Minneapolis, MN 55455, USA.; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.; Department of Computer Science and Engineering, University of Minnesota-Twin Cities, 200 Union Street, Minneapolis, MN 55455, USA; Program in Biomedical Informatics and Computational Biology, University of Minnesota-Twin Cities, 200 Union Street, Minneapolis, MN 55455, USA.; Departments of Molecular and Cell Biology and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Lipidomics Laboratory, University of California, Los Angeles, Los Angeles, CA 90095, USA.; Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].

DOI: 10.1016/j.chembiol.2022.06.004

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MeSH Terms: Cell Line, Tumor, Coenzyme A, Coenzyme A Ligases, Cystine, Ferroptosis, Lipid Peroxides, Phospholipid Hydroperoxide Glutathione Peroxidase