Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death
Open accessAbstract
Little is known about the regulation of nonapoptotic cell death. Using massive insertional mutagenesis of haploid KBM7 cells we identified nine genes involved in small-molecule-induced nonapoptotic cell death, including mediators of fatty acid metabolism (ACSL4) and lipid remodeling (LPCAT3) in ferroptosis. One novel compound, CIL56, triggered cell death dependent upon the rate-limiting de novo lipid synthetic enzyme ACC1. These results provide insight into the genetic regulation of cell death and highlight the central role of lipid metabolism in nonapoptotic cell death.
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Genetic and/or pharmacological inhibition of ACSL4 and LPCAT3 protects cells against ferroptosis at least in some settings.
“genetic and/or pharmacological inhibition of acyl-CoA synthetase long chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), both of which are involved in the incorporation of long PUFAs into cellular membranes, protects cells against ferroptosis (at least in some settings) [562–565].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [564]
FIN56 acts only as a ferroptosis inducer, while CIL56 also activates a non-ferroptotic mechanism at higher concentrations that depends on ACC1.
“While FIN56 acts solely as a ferroptosis inducer, CIL56 also activates a non-ferroptotic mechanism at higher concentrations and is dependent on ACC1 (acetyl-CoA carboxylase alpha) [32].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [32]
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- Authors
- Dixon, S. J., Winter, G. E., Musavi, L. S., Lee, E. D., Snijder, B., Rebsamen, M., Superti-Furga, G., & Stockwell, B. R.
- Affiliations
- Columbia University (US)
- Austrian Academy of Sciences (AT)
- Austrian Academy of Sciences , of the, of the of the , Lazarettgasse 14 , ,
- Corresponding author
- Dixon, Scott J.
- Stockwell, Brent R.
- ORCID
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-05-12
- Volume
- 10
- Issue
- 7
- Pages
- 1604-1609
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- PMC
- PMC4509420
- OpenAlex
- W323406638
- Cited by
- 1,043
- References
- 26
- Citations by year
- 2026: 91 · 2025: 154 · 2024: 194 · 2023: 163 · 2022: 141 · 2021: 121 · 2020: 75 · 2019: 36 · 2018: 31 · 2017: 16 · 2016: 18 · 2015: 1
- FWCI
- 9.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- ACS Chemical Biology (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (4R00CA166517, 5R01CA097061, R01CA161061)
- National Institute of General Medical Sciences (5R01GM085081)
- Schweizerische Nationalfonds zur F?rderung der Wissenschaftlichen Forschung (NA)
- Austrian Academy of Sciences (NA)
- New York State Stem Cell Science, New York State Department of Health - Wadsworth Center (NA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- non-apoptotic cell death, lipid metabolism, ferroptosis, fatty acid metabolism, lipid remodeling, ACSL4, LPCAT3, acetyl-CoA carboxylase 1, insertional mutagenesis, de novo lipogenesis
- MeSH terms
- Gene Expression Regulation, Haploidy, Humans, Mutagenesis, Insertional, Apoptosis, Cell Line, Tumor, Lipid Metabolism, Small Molecule Libraries
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