ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition
Open accessAbstract
Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.
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Inducible or tissue-specific ablation of Gpx4 in mice provokes acute renal or hepatic injury, neurodegeneration, and defective immunity to infection, all preventable or mitigated by ferroptosis-inhibiting strategies.
“the inducible or tissue-specific ablation of Gpx4 in mice provokes a variety of pathological conditions, including acute renal or hepatic injury [547, 563, 589], neurodegeneration [550, 590, 591], and defective immunity to infection [567], all of which can be prevented or mitigated by ferroptosis-inhibiting strategies.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [563]
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 [563]
Iron affects lipid peroxidation through interactions with iron-dependent oxidases such as lipoxygenase, subsequently activating ferroptosis to accelerate AD progression.
“Iron can affect lipid peroxidation through interactions with iron-dependent oxidases such as lipoxygenase, subsequently activating ferroptosis to accelerate AD progression [541, 546, 547].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [546]
Among overlapping genes, the authors identified known regulators of apoptosis (TP53, IKBIP), factors of neuronal survival (XIAP, GDPGP1, MAP3K1), and genes not previously implicated in neuronal survival (IGF2BP1, IGF2BP3).
“Among these genes, we identified known regulators of apoptosis, such as TP53, IKBIP, and factors specifically of neuronal survival, such as XIAP17–20, GDPGP121 and MAP3K123,22–24, as well as genes not previously implicated in neuronal survival, such as IGF2BP1 and IGF2BP3.”
From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [24]
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- Authors
- Doll, S., Proneth, B., Tyurina, Y. Y., Panzilius, E., Kobayashi, S., Ingold, I., Irmler, M., Beckers, J., Aichler, M., Walch, A., Prokisch, H., Trümbach, D., Mao, G., Qu, F., Bayir, H., Füllekrug, J., Scheel, C. H., Wurst, W., Schick, J. A., Kagan, V. E., Angeli, J. P. F., & Conrad, M.
- Affiliations
- Helmholtz Munich (DE)
- University of Pittsburgh (US)
- Heidelberg University (DE)
- Corresponding author
- Angeli, José Pedro Friedmann
- Conrad, Marcus
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2016-11-14
- Volume
- 13
- Issue
- 1
- Pages
- 91-98
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5610546
- OpenAlex
- W2549188196
- Cited by
- 4,293
- References
- 53
- Citations by year
- 2026: 761 · 2025: 723 · 2024: 775 · 2023: 640 · 2022: 553 · 2021: 373 · 2020: 219 · 2019: 121 · 2018: 66 · 2017: 48 · 2016: 7 · 2015: 1 · 2014: 1 · 2012: 1
- FWCI
- 71.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL114453)
- National Institute of Allergy and Infectious Diseases (U19AI068021)
- National Institute of Neurological Disorders and Stroke (R01NS061817, R01NS076511)
- National Institute of Environmental Health Sciences (R01ES020693)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- ACSL4, ferroptosis, GPX4, omega-6 fatty acids, membrane lipid composition, ferroptosis resistance, basal-like breast cancer, thiazolidinediones, necrosis, CRISPR screen
- MeSH terms
- Phospholipid Hydroperoxide Glutathione Peroxidase, Animals, Cell Line, Cell Survival, Coenzyme A Ligases, Female, Glutathione Peroxidase, Humans, Hypoglycemic Agents, Mammary Neoplasms, Experimental, Necrosis, Cell Death, Apoptosis, Mice, Knockout, Thiazolidinediones, Mice
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