Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis
Open accessAbstract
Apoptosis is one type of programmed cell death. Increasingly, non-apoptotic cell death is recognized as being genetically controlled, or 'regulated'. However, the full extent and diversity of alternative cell death mechanisms remain uncharted. Here we surveyed the landscape of pharmacologically accessible cell death mechanisms. In an examination of 56 caspase-independent lethal compounds, modulatory profiling showed that 10 compounds induced three different types of regulated non-apoptotic cell death. Optimization of one of those ten resulted in the discovery of FIN56, a specific inducer of ferroptosis. Ferroptosis has been found to occur when the lipid-repair enzyme GPX4 is inhibited. FIN56 promoted degradation of GPX4. FIN56 also bound to and activated squalene synthase, an enzyme involved in isoprenoid biosynthesis, independent of GPX4 degradation. These discoveries show that dysregulation of lipid metabolism is associated with ferroptosis. This systematic approach is a means to discover and characterize novel cell death phenotypes.
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CIL56- and FIN56-induced death involves lipid-ROS generation and is suppressed by vitamin E and iron chelators, confirming they are ferroptosis inducers.
“CIL56-induced and FIN56-induced cell death is accompanied by lipid-ROS generation; vitamin E and iron chelators suppressed cell death induced by these compounds [31], confirming that they are ferroptosis inducers.”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [31]
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- Authors
- Shimada, K., Skouta, R., Kaplan, A., Yang, W. S., Hayano, M., Dixon, S. J., Brown, L. M., Valenzuela, C. A., Wolpaw, A. J., & Stockwell, B. R.
- Affiliations
- Columbia University (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Stockwell, Brent R
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2016-05-09
- Volume
- 12
- Issue
- 7
- Pages
- 497-503
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC4920070
- OpenAlex
- W2345350059
- Cited by
- 1,017
- References
- 40
- Citations by year
- 2026: 85 · 2025: 130 · 2024: 160 · 2023: 164 · 2022: 148 · 2021: 130 · 2020: 86 · 2019: 60 · 2018: 32 · 2017: 16 · 2016: 4 · 2015: 1
- FWCI
- 33.37
- 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)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1dp2od006740-01, 1k99ca166517-01)
- National Cancer Institute (R35CA209896, R01CA097061, R01CA161061, K99 CA166517, R00CA166517)
- National Institute of General Medical Sciences (R01GM085081)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK114217)
- 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
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- ferroptosis, GPX4, squalene synthase, non-apoptotic cell death, regulated cell death, isoprenoid biosynthesis, lipid metabolism, cholesterol biosynthesis
- MeSH terms
- Dose-Response Relationship, Drug, Humans, Iron, Oximes, Structure-Activity Relationship, Sulfonamides, Apoptosis, Lipid Metabolism
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