Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis
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High Resolution Image Download MS PowerPoint Slide Lipoxygenases (LOXs) have been implicated as central players in ferroptosis, a recently characterized cell death modality associated with the accumulation of lipid hydroperoxides: the products of LOX catalysis. To provide insight on their role, human embryonic kidney cells were transfected to overexpress each of the human isoforms associated with disease, 5-LOX, p12-LOX, and 15-LOX-1, which yielded stable cell lines that were demonstrably sensitized to ferroptosis. Interestingly, the cells could be rescued by less than half of a diverse collection of known LOX inhibitors. Furthermore, the cytoprotective compounds were similarly potent in each of the cell lines even though some were clearly isoform-selective LOX inhibitors. The cytoprotective compounds were subsequently demonstrated to be effective radical-trapping antioxidants, which protect lipids from autoxidation, the autocatalytic radical chain reaction that produces lipid hydroperoxides. From these data (and others reported herein), a picture emerges wherein LOX activity may contribute to the cellular pool of lipid hydroperoxides that initiate ferroptosis, but lipid autoxidation drives the cell death process.
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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 [547]
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- Authors
- Shah, R., Shchepinov, M. S., & Pratt, D. A.
- Affiliations
- University of Ottawa (CA)
- Retrotope (United States) (US)
- Corresponding author
- Pratt, Derek A.
- Venue
- ACS Central Science
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-02-07
- Volume
- 4
- Issue
- 3
- Pages
- 387-396
- ISSN
- 2374-7943 (ISSN-L)
- 2374-7951
- PMC
- PMC5879472
- OpenAlex
- W2786707817
- Cited by
- 782
- References
- 65
- Citations by year
- 2026: 90 · 2025: 137 · 2024: 143 · 2023: 119 · 2022: 103 · 2021: 87 · 2020: 57 · 2019: 31 · 2018: 15
- FWCI
- 35.98
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- ACS Central Science (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Canada Foundation for Innovation
- Canada Research Chairs
- Natural Sciences and Engineering Research Council of Canada
- 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 › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- lipoxygenase, ferroptosis, 5-lipoxygenase, 15-lipoxygenase-1, lipid hydroperoxides, lipid autoxidation, radical-trapping antioxidants, cell death, human embryonic kidney cells
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