iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4
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Here, we identify iPLA2β as a critical regulator for p53-driven ferroptosis upon reactive oxygen species (ROS)-induced stress. The calcium-independent phospholipase iPLA2β is known to cleave acyl tails from the glycerol backbone of lipids and release oxidized fatty acids from phospholipids. We found that iPLA2β-mediated detoxification of peroxidized lipids is sufficient to suppress p53-driven ferroptosis upon ROS-induced stress, even in GPX4-null cells. Moreover, iPLA2β is overexpressed in human cancers; inhibition of endogenous iPLA2β sensitizes tumor cells to p53-driven ferroptosis and promotes p53-dependent tumor suppression in xenograft mouse models. These results demonstrate that iPLA2β acts as a major ferroptosis repressor in a GPX4-independent manner. Notably, unlike GPX4, loss of iPLA2β has no obvious effect on normal development or cell viability in normal tissues but iPLA2β plays an essential role in regulating ferroptosis upon ROS-induced stress. Thus, our study suggests that iPLA2β is a promising therapeutic target for activating ferroptosis-mediated tumor suppression without serious toxicity concerns.
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Each type of PLA2 has substrate-specific activity, and depending on the substrate, PLA2 can either promote or block ferroptosis.
“Each type of PLA2 has a substrate-specific activity, and depending on the substrate, PLA2 can either promote or block ferroptosis (28–31).”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [28]
The Results section reports that iPLA2β cleaves peroxidized lipids and suppresses p53-mediated ferroptosis; it also finds that iPLA2γ does not suppress ferroptosis in the tested cells. These findings support differences among PLA2 enzymes, but our copy does not establish that each type has a distinct substrate-specific activity or that a PLA2 promotes ferroptosis depending on its substrate. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredInhibition of calcium-independent iPLA2β fostered p53-driven ferroptosis and tumor suppression by depleting the pool of oxidized lipids in response to ROS-generating drugs.
“In contrast, inhibition of the calcium-independent iPLA2β, which cleaves acyl tails from the glycerol backbone of lipids, fostered p53-driven ferroptosis and tumor suppression by depleting the pool of oxidized lipids in response to ROS-generating drugs (28).”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [28]
The Results section on xenograft models reports that loss of iPLA2β enhances p53-mediated ferroptosis and p53-dependent tumor suppression. But the Results section on peroxidized membrane lipids says iPLA2β itself reduces their levels; the claim reverses that mechanism by saying inhibition depletes oxidized lipids. Page numbers are unavailable in our copy. (LLM, conf=0.92)
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- Authors
- Chen, D., Chu, B., Yang, X., Liu, Z., Jin, Y., Kon, N., Rabadan, R., Jiang, X., Stockwell, B. R., & Gu, W.
- Affiliations
- Herbert Irving Comprehensive Cancer Center (US)
- Columbia University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Gu, Wei
- ORCID
- Venue
- Nature Communications
- Published
- 2021-06-15
- Volume
- 12
- Issue
- 1
- Pages
- 3644-3644
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8206155
- OpenAlex
- W3168103972
- Cited by
- 348
- References
- 43
- Citations by year
- 2026: 51 · 2025: 72 · 2024: 88 · 2023: 86 · 2022: 40 · 2021: 10
- FWCI
- 36.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (5R01CA216884, 5R01CA085533, 5R01CA254970, 5RO1CA224272)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- iPLA2β, phospholipase A2, ferroptosis, p53, lipid peroxidation, reactive oxygen species, tumor suppression, cancer therapy targets
- MeSH terms
- A549 Cells, Ferroptosis, Phospholipid Hydroperoxide Glutathione Peroxidase, Animals, Cell Survival, Disease Models, Animal, Fatty Acids, Female, Humans, Mice, Nude, Phospholipids, Tumor Suppressor Protein p53, Reactive Oxygen Species, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Group VI Phospholipases A2
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