ArticleProceedings of the National Academy of Sciences of the United States of America2016
Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1,407 papers, 1 of them a synthesis that pooled it.
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Who cites it
1,407 citing papers in PubMed, 1 synthesis or guideline pooled it, 2,213 citations in OpenAlex.
- Bibliometric analysis and visualization of ferroptosis in metabolic dysfunction-associated steatotic liver disease (MASLD): a comprehensive review.Frontiers in pharmacology · 2026Pooled it
- CircRNA-mediated regulation of ferroptosis in cancer: mechanistic networks and therapeutic implications.Cancer gene therapy · 2026Review
- Stress-induced vtRNA1-1 modulates redox homeostasis and ferroptosis susceptibility in hepatocellular carcinoma cells.Redox biology · 2026Article
- Integrated multi-omics analysis reveals the molecular landscape and therapeutic strategies in Chinese cervical cancer patients.PLoS biology · 2026Article
- Ferroptosis in liver biology and diseases.Hepatology communications · 2026Review
- Integrative multi-omics analysis identifies LIPA as a prognostic hub and ferroptosis regulator in lung adenocarcinoma.Molecular and cellular biochemistry · 2026Article
- Peroxiredoxin 4 Involved in Spermatogenesis by Affecting Oxidative Stress and Ferroptosis.Andrology · 2026Article
- Metabolic Vulnerability and Regenerative Failure of the External Urethral Sphincter: A Ferroptosis-Associated Framework for Stress Urinary Incontinence.Biomolecules · 2026Review
- STRA6-mediated ferroptosis and its potential association with antioxidant stress pathways in glioblastoma.iScience · 2026Article
- Ferroptosis in kidney disease.Nature reviews. Nephrology · 2026Review
- Dystrophin Deficiency Creates a Pro-Ferroptotic Environment in Diaphragm of mdx Mice That Is Modified by Diet and Glucocorticoid Treatment.Biomolecules · 2026Article
- Spatiotemporal iron-hijacking hydrogel reprograms host-pathogen iron homeostasis for fungal keratitis therapy.Cell reports. Medicine · 2026Article
- The Emerging Role of Ferroptosis in Pediatric Cancer Biology and Therapy.International journal of molecular sciences · 2026Review
- Harnessing copper-iron crosstalk: A novel strategy to combat hepatocellular carcinoma.Medical oncology (Northwood, London, England) · 2026Review
- Deferiprone Modulates Ferroptosis to Protect Macrophages and Liver during Neospora caninum Infection.Acta parasitologica · 2026Article
- Polyunsaturated fatty acid sequestration protects against mitochondrial dysfunction-induced ferroptosis.EMBO reports · 2026Article
- Ferroptosis: Newly Emerged Regulator for Human Disease.MedComm · 2026Review
- Ferroptosis in skeletal muscle: from molecular mechanisms to therapeutic interventions.Journal of orthopaedic translation · 2026Review
- RNA modifications as determinants of cancer cell death: from epitranscriptomic mechanisms to therapeutic targeting.Functional & integrative genomics · 2026Review
- The Substrate-Engine Model of Ferroptosis: Stage-Specific Targeting of Acyl-CoA Synthetase Long-Chain Family Member 4 and 5‑Lipoxygenase in Alzheimer's Disease.ACS pharmacology & translational science · 2026Review
1,347 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 4 institutions in 1 country.
Funding
Abstract
Ferroptosis is form of regulated nonapoptotic cell death that is involved in diverse disease contexts. Small molecules that inhibit glutathione peroxidase 4 (GPX4), a phospholipid peroxidase, cause lethal accumulation of lipid peroxides and induce ferroptotic cell death. Although ferroptosis has been suggested to involve accumulation of reactive oxygen species (ROS) in lipid environments, the mediators and substrates of ROS generation and the pharmacological mechanism of GPX4 inhibition that generates ROS in lipid environments are unknown. We report here the mechanism of lipid peroxidation during ferroptosis, which involves phosphorylase kinase G2 (PHKG2) regulation of iron availability to lipoxygenase enzymes, which in turn drive ferroptosis through peroxidation of polyunsaturated fatty acids (PUFAs) at the bis-allylic position; indeed, pretreating cells with PUFAs containing the heavy hydrogen isotope deuterium at the site of peroxidation (D-PUFA) prevented PUFA oxidation and blocked ferroptosis. We further found that ferroptosis inducers inhibit GPX4 by covalently targeting the active site selenocysteine, leading to accumulation of PUFA hydroperoxides. In summary, we found that PUFA oxidation by lipoxygenases via a PHKG2-dependent iron pool is necessary for ferroptosis and that the covalent inhibition of the catalytic selenocysteine in Gpx4 prevents elimination of PUFA hydroperoxides; these findings suggest new strategies for controlling ferroptosis in diverse contexts.
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