Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis
Open accessAbstract
Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.
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Oxidation of PUFAs containing phosphatidylethanolamine (PE) molecular species generates ferroptosis signals.
“In particular, the oxidation of PUFAs containing phosphatidylethanolamine (PE) molecular species generates ferroptosis signals (18).”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [18]
The Discussion identifies oxidized arachidonic- and adrenic-acid-containing PE species as ferroptotic death signals, supporting the claim’s central point. The Results section on oxygenated PE in Gpx4 KO cells and kidney narrows this finding: only two of 36 oxidizable PUFA-containing PE species were identified as signal precursors. The claim does not convey that specificity. (LLM, conf=0.83)
Experimental — accuracy not yet measuredGenetic 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 [562]
Ferroptosis involves preferential oxidation of specific phosphatidylethanolamine-containing PUFAs such as arachidonic and adrenic acid.
“Recent evidence indicates that ferroptosis involves the preferential oxidation of specific phosphatidylethanolamine-containing polyunsaturated fatty acids (PUFAs) such as arachidonic and adrenic acid [562].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [562]
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- Authors
- Kagan, V. E., Mao, G., Qu, F., Angeli, J. P. F., Doll, S., Croix, C. S., Dar, H. H., Liu, B., Tyurin, V. A., Ritov, V. B., Kapralov, A. A., Amoscato, A. A., Jiang, J., Anthonymuthu, T., Mohammadyani, D., Yang, Q., Proneth, B., Klein-Seetharaman, J., Watkins, S., Bahar, I., Greenberger, J., Mallampalli, R. K., Stockwell, B. R., Tyurina, Y. Y., Conrad, M., & Bayır, H.
- Affiliations
- University of Pittsburgh (US)
- Helmholtz Munich (DE)
- Columbia University (US)
- Corresponding author
- Kagan, Valerian E
- Conrad, Marcus
- Bayır, Hülya
- ORCID
- Kagan, Valerian E
- Qu, Feng
- Doll, Sebastian
- Dar, Haider Hussain
- Liu, Bing
- Tyurin, Vladimir A
- Kapralov, Alexandr A
- Amoscato, Andrew A
- Jiang, Jianfei
- Anthonymuthu, Tamil
- Mohammadyani, Dariush
- Yang, Qin
- Proneth, Bettina
- Klein-Seetharaman, Judith
- Watkins, Simon
- Greenberger, Joel
- Mallampalli, Rama K
- Stockwell, Brent R
- Tyurina, Yulia Y
- Conrad, Marcus
- Bayır, Hülya
- Venue
- Nature Chemical Biology
- Published
- 2016-11-14
- Volume
- 13
- Issue
- 1
- Pages
- 81-90
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5506843
- OpenAlex
- W2550324626
- Cited by
- 3,029
- References
- 57
- Citations by year
- 2026: 490 · 2025: 472 · 2024: 513 · 2023: 465 · 2022: 381 · 2021: 272 · 2020: 198 · 2019: 111 · 2018: 61 · 2017: 54 · 2016: 6 · 2015: 1 · 2014: 1
- FWCI
- 68.62
- 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)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Warwick Research Archive Portal (University of Warwick) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL081784, R01HL098174, P01HL114453, R01HL097376, R01HL096376)
- National Cancer Institute (R35CA209896)
- National Institute of General Medical Sciences (P41GM103712)
- National Institute of Allergy and Infectious Diseases (U19AI068021)
- National Institute of Neurological Disorders and Stroke (R01NS061817, R01NS084604, R37NS061817, R01NS076511)
- National Institute of Environmental Health Sciences (R01ES020693)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- ferroptosis, arachidonic acid, adrenic acid, lipoxygenase, vitamin E, tocopherols, tocotrienols, GPX4, endoplasmic reticulum, lipid peroxidation
- MeSH terms
- Animals, Cell Line, Coenzyme A Ligases, Fatty Acids, Unsaturated, Female, Male, Mice, Inbred C57BL, Phospholipids, Arachidonic Acid, Cell Death, Mice, Knockout, Mice
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