Dihydroxy‐Metabolites of Dihomo‐γ‐linolenic acid drive ferroptosis‐mediated neurodegeneration
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Abstract
Even after decades of research, the mechanism of neurodegeneration remains understudied, hindering the discovery of effective treatments for neurodegenerative diseases. Recent reports suggest that ferroptosis could be a novel therapeutic target for neurodegenerative diseases. While polyunsaturated fatty acid (PUFA) plays an important role in neurodegeneration and ferroptosis, how PUFAs may trigger these processes remains largely unknown. PUFA metabolites from cytochrome P450 and epoxide hydrolase metabolic pathways may modulate neurodegeneration. Here, we test the hypothesis that specific PUFAs regulate neurodegeneration through the action of their downstream metabolites by affecting ferroptosis. We find that the PUFA dihomo-γ-linolenic acid (DGLA) specifically induces ferroptosis-mediated neurodegeneration in dopaminergic neurons. Using synthetic chemical probes, targeted metabolomics, and genetic mutants, we show that DGLA triggers neurodegeneration upon conversion to dihydroxyeicosadienoic acid through the action of CYP-EH (CYP, cytochrome P450; EH, epoxide hydrolase), representing a new class of lipid metabolites that induce neurodegeneration via ferroptosis.
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Dihomo-gamma-linolenic acid, a metabolite of gamma-linolenic acid, has been implicated in inducing ferroptosis-mediated neurodegeneration, particularly in dopaminergic neurons.
“Notably, dihomo‐gamma‐linolenic acid (DGLA), a metabolite of the polyunsaturated FA GLA, has been implicated in inducing ferroptosis‐mediated neurodegeneration, particularly in dopaminergic neurons. 27”
From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [27]
The Results and Conclusion report that DGLA treatment triggers neurodegeneration predominantly in dopaminergic neurons of C. elegans, with ferroptosis implicated particularly at early stages. Our copy does not establish the claim’s additional description of DGLA as a metabolite of GLA (searched for GLA and its conversion to DGLA). (LLM, conf=0.86)
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Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes
Tian, X., Rivera, E. K., Hwang, I., Nikitina, A. A., Smith, J. A., Cho, Y. J., Sala‐Jarque, J., DuBose, A., Andriola, C., Gollan‐Myers, T., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70589 · Cited by 7 · see citing works
- Authors
- Sarparast, M., Pourmand, E., Hinman, J., Vonarx, D., Reason, T., Zhang, F., Paithankar, S., Chen, B., Borhan, B., Watts, J. L., Alan, J., & Lee, K. S. S.
- Affiliations
- Michigan State University (US)
- Washington State University (US)
- Corresponding author
- Alan, Jamie
- Lee, Kin Sing Stephen
- ORCID
- Venue
- ACS Central Science
- Publisher
- American Chemical Society (ACS)
- Published
- 2023-03-16
- Volume
- 9
- Issue
- 5
- Pages
- 870-882
- ISSN
- 2374-7943 (ISSN-L)
- 2374-7951
- PMC
- PMC10214511
- OpenAlex
- W4327554146
- Cited by
- 33
- References
- 107
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 5 · 2023: 10
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- ACS Central Science (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- Michigan State University
- National Institutes of Health (P40 OD010440)
- National Institute of General Medical Sciences (R01 GM133883, R35 GM146983, T32 GM142521)
- Pearl Aldrich Endowment for Aging Research
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Keywords
- dihomo-gamma-linolenic acid, ferroptosis, neurodegeneration, polyunsaturated fatty acid metabolites, cytochrome P450, epoxide hydrolase, dopaminergic neurons, lipid metabolites, neurodegenerative diseases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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