Dihydroxy-Metabolites of Dihomo-γ-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration

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.