An endogenous polyunsaturated fatty acid, dihomo‐gamma‐linoleic acid, induces neurodegeneration in C. elegans via ferroptosis

Ferroptosis, an iron‐dependent non‐apoptotic programmed cell death, becomes a novel target and mechanism for age‐associated neurodegenerative diseases. Although several ferroptosis regulatory proteins have been identified, the signaling molecules and the pathways of ferroptosis remain largely unknown. Despite membrane lipid peroxidation being one of the molecular hallmarks of ferroptosis, how polyunsaturated fatty acids (PUFAs) involved in the ferroptosis pathway is understudied. Here, we hypothesize that a specific PUFA and/or its downstream metabolites are lipid mediators of ferroptosis. However, it is challenging to identify by which metabolites regulate ferroptosis and to study the associated mechanism due to many different endogenous PUFAs are presented endogenously and each PUFAs can be metabolized to almost a hundred of metabolites.To take on these challenges, we employed Caenorhabditis elegans (C. elegans) as a novel biological model due to the availability of many genetic and imaging tools, conserved ferroptosis pathways between mammal and C. elegans, and adaptability for high‐throughput whole animal aging study. Using the well‐established fluorescent imaging assay in C. elegans, we showed that treatment of dihomo‐gamma‐linoleic acid (DGLA), but not other PUFAs, induces significant (>40% as compared to control) degeneration in dopaminergic neurons immediately after 1 day of treatment. We also found that treatment of DGLA does not affect other somatic tissues of the C. elegans. Our lipidomic analysis demonstrated that DGLA is well‐absorbed by C. elegans. Besides, our results indicated that DGLA triggers neurodegeneration in dopaminergic neurons, likely through ferroptosis. Using our oxidized lipid metabolites analysis and synthetic chemical probes, we revealed that DGLA likely triggers neurodegeneration viatheir oxidized metabolites. Finally, we will also present the potential ferroptosis signaling pathways triggered by DGLA based on our RNA‐seq experiments.Our results will help us identify novel lipid mediators for ferroptosis, which will lead to a better understanding of the molecular mechanism of ferroptosis. Our findings regarding the neuronal specific effects triggered by DGLA also revive a novel cell‐specific regulatory mechanism of ferroptosis. Lastly, our study will find novel therapeutic targets for either preventative treatment or cure for neurodegenerative diseases.