Eicosapentaenoic acid reprograms cerebrovascular metabolism and impairs repair after brain injury, with relevance to chronic traumatic encephalopathy

Repetitive mild traumatic brain injury (rmTBI) precedes chronic traumatic encephalopathy (CTE) and involves neurovascular dysfunction. Omega-3 polyunsaturated fatty acids (PUFA) are promoted as neuroprotective but their long-term effects after brain injury remain uncertain. We uncover a metabolic vulnerability associated with cerebral accumulation of eicosapentaenoic acid (EPA), a major PUFA derived from fish oil. In a fish oil diet model, EPA accumulates at baseline yet is selectively depleted after rmTBI, consistent with mobilization during injury-associated metabolic remodeling. This pattern coincides with matrix remodeling, endothelial degeneration, and impaired neurovascular function. Cortical transcriptomics indicate reduced angiogenic programs with increased fatty acid metabolism, and lipidomics links EPA to maladaptive lipid engagement. Mechanistic studies using metabolically adapted endothelial cells show that EPA selectively impairs reparative function. Analysis of postmortem CTE brain tissue reveals parallel vascular and metabolic gene expression changes, strengthening translational relevance. Together, these findings challenge the assumption of uniform omega-3 neuroprotection after brain injury.