The ApoC2 mimetic peptide D6PV enhances remyelination by stimulating oxidative phosphorylation in oligodendrocytes

Abstract Failure of remyelination drives neurodegeneration in demyelinating disorders such as multiple sclerosis (MS), with disrupted lipid handling and metabolic stress in oligodendrocyte precursor cells (OPCs) posing major barriers to repair. Here, we identify the dual ApoC-II mimetic–ApoC-III antagonist peptide D6PV as a metabolic modulator that directly enhances OPC differentiation and myelin repair. Across ex vivo and in vivo models of chemically induced demyelination, D6PV promotes oligodendrocyte maturation and restores myelin integrity independently of lipoprotein hydrolysis or modulation of lipid droplet-containing phagocytes. Guided by transcriptomics analyses, we find that D6PV stimulates mitochondrial oxidative phosphorylation and fatty acid β-oxidation, while suppressing inflammatory transcriptional programs, thereby driving OPCs toward a myelinating phenotype. Notably, D6PV does not alter peripheral immune composition or autoimmune-driven pathology in the experimental autoimmune encephalomyelitis model, indicating a central nervous system (CNS) cell-autonomous effect. These findings reveal a metabolism-linked pathway for remyelination and position D6PV as a promising therapeutic strategy to enhance CNS repair in demyelinating diseases.