Metabolic reprogramming of glial cells: Fatty acid pathways as regulators of remyelination in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disorder characterized by neuroinflammation and progressive demyelination, resulting in irreversible neuronal damage and disability. Although current immunomodulatory treatments slow disease progression, they can't effectively promote myelin regeneration. Recent research has emphasized the critical role of glial cells—microglia, astrocytes, and oligodendrocytes—in myelin repair, with fatty acid (FA) metabolism emerging as a central regulator of this process. Fatty acids are essential not only for maintaining myelin structure but also for the metabolic reprogramming of glial cells during remyelination. Microglial activation, influenced by FA signaling, can result in either pro-inflammatory or reparative phenotypes, which in turn affect remyelination efficiency. Similarly, astrocytes contribute to remyelination through cholesterol synthesis and FA oxidation; however, their reactive states can either promote or inhibit myelin repair, depending on the metabolic context. Oligodendrocyte precursor cells, crucial for myelin regeneration, are also regulated by fatty acids, impacting their differentiation and survival. Disruptions in FA metabolism or imbalanced glial activation can impair remyelination, underscoring the need for therapies targeting these metabolic pathways. This review examines the complex relationship between fatty acid metabolism and glial cell function, emphasizing the potential of targeting lipid signaling pathways to enhance remyelination in MS. Targeting fatty acid metabolism represents a promising yet still experimental therapeutic approach for MS and related demyelinating diseases. By modulating glial metabolism and immune responses, this strategy has the potential to decelerate disease progression and restore neural function, though further validation is required to translate these mechanisms into clinical applications. Targeting fatty acid metabolism can regulate glial cell functions and enhance myelin repair. We emphasize the temporal and context-dependent roles of fatty acid metabolism, providing new therapeutic approaches to promote myelin regeneration in multiple sclerosis. • Fatty acid metabolism coordinates glial cell myelin regeneration. • Timing of metabolic interventions determines remyelination success. • Glial cells metabolically interact with neurons to balance inflammation and repair. • Metabolic reprogramming of glial cells offers treatment potential for remyelination.