Immunometabolic reprogramming in multiple sclerosis: from pathogenic amplifier to therapeutic target in neuroinflammation and remyelination

Multiple sclerosis (MS) has conventionally been considered a prototypical autoimmune disorder. While modern immunotherapies effectively control relapsing conditions, they fail to avert progressive neuroinflammation, neurodegeneration, and remyelination failure. This review offers an evidence-based recontextualization. The pathogenesis of multiple sclerosis is multifactorial, resulting from the interaction of genetic predisposition (especially HLA alleles), environmental factors (particularly Epstein-Barr virus infection), B-cell-mediated autoimmunity, and localized CNS inflammation. In this intricate environment, cellular metabolic dysregulation is a notable factor and potentially adjustable enhancer of disease progression, functioning within the extensive multifactorial pathogenic context, where the bioenergetic programming of immune and neural cells determines inflammatory or protective responses. Proinflammatory Th17 cells and M1 microglia depend on aerobic glycolysis and glutaminolysis regulated by mTOR and HIF-1α, whereas regulatory T cells, M2 microglia, and neurons require fatty acid oxidation and oxidative phosphorylation via AMPK. In multiple sclerosis, glycolysis disrupts metabolic equilibrium, sustaining chronic neuroinflammation and obstructing repair processes. Established multiple sclerosis therapies, dimethyl fumarate and teriflunomide, exhibit direct, previously unrecognized metabolic effects, validating this pathway as therapeutically viable. Emerging strategies intentionally target these vulnerabilities: glutaminase inhibitors to counteract pathogenic Th17 cells, AMPK activators such as metformin to enhance remyelination, mTOR inhibitors to restore immune tolerance, and NAD + precursors to rejuvenate mitochondrial function. Transitioning from broad immunosuppression to specific metabolic reprogramming offers remarkable opportunities for tackling chronic neuroinflammation and correcting remyelination deficits in progressive multiple sclerosis. Immuno-metabolic pharmacology is a promising field; however, its clinical application necessitates stringent validation via meticulously designed trials and dependable biomarkers.