Energy-Metabolic Imbalance of Oligodendrocytes in Multiple Sclerosis: Mechanisms, Network Coupling, and Advances in Metabolism-Targeted Therapies.

Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system (CNS), are principal targets of autoimmune attack in multiple sclerosis (MS), resulting in demyelination and impaired neural conduction. Recent studies indicate that white matter in patients with MS exhibits increased aerobic glycolysis alongside reduced oxygen consumption-a metabolic mismatch between glucose utilization and oxygen consumption-that correlates with disability accumulation. Dysregulated energy metabolism is also a central mechanism limiting remyelination in MS. In MS, this dysregulation is characterized primarily by abnormal availability of metabolic substrates entering the CNS; in turn, it disrupts glucose and lipid metabolism within OLs, leading to mitochondrial dysfunction and a diminished capacity for myelin repair. Pharmacological studies employing metabolic intermediates as interventions have shown that correcting energy-metabolism disturbances in OLs can promote remyelination and mitigate MS symptoms, highlighting the metabolic-epigenetic axis as a potential therapeutic target. Clinical and translational research further suggests that modulation of metabolic pathways may enhance remyelination and improve brain energy homeostasis. Future work should integrate metabolomics, multimodal imaging, and multi-omics approaches to map neuron-glia metabolic-coupling networks with precision and to test, in high-quality randomized controlled trials, the efficacy and safety of metabolism-targeted therapies.