Beyond the Wiring: White Matter as a Dynamic Regulator of Brain Function and Disease.

White matter, constituting nearly half of the human brain, is increasingly recognized as a dynamic regulator of neural communication, metabolism, and cognition rather than a passive conduit for signal transmission. Recent advances in neuroimaging, molecular biology, and single-cell transcriptomics have revealed that myelin and oligodendrocytes play essential roles in neural plasticity and disease. Here, we synthesize current understanding of white matter organization and myelin function, emphasizing its contributions to conduction efficiency, metabolic support, and network optimization. We further discuss mechanisms of myelin plasticity and highlight its role in learning, adaptation, and repair. Integrating evidence across developmental, immune-mediated, neurodegenerative, and psychiatric disorders, we propose that white matter pathology constitutes a primary driver of brain dysfunction. Finally, we summarize emerging regenerative strategies-including cell and gene therapies, OPC-targeted interventions, and neuromodulation-highlighting translational opportunities for restoring myelin integrity and circuit function. This review reframes white matter as a promising therapeutic frontier.