Restoration of glucose metabolic homeostasis for treating CNS diseases: mechanistic insights and potential clinical prospect

Brain glucose metabolism orchestrates central nervous system (CNS) homeostasis via cell-type-specific metabolic networks and metabolite-mediated signaling. Recent studies have shown that dysregulated glucose metabolism can disrupt energy balance, antioxidant system stability, and neuroimmune communication, in turn exacerbating CNS diseases. Impaired neuronal oxidative phosphorylation (OXPHOS) causes energy deficits and mitochondrial dysfunction, leading to neuronal cell death. Damaged astrocyte PPP support system impairs antioxidant defenses, leading to cumulative lipid peroxidation and thus exacerbating oxidative stress. Metabolic reprogramming in microglia further links overactivation of glycolysis to neuroinflammation. Crucially, glucose-derived metabolites drive post-translational modifications (PTMs), including glycosylation, lactylation, acetylation, and succinylation, that regulate chromatin states, protein function, and pathogenic signaling pathways in CNS diseases. Therefore, therapeutic strategies targeting glucose metabolism, including targeting the glucose metabolic pathways to restore metabolic flexibility, managing the metabolism-induced PTMs, and bypassing the impaired pathways with alternative fuels, offer promising opportunities for treating CNS disorders. However, the compensatory mechanisms inherent to interconnected metabolic networks undermines single-target therapies, necessitating combination strategies to simultaneously address multiple nodes. This review provides an overview of recent advances in understanding the cell-specific glucose metabolism, glucose metabolite-driven PTMs, and their pathogenic significance in CNS diseases. We further discuss the regulators involved in different strategies to restore glucose metabolic homeostasis. Future work should integrate novel tools such as single-cell spatial metabolomics and AI-driven modelling to develop combination therapies targeting brain's constantly adjusting metabolic system, ultimately translating these discoveries into clinical treatments for metabolic dysregulation.