The metabolic reprogramming of lactate in the nervous system

Lactate, a critical energetic substrate and signaling molecule in the central nervous system (CNS), plays a pivotal role in maintaining neurophysiological homeostasis and driving the pathogenesis of neurodegenerative disorders through metabolic reprogramming. Herein, this review systematically summarizes recent progress in molecular mechanisms governing lactate metabolic reprogramming as well as its multiple biological functions in the central nervous system. Under physiological conditions, lactate regulates energy distribution via the astrocyte-neuron lactate shuttle, while mediates neural communication through receptors including G Protein-Coupled Receptor 81 and N-Methyl-d-Aspartate Receptor, thereby modulating synaptic plasticity and memory consolidation. In neurodegenerative pathologies (such as Alzheimer's and Parkinson's diseases), dysregulated lactate reprogramming is observed in the form of dynamic lactate imbalance, altered expression of monocarboxylate transporters and lactate dehydrogenase, and defective mitochondrial energy coupling. These perturbations further enhance neuronal damage by triggering neuroinflammation and perturbing epigenomic homeostasis (e.g., histone lactylation). Critical knowledge gaps remain unresolved: (1) The temporal dynamics of lactate flux during disease progression remain uncharacterized; (2) The spatial heterogeneity of lactate distribution across brain nuclei and its regulatory mechanisms are debated; (3) Consensus is lacking regarding functional alterations of core lactate metabolic components; and (4) The precise signaling cascades through which lactate modulates neurodegeneration require elucidation. By integrating contemporary research on central nervous system lactate reprogramming, this work provides novel perspectives on neurodegenerative disease mechanisms and establishes a theoretical framework for developing targeted therapeutic strategies that modulate lactate metabolism.