Lactate as a metabolic-epigenetic hub in neurological disorders

Lactate, once considered merely a metabolic waste product of glycolysis, has emerged as a pivotal signaling molecule that bridges cellular metabolism and epigenetic regulation in the central nervous system. The discovery of protein lactylation in 2019 revealed a novel post-translational modification that directly linked lactate accumulation to changes in gene expression, fundamentally reshaping our understanding of how metabolic states influenced neural function and dysfunction. This comprehensive review synthesizes recent advances in lactate biology, encompassing the expanding enzymatic landscape of lactylation-including newly identified writers, erasers, and readers-and their roles in neurodegenerative diseases. We critically re-examine metabolic coupling models beyond the classical astrocyte-neuron lactate shuttle (ANLS), incorporating neuronal glycolytic capacity, oligodendrocyte-specific relay mechanisms, and cell type-specific monocarboxylate transporter (MCT) expression patterns. Furthermore, we explore the concentration-dependent duality of lactate effects through G protein-coupled receptor 81 (GPR81)/hydroxycarboxylic acid receptor 1 (HCAR1) signaling, the functional significance of non-histone lactylation in neural cells, and the interplay between lactylation and mitochondrial quality control, ferroptosis, and adult hippocampal neurogenesis. Finally, we discuss emerging therapeutic strategies targeting lactate metabolism and lactylation modifications -ranging from lactate dehydrogenase (LDH) inhibitors and MCT modulators to exercise-induced neuroprotection-and identify critical challenges for clinical translation. By integrating these cutting-edge findings, we provide an updated theoretical framework that positions lactate as a central node connecting metabolic reprogramming with epigenetic dysregulation in neurodegeneration.