Mechanisms for Regulatory Effects of Exercise on Metabolic Diseases from the Lactate-Lactylation Perspective

Metabolic diseases, including cardiovascular diseases, type 2 diabetes mellitus (T2DM), osteoporosis, and non-alcoholic fatty liver disease (NAFLD), constitute a major global health burden associated with chronic morbidity and mortality. Lactate, once considered as a metabolic byproduct, has emerged as a key regulator of cellular reprogramming through lactylation, a novel post-translational modification (PTM) that dynamically couples metabolic flux to chromatin remodeling. Lactylation exerts dual regulatory roles as a signaling molecule via GPR81/GPR4-mediated pathways and as a substrate for the covalent modification of histones and metabolic enzymes. Pathologically, chronic hyperlactatemia suppresses mitochondrial biogenesis, driving metabolic cardiomyopathy through the epigenetic silencing of oxidative metabolism genes. Conversely, exercise-induced lactate surges transiently enhance insulin sensitivity via AMPK/PGC-1α/GLUT4 signaling, resolve inflammation through GPR81-mediated M2 macrophage polarization, and restore mitochondrial function via lactylation-dependent pathways. This review delineates lactylation as a spatiotemporal rheostat: chronic dysregulation perpetuates metabolic disorders, whereas acute exercise-mediated lactylation remodels transcriptional networks to restore metabolic homeostasis. Future research should integrate multiomics to clarify lactylation's spatiotemporal dynamics, tissue-specific thresholds, metabolism-immunity interactions, and metabolic-epigenetic crosstalk for the precision management of metabolic diseases.