From fuel to epigenetic signal: Lactate-lactylation axis orchestrates diabetic complications.

Lactate, traditionally regarded as a metabolic waste product, is now recognized as a pivotal signaling molecule and epigenetic regulator. Emerging evidence indicates that the metabolic reprogramming driven by hyperglycemia elevates the overall levels of lactate and lactylation, further promoting the progression of diabetes mellitus. This review emphasizes that lactate-lactylation axis dysregulation serves as a unified mechanism to drive multiple diabetic complications-diabetic cardiomyopathy, diabetic kidney disease, diabetic retinopathy, and median vascular calcification. Abnormal lactate metabolism enhances global lactylation levels, which remodels macrophage polarization, disrupts mitochondrial function, aggravates fibrosis and aberrant angiogenesis. Mechanistically, lactylation is dynamically modulated by writers (e.g., p300/CBP), erasers (e.g., HDAC1-3), regulators (e.g., GPR81), and profoundly impacts gene expression and protein functions in both histone and non-histone modifications. Nonetheless, key questions remain unresolved, such as the contextual duality of lactylation in either resolving or aggravating inflammation, and the uncertainties of enzymatic route for mammalian lactyl-CoA formation, suggesting that lactylation-associated evidence is still limited. Ultimately, this review underscores the therapeutic potential for diabetic complications management by targeting lactate-lactylation axis in metabolic-epigenetic manner.