Lactate-lactylation axis as an emerging metabolic-epigenetic pathway in diabetic microvascular complications

Lactate, once viewed merely as a glycolytic byproduct, is now recognized as a key signaling molecule and epigenetic regulator through the recently identified post-translational modification known as lactylation. In diabetic microvascular complications, including diabetic retinopathy (DR), diabetic kidney disease (DKD), and diabetic peripheral neuropathy (DPN), persistent hyperglycemia promotes metabolic reprogramming toward glycolysis and leads to excessive lactate production. This sustained metabolic stress drives cellular changes, such as mitochondrial dysfunction, chronic inflammation, and epigenetic alterations, which closely mirror hallmarks of premature aging. This review synthesizes emerging evidence linking the lactate-lactylation axis to the development of microvascular injury in diabetes, framing these complications as manifestations of accelerated cellular and metabolic aging. We outline the molecular framework of lactylation, including its writers, erasers, and readers, and summarize how lactate-induced histone and non-histone lactylation reshapes gene transcription in retinal, renal, and peripheral nerve cells. In DR and DKD, accumulating studies indicate that lactylation contributes to cellular dysfunction across multiple microvascular cell types, while in DPN, although evidence remains limited, lactylation may influence Schwann cell biology and axonal integrity under metabolic stress. Notably, lactate-driven epigenetic remodeling reinforces features of metabolic memory and tissue-specific aging, such as mitochondrial dysfunction, chronic inflammation, and cellular senescence, by maintaining maladaptive transcriptional programs that persist despite glycemic control. We further discuss the therapeutic potential of modulating lactylation pathways and the possible utility of lactate as a biomarker. By integrating metabolic, epigenetic, and aging perspectives, this review highlights the lactate-lactylation axis as a converging pathway that mechanistically links hyperglycemia to the premature aging phenotype of diabetic microvasculature, and outlines future avenues for diagnostic and therapeutic innovation.