Lactylation-Driven Epigenetic Modulation: A New Frontier in Vascular Aging and Associated Disorders

Vascular aging is a fundamental process driving age-related cardiovascular and cerebrovascular diseases, characterized by endothelial dysfunction, vascular smooth muscle cell (VSMC) senescence, and extracellular matrix (ECM) remodeling. Recent studies have unveiled protein lactylation, a novel post-translational modification where lactate covalently binds to lysine residues, as a critical metabolic-epigenetic mechanism linking glycolytic flux to vascular pathophysiology. Under conditions such as hypoxia, hyperglycemia, or oxidative stress, accumulated lactate is converted to lactoyl-CoA and transferred by enzymes like p300/CBP to modify histones and non-histone proteins, thereby regulating gene expression and cellular functions. This article comprehensively summarizes the dual roles of lactylation in vascular aging and associated disorders. Lactylation promotes endothelial inflammation, VSMC osteogenic transition, and ECM calcification through specific targets such as H3K18la, NF-κB, and metabolic enzymes, thereby accelerating atherosclerosis, diabetic vasculopathy, pulmonary hypertension, and aortic aneurysms. Conversely, in certain contexts, it supports reparative macrophage polarization and plaque stability. The interplay between lactylation and other modifications further fine-tunes vascular homeostasis. Emerging therapeutic strategies, including small-molecule inhibitors of lactylation writers p300/CBP, lactate-lowering agents, and natural compounds, show promise in preclinical models. However, challenges remain in specificity, detection, and clinical translation. Future research should integrate multi-omics approaches and spatial technologies to elucidate cell-specific lactylation networks, facilitating the development of targeted interventions against vascular aging and its complications.