Lactylation Modification: From Basic Biological Process to Clinical Cardiovascular Diseases

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide and are hallmarked by profound disturbances in energy metabolism and maladaptive tissue remodeling. Lactate, long dismissed as a metabolic waste product, is now recognized as a context-dependent central carbon source and signaling metabolite. A key recent advance is the discovery of lysine lactylation (Kla), an evolutionarily conserved posttranslational modification that couples lactate abundance to chromatin state and protein function. Here, we synthesize current knowledge on the biogenesis and enzymatic regulation of Kla, and delineate how lactate-driven histone and nonhistone lactylation remodel transcriptional and signaling networks controlling fibrosis, energy metabolism, immune and inflammatory responses, and angiogenesis. We then focus on emerging evidence that Kla is a nodal regulator across major cardiovascular pathologies-including atherosclerosis, myocardial infarction and ischemia/reperfusion injury, heart failure, valvular and arterial calcification, and pulmonary hypertension-where it can act as a context-dependent "accelerator" or "brake" of disease progression. Finally, we outline a translational framework that targets the lactate-lactylation axis at 3 levels: lactate transport, lactate production, and lactylation writers/erasers, highlighting opportunities and challenges for therapeutic intervention. Together, these insights position protein lactylation as a pivotal metabolic-epigenetic interface in the cardiovascular system and a promising entry point for precision therapies in CVDs.