From Byproduct to Regulator: The Expanding Role of Lactate and Lactylation in Cardiovascular Physiology and Disease.

Metabolic reprogramming plays a critical role in the pathogenesis of cardiovascular diseases. Historically regarded as a metabolic waste product, lactate has recently emerged as a critical regulator of vascular biology, exerting both metabolic and signaling functions. Moreover, the discovery of protein lactylation, a novel post-translational modification derived from lactate, has revealed a direct link between metabolic flux and gene regulation. This review provides a comprehensive overview of the evolving roles of lactate and lactylation in cardiovascular physiology and disease, offering insights into potential therapeutic interventions. It first provides a historical perspective of lactate and lactylation, followed by an overview of lactate metabolism, lactate shuttle theory and signaling pathways. It then discusses the mechanism and regulation of lactylation, focusing on its writers, erasers, and readers. Finally, this review summarizes clinical implications of lactate and lactylation in various cardiovascular diseases, including atherosclerosis, pulmonary hypertension, myocardial infarction, heart failure, and diabetic vascular complications. A deeper understanding of the mechanisms underlying the lactate-lactylation axis may facilitate the development of new therapeutic strategies to prevent or treat cardiovascular diseases.