Lactylation at the metabolic-epigenetic interface in cardiovascular diseases: context-dependent mechanisms and translational roadmap

BACKGROUND: Lysine lactylation has redefined lactate's biological role from a metabolic byproduct to a signaling molecule. This post-translational modification directly couples cellular energetics with gene regulation, creating a metabolic-epigenetic axis particularly relevant to cardiovascular pathophysiology. Ischemic and inflammatory stress drive glycolytic reprogramming and lactate accumulation in these diseases. Lactylation modifies both histone and non-histone proteins, enabling metabolic states to reshape chromatin accessibility and protein function. However, therapeutic translation faces critical barriers. These include incomplete characterization of the cardiovascular lactylome, absence of selective pharmacological modulators, and insufficient understanding of how lactylation effects vary across cell types, disease stages, and metabolic contexts. AIM OF REVIEW: We systematically dissect lactylation biology across 5 cardiovascular pathologies to define regulatory mechanisms and therapeutic vulnerabilities. We examine glycolysis-lactylation circuits driving pulmonary arterial smooth muscle hyperproliferation in hypertension; dual roles in atherosclerotic plaque stability versus calcification; M2 macrophage-mediated repair versus fibrotic remodeling in myocardial infarction; the metabolic paradox of lactate accumulation with reduced α-myosin heavy chain lactylation impairing contractility in heart failure; and neonatal glycolytic metabolism enabling histone lactylation-driven cardiomyocyte proliferation with metabolic barriers in diabetic contexts. Key Scientific Concepts of Review: Lactylation functions through dual substrates: histone modifications orchestrate inflammatory resolution and cell cycle activation, while non-histone modifications (α-myosin heavy chain, Snail1) directly govern contractility and pathological remodeling. Context-dependent dichotomies emerge across diseases, with protective angiogenesis versus maladaptive fibrosis in infarction and plaque stabilization versus calcification in atherosclerosis. Critically, metabolic paradoxes challenge lactate-lactylation correlations: heart failure shows lactate accumulation yet reduced modification, while diabetic advanced glycation end-products competitively inhibit lactylation. Therapeutic strategies require integrating metabolic reprogramming, site-selective targeting, and temporal control. This review systematically dissects these mechanistic complexities to establish a translational framework that guides precision cardiovascular medicine through metabolic-epigenetic intervention strategies.