Valine metabolism in cardiovascular disease: Mechanistic insights and translational perspectives

Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality worldwide, and metabolic remodeling is increasingly recognized as a key factor of disease progression. Beyond fatty acids and glucose, branched-chain amino acid (BCAA) metabolism-particularly valine-has emerged as an important regulator of cardiac energetics and mitochondrial function and is strongly associated with adverse cardiovascular outcomes. However, the mechanisms linking valine dysregulation to CVD and its translational relevance remain incompletely understood. Therefore, this review synthesizes current advancements in elucidating metabolic reprogramming in CVD, specifically focusing on valine metabolism. Herein, we discuss the mechanisms by which dysregulated valine catabolism and its bioactive intermediates-including 3-hydroxyisobutyrate and branched-chain α-ketoacids-promote mitochondrial dysfunction, lipid remodeling, inflammation, and thrombotic susceptibility. By incorporating evidence from clinical studies, experimental models, and systems-level analyses, we underscore the central role of valine metabolism in cardiac dysfunction and disease progression. Finally, we evaluate emerging therapeutic strategies targeting valine metabolic pathways, including dietary modulation and enzyme-based interventions, and outline major challenges that must be addressed to translate these approaches into clinical practice. Overall, this review examines the emerging evidence positioning valine metabolism as a potential metabolic hub connecting mitochondrial dysfunction with cardiovascular pathology, while acknowledging that causality remains incompletely established and that valine also serves essential physiological functions. Moreover, this review also underlines its potential as a target for precision diagnostics and metabolic therapy in CVD.