The role of pyruvate metabolism in cardiovascular diseases

Cardiovascular diseases remain the leading cause of mortality worldwide, with their incidence steadily rising in recent years. Pyruvate, the end product of glycolysis, serves as a critical metabolite in cellular energy metabolism by bridging cytoplasmic glycolysis and mitochondrial oxidative phosphorylation. Its synthesis, transport, and metabolic conversion are tightly regulated by a range of enzymes and transporters, including pyruvate kinase, mitochondrial pyruvate carriers, pyruvate dehydrogenase complex, glucose transporters, and lactate dehydrogenase. Emerging evidence suggests that dysregulation of pyruvate metabolism plays a pivotal role in the pathogenesis of various cardiovascular conditions, including heart failure, ischemia-reperfusion injury, diabetic cardiomyopathy, and pulmonary hypertension. This review aimed to provide a comprehensive and integrative overview of the role of pyruvate metabolism in cardiovascular diseases by systematically analyzing recent findings from both experimental and clinical studies. Unlike previous reviews that focus on isolated enzymes or specific disease types, we adopted a systemic perspective to elucidate the entire pyruvate metabolic network and its crosstalk with mitochondrial function, redox homeostasis, and inflammatory signaling pathways. We also discuss the regulatory roles of key signaling cascades, such as PI3K-AKT, and the implications of genetic variations in enzymes involved in pyruvate metabolism. Finally, we highlight potential molecular targets within this pathway that could be leveraged for therapeutic intervention. By mapping these interconnections, our review underscores the therapeutic potential of targeting pyruvate metabolism as a novel strategy for treating cardiovascular disorders. Significance Statement: Pyruvate metabolism plays a crucial role in cardiovascular disease development and has attracted growing interest. While previous reviews have examined enzymes like PDC and PKM2, they often focus narrowly on specific pathways or disease types. This review offers a more integrated, system-level perspective, highlighting the roles of pyruvate metabolism in mitochondrial function, redox balance, and inflammation. It also identifies potential metabolic targets, aiming to support future therapeutic strategies in treating cardiovascular conditions. (c) 2025 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.