Toward metabolic precision medicine in heart failure: Timing, tissue specificity, and network reconstruction

Heart failure (HF) remains a major global health burden, with high morbidity and mortality closely linked to disturbances in cardiac energy metabolism. Targeting metabolic reprogramming has emerged as a key strategy to overcome the limitations of conventional hemodynamic-based therapies. This review systematically elucidates critical alterations in the cardiac energy metabolism network associated with HF, including mitochondrial dysfunction, aberrant substrate utilization, and dysregulation at both the transcriptional and post-translational levels. It also explores multidimensional therapeutic strategies focused on restoring mitochondrial function, enhancing metabolic flexibility, and modulating the neurometabolic axis. Compounds such as metformin, Omecamtiv Mecarbil (OM), and SGLT2 inhibitors have demonstrated significant clinical benefits by optimizing energy substrate utilization, improving mitochondrial function, and enhancing autophagy. Future research should prioritize optimizing intervention timing, achieving tissue-specific targeting, and integrating systemic metabolic control to advance the evolution of HF management strategies.