Qishen Yiqi Formula Mitigates Heart Failure by Restoring Myocardial Energy Metabolism via AMPK: Insights from Multi-Omics Analysis

INTRODUCTION: Heart failure (HF), a life-threatening syndrome with complex pathogenesis, is closely linked to myocardial metabolic remodeling, the critical driver of cardiac dysfunction. Optimizing myocardial energy metabolism represents a promising therapeutic strategy. Qishenyiqi formula (QSYQ), a traditional Chinese herbal compound, demonstrates cardioprotective effects, but its mechanisms in modulating substrate utilization and metabolic remodeling in transverse aortic constriction (TAC)-induced HF remain unclear. OBJECTIVE: This study investigates the therapeutic potential and molecular mechanisms of QSYQ in TACinduced HF. METHODS: TAC-induced HF mice were treated with QSYQ (1170 or 585 mg/kg) or vehicle for four weeks. Cardiac function was assessed through echocardiography, hemodynamic measurements, histopathology, fibrosis analysis, and heart failure biomarkers (ANP and BNP). Mitochondrial ultrastructure was evaluated by transmission electron microscopy, while mitochondrial function was quantified by measuring ATP levels, reactive oxygen species, and membrane potential. Integrated proteomics and metabolomics analyses were performed to identify metabolic pathways, which were subsequently validated by molecular assays. RESULTS: QSYQ attenuated cardiac hypertrophy, fibrosis, and dysfunction in TAC mice, improving ejection fraction and hemodynamics. It restored mitochondrial integrity and function, evidenced by normalized ultrastructure, increased ATP synthesis, reduced ROS, and stabilized membrane potential. Multi-omics integration revealed QSYQ's regulation of myocardial glucose and fatty acid metabolism mediated through AMPK and downstream targets PPARα and PGC-1α. DISCUSSION: These findings position QSYQ as a promising therapeutic candidate that targets core metabolic disturbances in HF. CONCLUSION: QSYQ mitigates TAC-induced HF by improving mitochondrial bioenergetics and metabolic remodeling through the AMPK/PPARα/PGC-1α pathway, supporting its potential as a metabolic therapy for HF.