Ling-Gui-Zhu-Gan Decoction Ameliorates Heart Failure via Modulating Energy Metabolism and Lipid Homeostasis: Insights from Transcriptomics and Lipidomics

Background: Heart failure (HF) remains a global health challenge with limited therapeutic options. Ling-Gui-Zhu-Gan Decoction (LGZGD), a traditional Chinese medicine formula, has shown clinical efficacy in HF treatment, yet its molecular mechanisms remain unclear. Methods: This study investigated LGZGD's cardioprotective effects and underlying mechanisms using a doxorubicin-induced HF mouse model. Mice were divided into blank (KB), model (M), trimetazidine (QM), and LGZGD (LG) groups. Cardiac function was assessed via echocardiography, while myocardial injury and fibrosis were evaluated through histopathology. Transcriptomics and lipidomics analyses were performed to identify molecular pathways. Results: LGZGD significantly improved ejection fraction (EF) and fractional shortening (FS), alleviated myocardial vacuolization, and reduced fibrosis, outperforming trimetazidine. Transcriptomics revealed LGZGD modulated oxidative phosphorylation and ATP synthase activity, restoring energy metabolism. Lipidomics highlighted its regulation of glycerophospholipid metabolism, particularly phosphatidylethanolamine (PE) and phosphatidylcholine (PC), linked to anti-inflammatory and lipid homeostasis effects. Conclusion: Integrated omics data suggested LGZGD ameliorates HF by enhancing mitochondrial function, mitigating oxidative stress, and balancing lipid metabolism. These findings provide mechanistic insights into LGZGD's therapeutic benefits, supporting its potential as a multi-targeted intervention for HF through energy and lipid metabolic regulation.