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. This study was reviewed and approved by the Animal Ethics Committee of Shandong University of Traditional Chinese Medicine (Ethics approval number: []). All procedures were conducted in strict accordance with the "Guidelines for the Use of Experimental Animals." The animals used were 8-week-old male wild-type C57BL/6JNifdc mice (weight 23–25 g), provided by Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). All mice were housed in individually ventilated cages under standard environmental conditions: a 12-hour light/dark cycle, temperature of 22±1°C, and relative humidity of 50±10%. They had free access to standard laboratory chowing and drinking water. A one-week acclimatization period was provided prior to the experiment. A total of 40 mice were randomly divided into four groups (n = 10 per group): blank group (KB), model group (M), Trimetazidine treatment group (QM), and LGZGD treatment group (LG). M, QM, and LG groups received intraperitoneal injections of doxorubicin at a dose of 2.5 mg/kg, three times per week for 2 weeks (a total of 6 injections), for a cumulative dose of 15 mg/kg. Successful model establishment was defined by a reduction of left ventricular ejection fraction by 10% from baseline, confirmed via echocardiography. Mice in the KB group were injected with an equal volume of saline. Starting on day 8, mice in the LG group were administered LGZGD (raw herbal material) via gastric gavage at a dose of 6.6 g/kg, while mice in the QM group received trimetazidine via gastric gavage at a dose of 2 mg/kg/day (equivalent to the clinical dosage). Mice in the KB and M groups were gavaged with an equal volume of distilled water. The treatment continued for two weeks. Body weight was measured before modeling, after modeling, and following drug administration.