Xinmailong Injection Attenuates Doxorubicin-Induced Chronic Heart Failure by Regulating the SIRT1/Caspase-3 Axis and Metabolic Reprogramming: An Integrative Network Pharmacology and Metabolomics Study.

OBJECTIVE: Chronic heart failure (CHF) is characterized by progressive cardiac dysfunction, myocardial remodeling, apoptosis, and metabolic disturbance. Xinmailong injection (XML) has demonstrated therapeutic potential for CHF; however, its underlying mechanisms remain incompletely understood. METHODS: A total of 40 SPF rats were used to establish a doxorubicin-induced CHF model, with another 8 rats serving as the normal control group. The model rats were randomized into 5 groups (n = 8 per group): model, digoxin (0.025 mg/kg), XML low- (60 mg/kg), XML medium- (120 mg/kg), XML high- (240 mg/kg) groups with a 2-week intervention. Cardiac function, serum biomarkers, histopathology and cardiomyocyte apoptosis were detected. Untargeted metabolomics, network pharmacology, molecular docking and in vivo validation were integrated to explore the mechanisms of XML. RESULTS: XML dose-dependently elevated left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP) and maximum rate of left ventricular pressure change (± dp/dtmax), while reducing left ventricular end-diastolic pressure (LVEDP) (P < 0.01). It downregulated serum cardiac stress and myocardial injury markers (BNP, ANP, CK-MB, cTn-I, MYO, and LDH) and enhanced the activity of the antioxidant marker GSH-PX (P < 0.05 or P < 0.01); it alleviated myocardial necrosis, inflammatory infiltration and collagen deposition. Metabolomics indicated that XML reversed CHF-associated metabolic disorders mainly involving glycerophospholipids, linoleic acid, taurine and hypotaurine, pyrimidine metabolism, and the tricarboxylic acid (TCA) cycle. Network pharmacology screened 59 overlapping targets of XML and CHF, with sirtuin 1 (SIRT1) and caspase-3 as core hubs; molecular docking verified favorable binding affinities between XML's main active ingredients and the two targets (binding energy ≤  -4.65 kcal/mol). Consistent with above data, XML upregulated SIRT1 and B-cell lymphoma-2 (Bcl-2), downregulated BCL2-associated X protein (BAX) and cleaved caspase-3, restored the Bcl-2/BAX ratio and suppressed apoptosis of cardiomyocytes (P < 0.01). CONCLUSION: XML ameliorates doxorubicin-induced CHF via improving cardiac function, mitigating myocardial injury/fibrosis, restoring metabolic homeostasis and inhibiting cardiomyocyte apoptosis, which is closely related to regulating the SIRT1/caspase-3 axis and multiple metabolic pathways.