Network Pharmacology and Molecular Docking Reveal the Mechanisms of XOL in Treating Heart Failure.

BACKGROUND: Heart failure (HF) is a terminal stage of various cardiovascular diseases with high morbidity and mortality. Xintong Oral Liquid (XOL), a multi-herb traditional Chinese medicine, has shown clinical potential in improving cardiac function, but its molecular mechanisms remain unclear. This study aimed to elucidate the pharmacological mechanisms of XOL in HF treatment. METHODS: Active compounds and targets of XOL were obtained from TCMSP, and HF-related genes were collected from public databases. Feature target genes (FTGs) were identified by intersection analysis. Protein-protein interaction networks and centrality analyses were performed to identify core FTGs (CFTGs). GO and KEGG enrichment, molecular docking, and single-cell RNA-seq analyses were conducted to explore functional pathways and cell-type-specific expression. A transverse aortic constriction (TAC) mouse model was used to evaluate cardiac function by echocardiography, and RT-qPCR and Western blot were applied to validate CFTGs expression. RESULTS: A total of 7 bioactive compounds, including Quercetin and Luteolin, were identified, targeting 19 CFTGs such as EGFR, STAT3, IL6, and TP53. Enrichment analyses indicated involvement in JAK-STAT signaling, inflammatory responses, and apoptosis regulation. Molecular docking confirmed strong binding affinities, while single-cell analysis revealed elevated expression of EGFR and STAT3 in cardiomyocytes and fibroblasts, and IL1B in macrophages. XOL treatment dose-dependently improved cardiac function, as evidenced by increased ejection fraction and fractional shortening, and alleviated myocardial structural damage in TAC mice. Additionally, XOL suppressed TAC-induced upregulation of EGFR, IL1B, STAT3, TP53, IL6, HIF1A, and AKT1 and inhibited STAT3/AKT1 phosphorylation. CONCLUSIONS: XOL exerts cardioprotective effects through multi-component, multi-target, and multi-pathway mechanisms involving JAK-STAT and inflammatory signaling, providing a molecular basis for its clinical efficacy and guiding further HF research.