Integrating Network Pharmacology and Metabolomics to Decipher the Mechanisms Underlying the Therapeutic Effects of Wuzhi Dripping Pills Against MASLD.

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a progressive condition predisposing to cirrhosis and hepatocellular carcinoma, with prevalence rising globally. Yet effective therapies remain limited. Wuzhi Dripping Pills (WZDP), derived from Schisandra sphenanthera, possess hepatoprotective and anti-inflammatory properties, though their efficacy against MASLD remains unexplored. Methods: Network pharmacology predicted active ingredients and targets, followed by KEGG enrichment analysis. A high-fat diet MASLD rat model was established to evaluate WZDP effects on weight, liver index, and serum markers. Serum metabolomic profiling via UPLC-MS/MS, combined with multivariate statistics and KEGG annotation, identified perturbed pathways. Results: Twelve bioactive compounds and 434 WZDP targets were retrieved, of which 74 intersected with 838 MASLD-associated genes. Enrichment implicated AGE-RAGE, insulin resistance, and HIF-1 signaling. In vivo, WZDP significantly improved anthropometric and biochemical parameters. Metabolomic analysis distinctly separated WZDP-treated from model groups, highlighting phospholipase D signaling as a key differential pathway. Conclusions: This integrative approach confirms that WZDP confers therapeutic benefits in MASLD through coordinated regulation of neuroactive ligand-receptor interaction, bile acid biosynthesis, phospholipase D signaling, and arginine-proline metabolism. Our findings furnish a molecular and metabolic rationale for further mechanistic studies and drug discovery efforts.