Objective To predict and analyze the potential molecular mechanisms underlying the intervention ofZanthoxylum pericarpium in hepatocellular carcinoma (HCC) with a network pharmacology approach.

Methods UsingZanthoxylum pericarpium extract as the research subject, this study employed network pharmacology approaches—including active ingredient screening (oral bioavailability ≥ 30% and drug-likeness ≥ 0.18), target prediction and integration of literature-derived targets using databases such as TCMSP, construction of PPI networks, GO/KEGG enrichment analysis, and molecular docking validation—combined with amino acid sequence alignment and comprehensive ADME/TOX evaluation—to assess the clinical development potential of the core components from both drug-like properties and safety perspectives.

Results A total of 78 active compounds were screened and identified; subsequently, an in-depth analysis was conducted on the 372 associated target molecules.Enrichment analysis revealed that these targets were significantly enriched in cancer-related signaling pathways, the PI3K-AKT pathway, and the MAPK cascade network. Molecular docking revealed that 7 components, including tangeretin, diosmetin, and quercetin, exhibited stable binding to the core targets, with binding affinities approaching those of the positive control.Further comparative analysis revealed that multi-component-target pairings (e.g.,sanshool-HSP90AB1, diosmetin-STAT3, and tangeretin/quercetin-EGFR) share a consistent binding mode with the positive control at key amino acid residues, suggesting that these components may exert their biological effects through similar molecular mechanisms.ADMET analysis demonstrated that representative compounds within this system exhibit favorable pharmacokinetic properties, including excellent intestinal mucosal permeability, high blood-brain barrier penetration capability, and a safein vivo metabolism profile.

Conclusion Zanthoxyli Pericarpium exerts its anti-HCC effects through the coordinated regulation of multiple chemical constituents, diverse protein targets, and various metabolic pathways; its core active components mimic the binding mode of positive inhibitors, providing a theoretical framework for research into related mechanisms and for drug development.

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