Integrated network pharmacology and molecular docking reveal multi-target hepatotoxic mechanisms of Xanthii fructus

Xanthii fructus (XF), a traditional Chinese medicine, is commonly used for anti-inflammatory and analgesic purposes; however, its hepatotoxicity limits its use to some extent and the underlying mechanisms remain unclear. The present study aimed to explore the key targets and molecular pathways of XF-induced liver injury through an integrated network toxicology and molecular docking approach. Potential hepatotoxic components of XF were screened using the TCMSP and comparative toxicogenomics database databases. Targets associated with these components and liver injury were identified via SwissTargetPrediction, GeneCards, and online Mendelian inheritance in man. Protein-protein interaction networks were constructed using STRING and analyzed with Cytoscape. The Metascape platform was used for gene ontology/Kyoto encyclopedia of genes and genomes enrichment analysis, and molecular docking was performed to validate the interactions between the key components and targets. Five hepatotoxic active ingredients were finally screened, involving 74 hepatotoxic targets, and significantly enriched pathways were uncovered through rigorous Kyoto encyclopedia of genes and genomes analysis. The most prominent was pathways in cancer [P <.001; false discovery rate (q-value) <0.001], followed by Hepatitis B [P <.001; false discovery rate (q-value) <0.001]. Among them, TP53, HSP90AA1, JUN, and EP300 served as core targets. Molecular docking confirmed the strong binding affinity between the key targets and hepatotoxic components (binding energy: -6.83 to -9.28 kcal/mol). This study provides a preliminary framework for XF-induced hepatotoxicity, highlighting multi-component, multi-target interactions. Mechanistic predictions require preclinical validation. Future work should validate these findings experimentally and explore detoxification strategies to enable safer clinical use of XF.