Targeting STAT3 by erianin to overcome sorafenib resistance in hepatocellular carcinoma: Integrated network pharmacology with molecular docking, dynamics simulations, and in vitro validation.

Sorafenib (SOR) remains a clinically prevalent molecular targeted therapy for advanced inoperable hepatocellular carcinoma (HCC). However, the emergence of SOR resistance in HCC patients significantly compromises its therapeutic efficacy. Erianin (ERI), a bioactive component derived from the Chinese herbal medicine Dendrobium chrysotoxum Lindl., has demonstrated significant anticancer potential. In this study, we aimed to evaluate the potential molecular mechanisms underlying ERI-mediated reversal of SOR resistance in HCC from a network pharmacology perspective and identify its critical core targets. Initially, we employed multiple databases, including SwissTargetPrediction, Comparative Toxicogenomics Database, and GeneCards, to predict ERI targets and SOR resistance-related targets in HCC. Intersection genes were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, revealing significant enrichment in cancer-related processes and pathways. Subsequent screening using the cytoHubba plugin in Cytoscape identified the top 10 hub differential genes, which were cross-referenced with GEO microarray data (GSE94550) to prioritize STAT3 as the key mediator of ERI's SOR resistance reversal effect. Molecular docking and molecular dynamics simulations confirmed the strong binding affinity and stability between ERI and STAT3. In vitro assays demonstrated that ERI significantly inhibited the proliferation of SOR-resistant Huh7 cells, downregulated p-STAT3/STAT3 ratio, and synergistically enhanced SOR efficacy. Collectively, our findings establish ERI as a promising anticancer phytochemical with p-STAT3 inhibition as a potential mechanism for overcoming SOR resistance in HCC, warranting further translational development.