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Sorafenib is currently the first-line therapeutic agent for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance remains a major clinical challenge. Studies have reported that 1,25-dihydroxyvitamin D3 (1,25(OH)₂D₃) can synergize with multiple chemotherapeutic drugs to enhance their antitumor efficacy, but the combinatorial effect between 1,25(OH)₂D₃ and sorafenib has not yet been investigated. This study aimed to investigate the potential molecular mechanism by which 1,25(OH)₂D₃ reverses sorafenib resistance in hepatocellular carcinoma using network pharmacology, molecular docking, and experimental validation. We predicted a web-based pharmacological approach to predict potential targets of 1,25(OH)₂D₃ and its derivatives, as well as sorafenib resistance genes in hepatocellular carcinoma from public databases. We then constructed 1,25(OH)₂D₃ chemo-sensitizing expression profiles through intersection analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were employed to predict the potential pathways involved in 1,25(OH)₂D₃ chemosensitization, followed by molecular docking analysis and analysis of molecular dynamics simulations. Finally, experimental validation were conducted to elucidate the potential mechanisms by which 1,25(OH)₂D₃ enhances the sensitivity of HCC to sorafenib. Compound and target screening identified 730 predicted targets of 1,25(OH)₂D₃ and its derivatives, 1144 genes associated with sorafenib resistance in hepatocellular carcinoma, and 56 potential chemosensitization targets from the intersection analysis. KEGG analysis suggested that the chemosensitization effect of 1,25(OH)₂D₃ might be mediated by the FoxO signaling pathway. Molecular docking showed that both 1,25(OH)₂D₃ and its derivatives could stably bind to FOXO3A, a key gene in the FoxO family, and molecular dynamics simulation analysis further indicated that the two bind well together. In vitro experiments demonstrated the synergistic effects of 1,25(OH)₂D₃ and sorafenib, significantly inhibiting the viability and colony formation rate of sorafenib-resistant hepatocellular carcinoma cells. Additionally, the combination treatment promoted apoptosis and inhibited autophagy. Furthermore, the combination modulated the FOXO3A/FOXM1 signaling axis. This study reveals that 1,25(OH)₂D₃ enhances the chemosensitivity of hepatocellular carcinoma (HCC) to sorafenib, with underlying mechanisms potentially involving the targeted modulation of the FOXO3A/FOXM1 signaling axis and the reversal of sorafenib-resistant phenotypes through the regulation of apoptotic and autophagic pathways. Full article