Sanguinarine Suppresses Lung Adenocarcinoma via TGF-β1/Smad3 Pathway: Insights from Network Analysis and Experimental Validation

INTRODUCTION: This study elucidates molecular mechanisms underlying sanguinarine (SAN)- mediated inhibition of Lung Adenocarcinoma (LUAD) progression. METHODS: Potential targets for SAN and LUAD were obtained from public databases. A Protein-Protein Interaction (PPI) network was constructed, and core targets were visualized using Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed with DAVID, while Reactome, WikiPathways, and MSigDB Hallmark analyses utilized Enrichr. Core targets expression and immune infiltration in LUAD were validated using The Cancer Genome Atlas (TCGA). Molecular docking assessed binding affinity between SAN and core targets, and in vitro experiments confirmed SAN's suppression of LUAD progression via the TGF-β1/Smad3 pathway. RESULTS: Ten core targets of SAN in LUAD were identified. GO analysis revealed biological processes including proliferation, apoptosis, and signal transduction. Significantly enriched cancer-related pathways included PI3K-Akt, MAPK, Ras, and TGF-β signaling, the latter of which was significantly enriched across KEGG, Reactome, WikiPathways, and MSigDB Hallmark analyses. Molecular docking demonstrated a strong binding affinity between SAN and core targets. In vitro, SAN suppressed proliferation and autophagy in A549 cells while promoting apoptosis by inhibiting the TGF-β1/Smad3 signaling pathway. DISCUSSION: The results demonstrate SAN's multi-target action against LUAD, notably through the inhibition of TGF-β1/Smad3, providing a mechanistic basis within oncogenic networks. Limitations include reliance on in vitro models and the preclinical focus. Future work requires in vivo validation and clinical translation. CONCLUSION: This study identifies key targets and pathways for SAN's inhibition of LUAD progression, validating its effect through the suppression of TGF-β1/Smad3 and providing experimental evidence for clinical application in LUAD therapy.