Machine learning and molecular docking identify the anti-tumor activity of lobetyolin in non-small cell lung cancer by targeting the oncogenic factor GART

Background Lobetyolin, a bioactive polyacetylene, has demonstrated anti-tumor potential against various cancer types, including non-small cell lung cancer (NSCLC). This study aimed to elucidate the detailed molecular mechanisms underlying lobetyolin’s anti-NSCLC efficacy. Methods Differentially expressed proteins (DEPs) in NSCLC pathogenesis were analyzed, and the potential anti-tumor targets of lobetyolin in NSCLC were identified. Hub proteins were screened by machine learning, and their binding to lobetyolin was evaluated by molecular docking. Protein expression was detected by immunoblot assay and immunohistochemistry (IHC). The impact on cellular phenotypes was assessed by detecting cell viability, proliferation, apoptosis, migration, and invasion. Xenograft models were generated to analyze the role in vivo . Results A total of 24 potential anti-tumor targets of lobetyolin in NSCLC were identified. Glycinamide ribonucleotide transformylase (GART), mitogen-activated protein kinase kinase 1 (MAP2K1), mitogen-activated protein kinase 14 (MAPK14), caspase 7 (CASP7), and dihydrofolate reductase (DHFR) were identified as core targets, and their binding affinities for lobetyolin were −6.9, −7.2, −7.5, −6.0, and −7.9 kcal/mol, respectively. GART expression was upregulated in NSCLC samples and cells. Lobetyolin downregulated GART expression in H1299 and A549 NSCLC cells. Functionally, GART re-expression counteracted lobetyolin-mediated suppressive effects on NSCLC cell proliferation, migration, and invasion in vitro , and xenograft tumor growth in vivo . Conclusion This study identifies GART as a functionally significant oncoprotein in NSCLC and establishes lobetyolin as a promising lead compound that targets GART-dependent oncogenic pathways, providing a novel molecular basis for the anti-cancer activity of lobetyolin in NSCLC.