BACKGROUND: Lung cancer is a malignant tumor with a high incidence in China, especially non-small cell lung cancer (NSCLC), which is the main threat to human life, with terrible morbidity and mortality. The research on the treatment and mechanism of NSCLC has been the forefront and hotspot of research. Recent patents show that alpha-solanine (alpha-solanine) exhibits the best anti-cancer activity, although its target and related mechanism remain to be elucidated. OBJECTIVES: This study aims to explore the possible targets and mechanisms of alpha-solanine in the treatment of NSCLC through network pharmacology and experimental verification. METHODS: Network pharmacology was applied to screen the possible targets of alpha-solanine on NSCLC, construct core networks, and perform GO enrichment and KEGG pathway analysis to predict the mechanism of alpha-solanine against NSCLC. Experiments were implemented to verify the results of network pharmacology in vitro. The A549 and PC-9 cells were exposed to alpha-solanine to assess the anti-tumor effect. Cell apoptosis was determined by the Annexin-V/PI assay. Targeted energy metabolomics was used to validate the network pharmacology results, and energy metabolism pathway- related proteins were detected by immunofluorescence and western blot. RESULTS: Network pharmacology showed that there were 130 potential targets of alpha-solanine and NSCLC. GO, and KEGG analysis showed that the energy metabolism pathway is the main pathway for alpha-solanine to exert anti-tumor effects on NSCLC. Experimental results showed that alpha-solanine inhibited cell proliferation, migration, invasion and promoted cell apoptosis. At the same time, after alpha-solanine treatment, the energy metabolism pathway-related proteins, including GPI, ALDOA, TPI1, PKLR, LDHA, and ALDH3, were expressed reduced. In addition, alpha-solanine also affects the amino acid metabolism of A549 and PC-9 cells. CONCLUSION: Based on a combination of network pharmacological prediction and experimental verification, alpha-solanine may exert anti-NSCLC effects by regulating the energy metabolism pathway. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.