Integrative network pharmacology and in vitro validation reveal the mechanisms by which Apigenin reverses MET-TKI resistance in non-small cell lung cancer

Abstract Objective This study aimed to elucidate the molecular mechanisms by which Apigenin (APG) reverses MET-TKI resistance in non-small cell lung cancer (NSCLC). Methods Network pharmacology and molecular docking were used to identify potential targets and signaling pathways of APG. Functional enrichment and protein–protein interaction analyses were integrated with in vitro validation, including CCK-8, wound healing, flow cytometry, and Western blot assays. Results Key hub genes such as MET, IGF1R, and PTGS2 were identified, primarily enriched in the PI3K/AKT and MAPK pathways. APG inhibited cell proliferation and migration, enhanced apoptosis, and reduced phosphorylation of MET and AKT in MET-TKI–resistant EBC-1-TepR cells. Conclusion This study provides systematic evidence by integrating computational approaches with experimental methods, revealing that APG can regulate multiple targets related to drug resistance and inhibit the MET/PI3K/AKT signaling pathway. This indicates that APG can reverse acquired MET-TKI resistance in non-small cell lung cancer by targeting the core recovery pathways within the tumor. It offers a novel combination strategy for adjuvant treatment to overcome MET-TKI resistance in NSCLC.