Natural Lignan Vitexin B‐1 Induces Cell Cycle Arrest and Apoptosis via Targeting HSP90 Through EGFR Pathway in Non‐Small Cell Lung Cancer

Natural products, renowned for their chemical diversity, have been extensively explored for their anticancer potential. Lung cancer, primarily driven by non-small cell lung cancer (NSCLC), accounts for 85% of all cases. In this study, we screened an in-house library of 2000 small molecules, including bioactive compounds, and identified Vitexin B-1 (VB-1) as a potent growth inhibitor of A549 cells, with an IC50 value of 15.7 μM. VB-1 demonstrated consistent cytotoxicity across various cancer cell lines, including HCC827, H1975, MCF7, HeLa, K562, HL60, and HCT116, with IC50 values ranging from 2.64 to 15.7 μM. VB-1 induced apoptosis and G2/M cell cycle arrest in HCC827 cells. Network pharmacological analysis identified HSP90AA1 and HSP90AB1 as key molecular targets of VB-1 in NSCLC. Molecular docking and FITC-labeled geldanamycin fluorescence polarization assays revealed moderate binding affinities between VB-1 and these targets (IC50s of 0.5270 and 0.5274 μM, respectively). Additionally, Western blot analysis confirmed that VB-1 downregulated EGFR and key downstream signaling components, including AKT, p-AKT, p-ERK, and BRAF. In conclusion, VB-1 inhibits HSP90AA1 and HSP90AB1, exerting antitumor activity through EGFR targeting, and shows promise as a potential therapeutic agent for NSCLC, particularly in EGFR-mutant cells.