Abstract

Background Non-small cell lung cancer (NSCLC), which constitutes approximately 85% of all lung cancer cases, is a leading cause of cancer mortality worldwide. Isoginkgetin (ISO), a biflavonoid isolated from Ginkgo biloba leaves, has demonstrated anticancer effects against various malignancies. However, its anti-NSCLC effects are unclear. Objective To explore the therapeutic potential of ISO and its mechanism of suppressing NSCLC proliferation. To provide experimental evidence for the translational potential of ISO as a candidate clinical drug. Methods Cell cytotoxicity and proliferation were assessed by cell viability, propidium iodide staining, colony formation, and cell cycle detection assays. Cell migration was evaluated by wound healing and transwell assays. Reactive oxygen species and the mitochondrial membrane potential were detected by fluorescent staining. Malondialdehyde and glutathione content were quantified by commercial assay kits. Transcriptome analysis for exploring the mechanism of ISO inhibition in NSCLC. The relationships between ISO and the tribbles pseudokinase 3 (TRIB3)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway were investigated through Western blot, siRNA-mediated TRIB3 knockdown, and overexpression of TRIB3. Cellular thermal shift assay and surface plasmon resonance were explored to investigate the binding and direct interaction between ISO and TRIB3. A non-contact co-culture model of NSCLC cells and macrophages was used to assess macrophage polarization. The anti-NSCLC effect of ISO in vivo was evaluated in a BALB/c nude mouse subcutaneous tumor model. Results ISO suppressed the cell viability, proliferation, and migration of NSCLC cells. ISO induces oxidative stress in NSCLC cells, characterized by an increase in reactive oxygen species and malondialdehyde and a decrease in mitochondrial membrane potential and glutathione. ISO has a strong binding affinity and direct interaction for the TRIB3 protein. Furthermore, ISO i