Imperatorin suppresses NSCLC via interaction with PI3K/AKT pathway and PD-L1: Computational and experimental evidence

Background

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality globally, underscoring the critical need for novel therapeutic agents. Imperatorin (IMP), a natural furanocoumarin compound derived from various traditional Chinese medicine plants including Angelica dahurica (Baizhi) and Peucedanum praeruptorum (Qianhu), has shown promising anti-cancer properties. This study aimed to elucidate the therapeutic mechanisms of IMP against NSCLC.

Methods

The anti-NSCLC activity of IMP was evaluated through in vitro cytotoxicity and colony formation assays. Network pharmacology analysis was employed to identify potential targets of IMP in NSCLC. Molecular docking simulations predicted binding affinities and interactions between IMP and its targets. The antitumor efficacy and molecular mechanisms of IMP were further validated using in vivo xenograft models.

Results

IMP exhibited time-dependent growth inhibition in NSCLC cell lines H1975 and A549, with 48-hour IC50 values of 5.28 ± 0.50 µM and 14.17 ± 3.02 µM, respectively, while showing minimal cytotoxicity toward normal lung CCD19-Lu cells. In vivo, IMP significantly suppressed tumor growth in a nude mouse xenograft model. Network pharmacology identified 379 common targets between IMP and NSCLC, predominantly associated with the PI3K-AKT signaling pathway, with the PD-L1 signaling pathway emerging as an additional relevant target. Molecular docking analysis revealed strong interactions between IMP and key PI3K/AKT pathway proteins. Subsequent in vivo experiments confirmed that IMP treatment inhibited PI3K and AKT activation while downregulating PD-L1 expression.

Conclusions

Our findings demonstrate that IMP exerts multi-target effects against NSCLC, particularly through modulation of the PI3K/AKT and PD-L1 pathways, suggesting its potential as both a therapeutic agent and an immunomodulator in NSCLC treatment.