Compound 17 Inhibits Lung Cancer Progression via Inducing Cellular Apoptosis and Blocking TNF Signaling Pathway Activation.

Lung cancer ranks among the most commonly diagnosed malignancies worldwide, with dismal prognosis largely due to its intrinsic drug resistance and high recurrence rate. Herein, we synthesized 30 glycyrrhetinic acid derivatives and evaluated their anti-lung cancer potential both in vitro and in vivo. The biological effects of compound 17 on A549 cells were determined using MTT, colony formation, and Transwell assays. Flow cytometry, transcriptomic profiling, and RT-qPCR were performed to identify differentially expressed genes, followed by GO and KEGG enrichment analyses and molecular docking validation. A mouse xenograft tumor model was employed to assess therapeutic efficacy and systemic toxicity. Compound 17 exhibited dose-dependent inhibition of A549 cell proliferation, migration, and invasion, achieving an IC50 value of 0.6011 ± 0.05 μM. It induced G1-phase cell cycle arrest and apoptosis by inhibiting the TNF signaling pathway and modulating apoptosis-related proteins. In vivo experiments demonstrated that compound 17 exerted a tumor inhibition rate of 80.61% without observable toxic side effects. This study is the first to demonstrate that compound 17 exerts potent anti-lung cancer activity by targeting the TNF signaling pathway and activating the mitochondrial apoptosis pathway, providing a critical experimental foundation for its development as a novel therapeutic agent against lung cancer.