Ginsenoside Rh2 inhibits non-small-cell lung cancer malignant progression through targeting AURKA

Non-small-cell lung cancer (NSCLC) is one of the most common and deadly malignant tumors worldwide. Treatment still faces challenges, including drug resistance and a complex tumor microenvironment. The natural product ginsenoside Rh2 (G-Rh2) has antitumor potential with multiple targets and low toxicity. However, its specific molecular mechanisms in NSCLC remain unclear. The study integrated transcriptomics analysis (Gene Expression Omnibus (GEO) dataset GSE18842) with drug target prediction (SwissTargetPrediction) to identify common targets between G-Rh2 and NSCLC. Core targets were identified through protein-protein interaction (PPI) network analysis. Gene and protein expression was determined through real-time quantitative PCR (RT-qPCR) and Western blot. The mechanism of G-Rh2 and its association with AURKA were validated using molecular docking, in vitro cellular assays (colony formation, apoptosis, migration, glycolysis level detection, and macrophage co-culture), and in vivo nude mouse xenograft models. AURKA was identified as a core target of G-Rh2 against NSCLC. Its expression was significantly elevated in NSCLC tissues and cell lines, and was related to poor overall survival. G-Rh2 inhibited cell colony formation and migration while inducing apoptosis, downregulated hypoxia-inducible factor-1α (HIF-1α) expression, and reduced glucose consumption, lactate production, and adenosine triphosphate (ATP) levels, but these effects were reversed by Aurora kinase A (AURKA) overexpression. Besides, AURKA upregulation weakened the promotion of G-Rh2 on macrophage M1 polarization and the inhibition on M2 polarization. More importantly, G-Rh2 enhanced cisplatin (DDP) chemotherapy sensitivity both in vivo and in vitro, whereas AURKA overexpression reversed these effects. G-Rh2 regulates malignant progression in NSCLC by targeting AURKA. It inhibits proliferation and migration, induces apoptosis, reshapes the metabolic and immune microenvironment, and sensitizes chemotherapy. AURKA serves as a potential biomarker and combination therapy target for NSCLC treatment.