11-Oxo-mogroside V attenuates lung adenocarcinoma progression by disrupting metabolic homeostasis and suppressing TGFβ2/Myc-dependent oncogenic signaling

BACKGROUND: Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality worldwide, with nonsmokers comprising a notable proportion of cases. The complexity of its molecular pathogenesis poses substantial challenges for the development of effective therapeutic strategies. Traditional Chinese medicine-derived compounds have garnered attention for their multi-target engagement and favorable safety profiles. OBJECTIVE: This study aimed to characterize the antitumor effects and elucidate the mechanistic basis of 11-oxo-mogroside V, a bioactive triterpenoid saponin from Siraitia grosvenorii, in LUAD. METHODS: In vitro assays (CCK-8, flow cytometry, wound-healing, metabolic measurements) were performed on lung adenocarcinoma cells. In vivo efficacy was evaluated using a xenograft mouse model with bioluminescent monitoring and TUNEL staining. Transcriptomic profiling, molecular docking, immunoblotting, and co-immunoprecipitation elucidated mechanistic pathways. RESULTS: 11-oxo-mogroside V (800 μg/mL, 72 h) significantly reduced cell viability, induced G0/G1 arrest, and promoted apoptosis (apoptotic rate increased from 3.01% to 12.00%, P < 0.0001). Migration was suppressed (wound closure reduced from 77.66% to 43.98%, P < 0.0001). Metabolic disruption was evidenced by decreased intracellular ATP, glucose uptake, and LDH activity. In vivo, 11-oxo-mogroside V (100 mg/kg, daily) markedly inhibited tumor growth (photon flux reduced from 2.65 × 10¹⁰ to 1.50 × 10¹⁰, P < 0.0001) and increased apoptosis (TUNEL-positive cells from 0.40% to 5.97%, P < 0.0001). Mechanistically, RNA-seq analysis and molecular docking suggested TGFB2, HDAC1, and c-Myc as potential molecular targets, with docking simulations indicating favorable binding affinities. Western blot confirmed downregulation of TGFB2, Smad2/3, TGIF, HDAC1, c-Myc, and Bcl2, alongside upregulation of Bax, with co-IP demonstrating HDAC1-TGIF1 interaction. CONCLUSION: 11-oxo-mogroside V exerts potent anti-LUAD activity by disrupting metabolic homeostasis and suppressing TGFβ2/HDAC1/c-Myc signaling, positioning it as a promising lead compound for therapeutic development.