Antitumor effects of Santalol on non-small cell lung cancer via disruption of NF-κB-mediated lipid metabolism

BACKGROUND: Non-small cell lung cancer (NSCLC) poses significant therapeutic challenges, highlighting the urgent need for novel and effective therapeutic strategies. PURPOSE: This study aimed to investigate the antitumor potential of Santalol, a natural compound, in NSCLC and to explore its underlying molecular mechanisms, with a particular focus on lipid metabolism and NF-κB signaling. METHODS: The anti-tumor effects of Santalol were assessed in vitro using NSCLC cell lines (A549, PC9) via proliferation, cell cycle, apoptosis, migration, and invasion assays, along with EMT marker expression. Transcriptomic analysis (RNA sequencing) and functional assays (lipid metabolism, NF-κB phosphorylation) were used to explore molecular mechanisms. In vivo efficacy was evaluated using an A549 xenograft mouse model. RESULTS: Santalol dose-dependently inhibited NSCLC cell proliferation, induced G1 phase cell cycle arrest and apoptosis, and significantly suppressed migration, invasion, and modulated EMT markers. Transcriptomic and functional analyses revealed that Santalol altered genes associated with lipid metabolism and the NF-κB pathway. Specifically, Santalol reduced fatty acid synthase (FASN) activity, decreased intracellular free fatty acid levels, and inhibited NF-κB phosphorylation. In vivo, Santalol markedly suppressed tumor growth and reduced Ki67 expression without observable systemic toxicity. CONCLUSION: Santalol exerts robust anti-NSCLC effects by inhibiting proliferation, migration, and invasion. These effects are mechanistically associated with the modulation of lipid metabolism and the suppression of the NF-κB signaling cascade. Santalol represents a promising therapeutic candidate for NSCLC.