The metabolic dependency on GLUT3 mediates smoking-induced NSCLC progression

Cigarette smoking is strongly associated with aggressive non-small cell lung cancer (NSCLC), yet the mechanisms linking smoke exposure to metabolic reprogramming remain incompletely understood. Here, we integrated clinical, molecular, and functional analyses to define a smoking-associated metabolic axis in NSCLC. Lung cancer patients with a smoking history exhibited significantly higher tumor ¹⁸F-FDG uptake than never-smokers, suggesting an association between smoking exposure and increased tumor metabolic activity. Consistently, chronic exposure of NSCLC cells to cigarette smoke extract (CSE) or its ingredient benzo[α]pyrene (B[α]P) increased glucose uptake, glycolysis, ATP production, and malignant phenotypes, including proliferation, migration, and sphere formation. Mechanistically, GLUT3 protein, but not mRNA, was selectively upregulated in smoke-exposed tumors and cell models, suggesting post-transcriptional regulation. We identified miR-146a as a direct suppressor of GLUT3 through binding to its 3'UTR and found that cigarette smoke markedly reduced miR-146a expression. Smoker-derived NSCLC tumors exhibited lower miR-146a expression and higher GLUT3 levels, which were inversely correlated and associated with poor overall survival. Restoration of miR-146a reduced GLUT3 expression, glucose uptake, and tumor cell proliferation, supporting a central role for the miR-146a/GLUT3 axis in smoking-induced metabolic reprogramming. (-)Gallocatechin ((-)GC), a naturally occurring catechin, is further identified as a selective GLUT3 inhibitor and suppressed smoke-induced glucose uptake, tumor progression, and metastasis without detectable systemic toxicity. Collectively, these findings identify the miR-146a/GLUT3 axis as a key mechanism underlying smoking-driven metabolic reprogramming and establish GLUT3 as a potential metabolic target in NSCLC and other GLUT3-dependent malignancies.