NUAKs facilitate mTOR-mediated NSCLC proliferation and metastasis by modulating glucose metabolism and inhibiting p53 activity.

Non-small cell lung cancer (NSCLC) cells frequently exhibit aberrant glucose metabolism, characterized by elevated aerobic glycolysis, pentose phosphate pathway (PPP), and reduced oxidative phosphorylation. However, the specific mechanisms underlying the abnormal activation of glucose metabolism and its contribution to NSCLC tumorigenesis remain incompletely elucidated. In this study, we observed that both NUAK1 and NUAK2 mRNA expression levels were significantly elevated in NSCLC tissues compared to non-tumor tissues, and that high NUAK1/2 expression correlated with poor prognosis in NSCLC patients. Furthermore, NUAK1/2 promotes aerobic glycolysis and PPP in NSCLC cells and stimulates cellular proliferation and migration. Depletion or inhibition of NUAK1/2 results in decreased aerobic glycolysis, PPP activity, cell proliferation, and migration, leading to increased apoptosis of NSCLC cells. Mechanistically, NUAK1/2 enhances mTOR activity by suppressing the activity of p53, thereby promoting NSCLC cell growth and metastasis through the promotion of aerobic glycolysis and PPP. Our findings suggest that NUAK1/2 plays a crucial role in glucose reprogramming and tumorigenesis in NSCLC cells, indicating that targeting NUAK1/2 may represent a potential therapeutic strategy for NSCLC metabolism.