Febuxostat inhibits non‑small cell lung cancer cell proliferation under starvation conditions by modulating xanthine oxidoreductase‑associated autophagy

Febuxostat (FBX), a selective non-purine xanthine oxidoreductase (XOR) inhibitor clinically indicated for hyperuricemia, has recently attracted attention for its potential antitumor properties.Nevertheless, its potential therapeutic efficacy against non-small cell lung cancer (NSCLC) remains to be fully characterized.XOR expression and enzymatic activity were quantified in NSCLC lines (A549 and SK-MES-1) and compared with normal human bronchial epithelial BEAS-2B cells.The effects of XOR and FBX on cell proliferation, migration and invasion were evaluated using the cell counting kit-8, wound-healing and Matrigel-Transwell invasion assays, respectively.Apoptosis and autophagic flux under starvation conditions (FBS-free DMEM) were assessed using Annexin V/SYTOX staining, DCFH-DA, western blotting (p62 and LC3-II) and LysoTracker Red staining.The functional role of autophagy was validated through rescue experiments using the autophagy activator rapamycin.XOR was found to be markedly upregulated and hyperactive in NSCLC cells compared with normal epithelial cells.Small interfering RNA-mediated XOR knockdown attenuated NSCLC cell viability, migration and invasion.Pharmacological inhibition of XOR by FBX likewise impaired proliferative, migratory and invasive capacities, accompanied by marked suppression of autophagic flux.Notably, these antitumor effects were abrogated by rapamycin-induced autophagy activation.The present findings demonstrated that XOR is involved in the metabolic drive of NSCLC progression under nutrient-deprived conditions.Specifically, FBX exerted anticancer effects by blocking XOR-mediated pathways and suppressing protective autophagy, suggesting that repurposing FBX for NSCLC therapy warrants further preclinical investigation.