The early diagnostic methods for non-small-cell lung cancer (NSCLC) are limited, lacking effective biomarkers, and the late stage surgery is difficult and has a high recurrence rate. We investigated whether the effects of <i>FBXO45</i> in arcinogenesis and metastasis of NSCLC. The up-regulation of <i>FBXO45</i> expression in NSCLC patients or cell lines were observed. <i>FBXO45</i> gene promoted metastasis and Warburg effect, and reduced ferroptosis of NSCLC. <i>FBXO45</i> induced ZEB1 expression to promote Warburg effect and reduced ferroptosis of NSCLC. Sh-<i>FBXO45</i> reduced cancer growth of NSCLC in mice model. <i>FBXO45 </i>decreased the ubiquitination of ZEB1, leading to increased expression of ZEB1, which in turn promoted the Warburg effect and reduced ferroptosis in NSCLC. <i>In vivo</i> imaging, Sh-<i>FBXO45</i> also reduced ZEB1 expression levels of lung tissue in mice model. <i>FBXO45</i> in NSCLC through activating the Warburg effect, and the inhibition of ferroptosis of NSCLC by the suppression of ZEB1 ubiquitin, <i>FBXO45</i> may be a potential therapeutic strategy for NSCLC.