BACKGROUND: Research interest into regulation of gene expression by physical activity and its effect on cancer prognosis has intensified. This study investigated the role of an exercise-related gene, , in the progression of non-small cell lung cancer (NSCLC) and its potential as therapy target. METHODS: Using the GSE41914 dataset, which includes data related to exercise, and the Cancer Genome Atlas (TCGA)-NSCLC dataset, we identified differentially expressed genes (DEGs) and selected as a hub gene for further analysis. expression levels were measured in NSCLC cell lines and normal lung cells using assays. The functional roles of were investigated through small interfering RNA (siRNA) knockdown experiments, assessing effects on migration, cell proliferation, invasion, and apoptosis. The involvement of the PTEN/AKT signaling pathway was examined using the PTEN inhibitor SF1670. RESULTS: was downregulated in postexercise samples and upregulated in NSCLC samples, indicating its association with poor prognosis in NSCLC. Knockdown of in NSCLC cell lines resulted in reduced cell viability, migration, and invasion, alongside increased apoptosis. Western blotting revealed that knockdown upregulated PTEN levels and downregulated phosphorylated AKT (p-AKT), without altering total AKT levels. The addition of SF1670 partially reversed the effects of knockdown, indicating the involvement of the signaling pathway PTEN/AKT in -mediated tumorigenesis. CONCLUSIONS: is upregulated in NSCLC, which promotes cell invasion and migration via the PTEN/AKT signaling pathway. Targeting , potentially influenced by exercise, could be a promising therapy. Combining exercise with targeted treatments may enhance patient outcomes.