Structural maintenance of chromosome protein 4 (SMC4), is a key structural component of mitotic chromosomes. While existing evidence indicates a plausible link between SMC4 and oncogenic manifestations, its precise role in the trajectory of prostate cancer remains ambiguous. The Cancer Genome Atlas (TCGA) database analysis reveals that aberrant expression of SMC4 exhibits a robust prognostic association with metastatic progression. To investigate the function of SMC4, the SMC4 gene is knocked down in RM1-LM cells, a highly metastatic cell clone is developed, using the CRISPR/Cas9 system. The results show that SMC4 knockdown significantly diminished cell proliferation and migration in vitro. Furthermore, in a murine model, RM1-LM cells display higher lung metastasis capabilities than SMC4 knockdown cells. SMC4 knockdown inhibited the activation of mTOR and downregulated the expression of Rheb. KEGG enrichment analyses of the RNA-seq results reveal that cancer signaling pathways and metabolic pathways are enriched. The SMC4 interactome is uncovered through IP-MS and indicates that SMC4 interacts with GLUT1, encoded by Slc2a1. Glycolytic rate assay illustrates that knocking down SMC4 inhibits the cell glycolysis rate and ATP production. Collectively, the data suggests that the interaction between SMC4 and GLUT1, as confirmed by co-IP, promotes prostate cancer cell metastasis through the Rheb/mTOR pathway.© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.