SMC5 is a potential prognostic biomarker associated with genomic instability and drug sensitivity in colorectal cancer

The structural maintenance of chromosomes 5 (SMC5) complex plays a critical role in genome stability, but its prognostic significance in colorectal cancer (CRC) pathogenesis remains poorly understood. This study aimed to elucidate the prognostic potential of SMC5 in CRC progression, therapeutic response, and clinical outcomes. We analyzed whole-genome transcriptomic profiles and clinical data from TCGA to stratify CRC samples based on SMC5 expression. Differential gene expression, functional enrichment, and protein-protein interaction (PPI) network analyses were performed to identify SMC5-associated pathways. Unsupervised clustering classified patients into molecular subtypes, while drug sensitivity was assessed using pharmacological databases. In vitro and in vivo experiments validated the functional importance of SMC5 in chemosensitivity and DNA damage response. SMC5-high tumors exhibited enrichment in genomic stability pathways (DNA replication, homologous recombination), while SMC5-low tumors showed metabolic dysregulation (oxidative phosphorylation). A PPI network identified 18 hub genes, including BRCA1/2 and TOP2A, strongly correlated with SMC5 expression (Spearman |r| > 0.4). Unsupervised clustering revealed three molecular subtypes with distinct prognoses. Cluster 1 demonstrated enhanced sensitivity to topoisomerase inhibitors. A novel 7-gene prognostic signature (AUC = 0.685 for three years) predicted survival and therapeutic response. Functional studies showed that SMC5 overexpression increased oxaliplatin sensitivity possibly via exacerbated DNA damage. SMC5’s tumor-suppressive role depended on SMC5/6 complex integrity, as NSE4A knockdown abrogated SMC5-mediated chemosensitization. SMC5 is associated with genomic stability pathways and chemotherapeutic response in CRC. The SMC5-centered classification system offers prognostic and predictive value, with potential clinical utility for personalized therapy selection. Targeting the SMC5/6 complex may enhance chemosensitivity in defined molecular subgroups.