A Super-Enhancer-Related Ferroptosis Signature Predicts Survival and Immune Microenvironment in Colon Cancer Based on Bioinformatics Analyses and Experimental Validation

Abstract

Although immunotherapy has revolutionised cancer treatment, its benefits remain restricted to a minority of patients with colon cancer. Emerging evidence implicates super-enhancer (SE) networks and ferroptosis dysregulation as key oncogenic drivers, though their synergistic prognostic and immune microenvironment implications are unexplored. Super-enhancer-related ferroptosis genes (SEFGs) were identified by intersecting SE-associated and ferroptosis-related genes. Using TCGA-COAD (training) and GSE39582 (validation) cohorts, we established an 8-gene prognostic signature via LASSO Cox regression. This signature formed the basis of a clinical nomogram with robust calibration and discrimination (C-index = 0.813). High-risk patients exhibited significantly reduced overall survival. Elevated risk scores correlated with advanced stage, consensus molecular subtypes (CMS1/CMS4), high tumour mutation burden (TMB), high-level microsatellite instability (MSI) and enhanced immune cell infiltration, paradoxically coupled with immunosuppressive phenotypes including increased immune checkpoint gene expression and reduced immunotherapy responsiveness, alongside increased sensitivity to SE inhibitors. JQ-1 RNA-Seq profiling revealed three core SE-driven genes, TRIB2, CAV1 and ENO3, which were significantly downregulated upon SE inhibition. Among them, TRIB2 was distinguished by its SE recurrence, tumour overexpression, prognostic value and JQ-1 suppression. The SEFG signature facilitates simultaneous prediction of prognosis and assessment of the immune microenvironment, providing a potential tool for colon cancer management.