Objective To explore the potential mechanisms of glutathione peroxidase 4 (GPX4) in regulating ferroptosis in colon cancer and its impact on prognosis using bioinformatics techniques.Methods We collected the clinical data and transcriptome data of colon cancer patients from TCGA and GEO databases, analyzed the differential expression of GPX4 in colon cancer tissues and normal tissues, analyzed the immunohistochemistry results of GPX4 in colon cancer and normal tissues through HPA database, evaluated the relationship between GPX4 expression level and overall survival by KM survival curve, and determined the biological function of GPX4-related genes by GO and KEGG enrichment analysis. The predictive value of GPX4 in colon cancer was evaluated by nomogram, ROC curve and calibration curve.Results GPX4 expression is upregulated in a variety of cancers, and patients with high GPX4 expression in colon cancer have shorter survival time. The main biological functions of GPX4-related genes are related to "toxic substance response", "cellular detoxification", "cellular oxidant detoxification" and "antioxidant activity", and GPX4-related genes are enriched in "glutathione metabolism", "ferroptosis", "arachidonic acid metabolism", "selenocompound metabolism" and "thyroid hormone synthesis". Evaluation using calibration curves and time-dependent ROC analysis demonstrated that the nomogram model incorporating GPX4 expression and age effectively predicted 1-, 3-, and 5-year survival rates in patients with colon cancer.Conclusion GPX4 is highly expressed in colon cancer and is closely related to the poor prognosis of patients. GPX4 may affect the progression of colon cancer through ferroptosis-related pathways, and can be used as a potential biomarker for the prognosis evaluation of colon cancer.