The extensive morbidity of colorectal cancer (CRC) and the inferior prognosis of terminal CRC urgently call for reliable prognostic biomarkers. For this, we identified 704 differentially expressed genes (DEGs) by intersecting three datasets, GSE41328, GSE37364, and GSE15960 from Gene Expression Omnibus database, to maximize the accuracy of the results. Preliminary analysis of the DEGs was then performed using online gene analysis datasets, such as DAVID, UCSC Cancer Genome Browser, CBioPortal, STRING, and UCSC Cancer Genome Browser. Cytoscape was utilized to visualize the protein perception interaction network of DEGs, and the bubble map of GO and KEGG enrichment function was demonstrated using the R package. The Molecular Complex Detection (MCODE), Biological Network Gene Oncology (BiNGO) plug-in in Cytoscape, was applied to further screen the DEGs to obtain 15 seed genes, which were IL1RN, GALNT12, ADH6, SCN7A, CXCL1, FGF18, SOX9, ACACB, PRRX1, MZB1, SLC22A3, CNNM4, LY6E, IFITM2, and GDPD3. Among them, IL1RN, ADH6, SCN7A, ACACB, MZB1, and GDPD3 exhibited statistically significant survival differences, whereas limited studies were conducted in CRC. Based on the enrichment results of the "Gene Ontology"(GO) and "Kyoto Encyclopedia of Genes and genomes "(KEGG) as well as documented findings of key genes, we further emphasized the potential of IL1RN and PRRX1 as markers of immune infiltrates in CRC and confirmed our hypothesis by compiling data from the UALCAN, Tumor Immune Estimation Resource, and TISIDB databases for these two genes. The above-mentioned genes might offer a valuable insight into the diagnosis, immunotherapeutic targets, and prognosis of CRC.

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