Background: Colorectal cancer (CRC) is a common malignancy in the gastrointestinal tract. Keloid refers to abnormal scar tissue that forms on the skin or mucous membrane. The relationship between RRP9 and DDX21 and the two diseases is unclear.Methods: Download the colorectal cancer dataset GSE134834, GSE206800, GSE209892 and keloid dataset GSE44270 from the GEO database. Differentially expressed genes (DEGs) were screened and weighted gene co expression network analysis (WGCNA) was performed. The construction and analysis of protein-protein interaction (PPI) network, functional enrichment analysis, gene set enrichment analysis (GSEA). Gene expression heat map was drawn. The comparative toxicogenomics database (CTD) analysis was performed to find diseases most related to core genes. TargetScan screened miRNAs that regulated central DEGs. We conducted experimental validation using Western blotting and Polymerase Chain Reaction (PCR).Results: In the colorectal cancer dataset and the scar tissue dataset, we identified 1380 DEGs and 1000 DEGs, respectively. The enrichment pattern for scar tissue was similar to that of colorectal cancer. We identified two core genes, RRP9 and DDX21. CTD analysis indicated that RRP9 and DDX21 are associated with proliferation, scar tissue, colorectal tumors, scleroderma, and inflammation. We found that the core genes (RRP9 and DDX21) were highly expressed in colorectal cancer and scar tissue samples, while their expression was lower in normal samples. This was further validated through Western blotting (WB) and Polymerase Chain Reaction (PCR). Conclusions: The higher the expression of RRP9 and DDX21 in colorectal cancer and keloid, the worse the prognosis.