〔Abstract〕 Abstract Objective To predict and validate key targets for cisplatin( DDP) resistance in colorectal cancer to provide more options for precision medicine in clinical treatment. Methods Differentially expressed genes (DEGs) between normal colonic mucosa and colorectal cancer(CRC) were screened from the gene expression om- nibus(GEO) database . Key genes were identified using the STRING database and Cytoscape software . DEGs were subjected to enrichment analysis using the gene ontology ( GO) and kyoto encyclopedia of genes and genomes (KEGG) databases . Key targets were validated through RNA-seq , qRT-PCR , and Western blot. The versican (VCAN) gene overexpression vector was transfected into human ileocecal colorectal adenocarcinoma cell line HCT8 , and cell viability was assessed using the CCK-8 assay . Flow cytometry was used to assess apoptosis and cell cycle distribution . qRT-PCR and Western blot were performed to detect mRNA and protein levels of the target genes . Results In this study , 118 upregulated DEGs and 146 downregulated DEGs were identified from the GEO database . DEGs were mainly enriched in extracellular matrix degradation , extracellular matrix organization , and the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway . Based on protein-protein interaction network analysis , 20 hub genes were identified . By comparing the transcriptome sequencing results of the HCT8 pa- rental strain and DDP-resistant strain , the VCAN gene was further selected . In CRC tissues , the expression level of VCAN was higher than that in normal colonic mucosa , and patients with high VCAN expression had shorter overall survival (OS) and recurrence free survival(RFS) times . Overexpression of VCAN in CRC cells promoted cell pro- liferation (P < 0. 05 ) , increased resistance to DDP , reduced DDP-induced apoptosis ( P < 0. 05 ) , and G0 /G1 phase arrest (P < 0. 05) ; upregulation of VCAN activated the protein kinase B (AKT)-mammalian target of rapam- ycin ( mTOR) signaling pathway . Conclusion Bioinformatics and transcriptome sequencing identified VCAN as a key target gene for DDP resistance in CRC , potentially promoting CRC progression and DDP resistance by regula- ting the AKT-mTOR pathway .