Multifaceted transcriptional reprogramming supports oxaliplatin chemoresistance in colorectal cancer cells

Oxaliplatin resistance remains a critical barrier to effective colorectal cancer treatment. The molecular mechanisms underlying this resistance are not fully understood, highlighting the need to define the transcriptional alterations that contribute to therapeutic failure. Accordingly, a comparative transcriptome analysis was performed on oxaliplatin-resistant colorectal cancer cells (HCT-116-ROx) and their parental counterparts (HCT-116) using RNA sequencing in this study. Differentially expressed gene (DEG) analysis was conducted using a quasi-likelihood negative binomial model. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were carried out using the topGO and clusterProfiler packages, respectively. To confirm the robustness of the transcriptomic data, the genes with the most significant expression changes, based on false discovery rate–adjusted P value less than 0.05 and a |logFC| > 2 thresholds, were selected for validation by quantitative real-time PCR (qRT-PCR). A total of 313 DEGs were identified, including ALDH3A1 and TACSTD2 (upregulated) and IFITM1 (downregulated); these three genes were chosen for validation by qRT-PCR. Gene Ontology enrichment revealed significant changes in cell motility, redox regulation, and extracellular matrix remodeling. KEGG analysis indicated upregulation of ferroptosis, glutathione metabolism, and lysosome-related pathways, and downregulation of p53 signaling, oxidative phosphorylation, and cancer-specific pathways. Oxaliplatin-resistant colorectal cancer cells undergo multifaceted transcriptional reprogramming that promotes redox homeostasis, metabolic adaptation, and structural plasticity while suppressing apoptotic and mitochondrial functions. These changes support chemoresistance and may represent potential therapeutic targets to restore drug sensitivity.