Elucidating the Molecular Mechanisms of N-Nitrosodimethylamine-Induced Colorectal Cancer: A Network Toxicology and Molecular Docking Analysis

Background: N-nitrosodimethylamine (NDMA), a prevalent environmental contaminant found in food, water, and pharmaceuticals, is a recognized carcinogen strongly associated with colorectal cancer (CRC). However, the precise molecular mechanisms underlying NDMA-induced colorectal carcinogenesis remain incompletely understood. This study aimed to systematically investigate the molecular interactions between NDMA and CRC-related proteins to uncover potential mechanisms and therapeutic targets. Methods: We employed an integrated computational approach combining network toxicology and molecular docking. NDMA targets were identified using ChEMBL, STITCH, SwissTargetPrediction, and PharmMapper databases. CRC-associated genes were retrieved from GeneCards, OMIM, and TTD databases. Protein-protein interaction networks were constructed using STRING and analyzed with Cytoscape. Hub genes were identified through centrality analysis, validated using TCGA expression data, and subjected to molecular docking with AutoDock Vina. Results: We identified 370 NDMA targets and 1,575 CRC-related genes, with 91 overlapping genes representing potential mediators of NDMA-induced carcinogenesis. Enrichment analysis revealed significant involvement of xenobiotic response, MAPK signaling, and extracellular matrix remodeling pathways. Network analysis identified TP53, HSP90AB1, and HSP90AA1 as critical hub genes, all showing significant differential expression in CRC tissues (p < 0.05). Molecular docking revealed direct binding of NDMA to TP53 (-4.2 kcal/mol), HSP90AB1 (-4.6 kcal/mol), and HSP90AA1 (-3.8 kcal/mol), suggesting potential functional interference beyond genotoxic effects. Conclusion: This study elucidates multi-faceted mechanisms of NDMA-induced colorectal carcinogenesis, identifying TP53, HSP90AB1, and HSP90AA1 as key molecular targets. The convergence of network analysis, expression validation, and structural predictions provides a comprehensive framework for understanding NDMA toxicity and offers potential targets for preventing CRC in exposed populations.