Exploring potential mechanisms of triclosan and triclocarban in colorectal cancer development: an integrative study combining network toxicology, molecular docking, molecular dynamics simulation, machine learning, and experimental validation

Abstract Colorectal cancer (CRC) represents a significant global health challenge, with emerging evidence suggesting that environmental factors, including commonly used antimicrobial agents like triclosan (TCS) and triclocarban (TCC), may play a role in its pathogenesis. This study aimed to elucidate the molecular mechanisms by which TCS and TCC contribute to CRC development. We employed network toxicology and machine learning (ML) methodologies to pinpoint key targets related to CRC associated with TCS and TCC, further validating our bioinformatics findings through molecular docking, molecular dynamics (MD) simulations, and cellular thermal shift assay-western blotting (CETSA-WB). Our results revealed that the identified CRC targets associated with TCS and TCC were predominantly involved in pathways such as chemical carcinogenesis-receptor activation, nitrogen metabolism, and neuroactive ligand-receptor interactions, with NR3C1, BCHE, MAOA, and XDH emerging as four core targets. The molecular interactions showed that the binding energies of TCS and TCC with the core targets were all below −7 kcal/moL, ensuring stable binding, particularly between MAOA and TCC, a finding corroborated by CETSA-WB. In conclusion, TCS and TCC potentially facilitate CRC development through multiple pathways and targets, highlighting NR3C1, BCHE, MAOA, and XDH, especially MAOA, as pivotal components in this complex process. Future research should further explore these interactions to inform preventive strategies and therapeutic interventions against CRC.