Sudan II and IV induce liver carcinogenesis through interactions with AKR1D1 in computational and experimental studies insights from the Taiwan Sudan Red chili pepper incident.

Sudan dyes, a group of synthetic azo dyes, are widely used in industrial applications despite their potential health hazards. Recent incidents, such as the Taiwan Sudan Red chili pepper contamination, have underscored significant food safety concerns and the need for a better understanding of these compounds' toxicity and pathogenic mechanisms. This study combines computational biology, bioinformatics, and experimental validation to investigate the pathogenic effects of Sudan I, II, III, and IV on liver-associated proteins and their potential contribution to liver carcinogenesis. We utilized AlphaFold2 and molecular docking to predict the binding interactions between Sudan dyes and key hepatic enzymes, particularly AKR1D1, and further assessed the stability of these interactions through molecular dynamics simulations. Results show that while CYP1A1 is involved in the oxidative metabolism of Sudan compounds, it fails to fully metabolize them, thereby allowing interaction with AKR1D1. Sudan II and IV, in particular, exhibited stable binding to AKR1D1, potentially contributing to bile acid accumulation and promoting liver cancer. In contrast, Sudan III demonstrated lower binding stability, suggesting alternative pathogenic pathways. Experimental analysis using HepG2 liver cancer cells confirmed the tumor-promoting effects of Sudan II and IV, while Sudan III exerted proliferative effects only at higher concentrations. These findings underscore the complexity of the interactions between Sudan compounds and liver proteins and highlight the need for continued research to clarify their health risks and develop targeted prevention strategies.