Molecular mechanisms of non-pharmaceutical chemicals exposure-induced liver injury: a network toxicology approach

The exposure to non-pharmaceutical chemicals has been increasingly associated with liver injury, yet the underlying molecular mechanisms remain unclear. This study investigates the impact of three such chemicals-sunset yellow (SUN), tartrazine (TART), and triclosan (TRI)-on human HepaRG cells to elucidate potential toxicological targets and pathways. We conducted differential expression analysis on HepaRG cells exposed to SUN, TART, and TRI, identifying differentially expressed genes (DEGs). Intersection analyses were performed to uncover common targets, followed by heatmap visualization and enrichment analyses using GO and KEGG pathways. Protein-protein interaction (PPI) and immune cell infiltration analyses further elaborated the effects, complemented by molecular docking studies to assess chemical binding affinities. Our findings identified 47 upregulated and 123 downregulated DEGs as common targets across all chemical exposures. Enrichment analysis revealed significant alterations in biological processes related to liver metabolism and development. Four core toxic targets (KNG1, PLG, SERPINE1, SERPINF2) were identified with significant connectivity in PPI analysis, confirmed by altered gene expression. Immune cell infiltration analysis indicated modulation of various immune cell populations. The molecular docking study highlighted strong binding of TART and SUN to PLG, suggesting a potential mechanism of liver injury. This study provides insights into the molecular mechanisms of liver injury induced by non-pharmaceutical chemical exposure, identifying key toxicological targets and pathways. The results suggest that chemicals like SUN and TART can significantly alter liver function through specific gene expression changes and immune modulation, offering potential biomarkers and therapeutic targets for mitigating such toxic effects.