Study of mechanism of drug-induced liver injury caused by pyrethroid insecticides based on network toxicology and mendelian randomization

The widespread use of pyrethroid insecticides poses a public health hazard, and previous studies have shown that these insecticides may contribute to liver injury, but the mechanism of action has not been comprehensively investigated. The differentially expressed genes in the GSE102006 dataset and the targets from the GeneCards and OMIM databases were used as relevant targets for drug-induced liver injury (DILI). These targets were intersected with the predicted targets of pyrethroids, and 167 intersecting targets were obtained for protein-protein interaction (PPI) analysis and enrichment analysis. The PPI network consists of 1,378 edges. SRC, NFKB1, MAPK3, RELA are key targets in the network. Pathway enrichment showed that the intersection targets were significantly enriched in cAMP, calcium, PI3K-Akt, and VEGF signaling pathways. These signaling pathways extensively regulate cell growth, reproduction, apoptosis, and mediate inflammatory responses. In addition, this study identified a causal relationship between gene variants in PIM1 and FDFT1 and disease progression by mendelian randomization analysis. The results of molecular docking and molecular dynamics simulation further verify the strong and stable interaction between pyrethroids and these potential targets, suggesting their possible role in the mechanism of pyrethroid-related liver injury. These findings provide a theoretical foundation for future research into biomarkers of pyrethroid-induced DILI.