Network toxicology and single-cell transcriptomics nominate candidate pyrethroid-associated targets and pathways in...

Pyrethroid insecticides are widely used in agricultural and domestic settings. Increasing evidence suggests that pyrethroid exposure may harm multiple organ systems and is associated with potential carcinogenicity. However, the mechanisms linking pyrethroids to clear cell renal cell carcinoma (ccRCC) remain unclear. Using an integrative framework combining network toxicology, single-cell sequencing-based analyses, and molecular docking, we investigated putative core targets and associated signaling pathways through which six prevalent pyrethroid active ingredients in household insecticides may be involved in ccRCC development. We retrieved 710 putative targets of pyrethroid insecticides from three in silico databases (SwissTargetPrediction, SEA, and TargetNet). In parallel, 2633 ccRCC-associated genes were collected from GeneCards and OMIM. Differential expression analysis of the GSE36895 dataset was then used for cross-validation, yielding 50 overlapping genes between pyrethroid-related targets and ccRCC. Functional enrichment suggested that these genes were primarily involved in pathways including chemokine signaling, IgSF cell adhesion molecule signaling, and the p53 signaling pathway. Utilizing three machine-learning algorithms, PNP and TYMS were prioritized as the most informative hub genes. Immune infiltration analyses further evaluated associations between these genes and immune cell populations, while single-cell transcriptomic analyses characterized their expression patterns and cellular distribution across ccRCC subtypes. Finally, molecular binding and in vitro experiments demonstrated that pyrethroid compounds enhance the expression of PNP and TYMS, thereby promoting the development of ccRCC. Overall, our research suggests that PNP and TYMS are candidate targets of pyrethroid insecticides involved in ccRCC, providing a mechanistic foundation for future targeted therapies.