Dysregulation of atrazine-associated core gene networks and risk prediction in human cancers: Insights from integrated transcriptomics and network toxicology analyses.

Atrazine, a widely used chlorotriazine herbicide, persists in aquatic environments and poses potential carcinogenic risks. While epidemiological studies link atrazine exposure to malignancies, its intrinsic molecular mechanisms across organ systems remain incompletely understood. This study employed integrated network toxicology and transcriptomic analyses to clarify atrazine-associated oncogenic pathways in liver hepatocellular carcinoma (LIHC), kidney renal clear cell carcinoma (KIRC), lung adenocarcinoma (LUAD), and sarcoma (SARC). Transcriptomic data from The Cancer Genome Atlas (TCGA) for these cancers were analyzed to identify atrazine-related genes. Protein-protein interaction networks were constructed and analyzed to identify hub genes. Functional enrichment, immune microenvironment analyses, and survival analysis were performed. Molecular docking validated atrazine-target binding, and independent datasets were used for hub gene expression and pan-cancer relevance validation. We identified 92 (LUAD), 136 (LIHC), 137 (KIRC), and 161 (SARC) atrazine-associated targets. Hub genes including CDC6, MCM5/7, UBE2C, FEN1, CDCA8, and VIM were differentially expressed across these cancers. Enrichment analyses revealed atrazine disruption of core pathways, including cell cycle progression and chromosomal instability, epithelial-mesenchymal transition, metabolic reprogramming, and senescence-associated secretory pathways. Molecular docking confirmed high-affinity binding between atrazine and key targets. Pan-cancer validation implicated these hub genes in multiple additional malignancies. Transcription factor analysis nominated HSD17B8 as a key regulatory node. This study demonstrates that atrazine promotes carcinogenesis by dysregulating conserved networks governing genomic stability, cell proliferation, metabolic adaptation, and immune microenvironment remodeling, providing a mechanistic framework linking aquatic atrazine exposure to multi-organ carcinogenesis and nominating HSD17B8-associated pathways for therapeutic intervention. These findings underscore the imperative for enhanced environmental monitoring of atrazine contamination.