Environmental exposure to heavy metals and their potential impact on prostate cancer prognosis-related gene expression.

The association between prostate cancer (PCa) and environmental heavy metal exposure is recognized, but molecular mechanisms for mixed metal effects remain unclear. This study employed bioinformatics and NHANES data analysis (logistic regression, dose-response, correlation) to investigate the relationship between blood lead, cadmium, mercury, and mixed metals with self-reported PCa. Significant associations were found. Weighted Quantile Sum (WQS) and quantitative g-computation (qgcomp) analyses confirmed synergistic effects of the metal mixture. Comparative Toxicogenomics Database (CTD) screening identified CNOT3 as a key response gene to lead/mercury. Functional enrichment analysis implicated CNOT3 in cancer pathways. TCGA data validated CNOT3 overexpression in PCa and its prognostic value. Critically, in vitro and in vivo experiments established CNOT3 as a novel oncogene, with its knockdown significantly inhibiting tumor growth (p < 0.001). This study is the first to demonstrate that mixed heavy metal exposure synergistically increases PCa risk and identifies CNOT3 as a biologically significant biomarker and therapeutic target in heavy metal-related PCa development.