Phthalate exposure and hepatocellular carcinoma: Unraveling mechanisms through network toxicology

Phthalates are typical environmental pollutants that, as plasticizers, are released into the environment through waste, accumulate in organisms, and have reproductive toxicity and potential carcinogenic risks. However, the specific regulatory mechanisms by which phthalates induce liver cancer are still unclear. This study investigates the role of CYP2C9 in liver cancer (LIHC) and its interaction with plasticizers such as BBP and DBP. Toxicological analyses reveal that CYP2C9 is significantly downregulated in LIHC, correlating with poorer patient survival rates. Differential expression analysis using TCGA and GTEx databases confirms high CYP2C9 expression in liver cells, negatively associated with immune cell infiltration. Methylation and mutation analyses indicate a significant relationship between CYP2C9 expression and methylation levels. Additionally, molecular dynamics simulations demonstrate strong binding stability between CYP2C9 and BBP. These findings underscore the critical role of CYP2C9 in liver cancer progression and support its potential as a therapeutic target.