Association between phthalate exposure and liver cancer risk based on epidemiology and network toxicology
- VernacularTitle:基于流行病学与网络毒理学探究邻苯二甲酸酯暴露与肝癌风险的相关性
- Author:
Huiying LUO
1
;
Xuemei WANG
1
;
Jiayao YANG
1
Author Information
- Publication Type:Investigation
- Keywords: phthalates; liver cancer; network toxicology; uridine-cytidine kinase 2; glucose-6-phosphate dehydrogenase; albumin
- From: Journal of Environmental and Occupational Medicine 2026;43(3):317-325
- CountryChina
- Language:Chinese
-
Abstract:
Background Liver cancer is one of the common malignant tumors. Phthalates (PAEs), as a widely used class of plasticizers, can participate in the occurrence and progression of liver diseases through multiple pathways. Objective To explore the association between PAEs exposure and liver cancer risk and to provide a scientific basis for the prevention of environment-related tumor risk events. Methods Chi-square test and logistic regression were employed to analyze data from the National Health and Nutrition Examination Survey (NHANES) database between 2001 and 2018, to investigate the association between PAEs exposure and liver cancer. Network toxicology combined with machine learning was used to screen independent prognostic genes associated with PAEs and liver cancer, and to evaluate their correlations with tumor immunity, tumor pathway activation, and tumor drug resistance. Finally, the prediction results were validated using GEO datasets, molecular docking, and molecular dynamics simulations. Results After screening,
11378 eligible samples were obtained from the NHANES database, including 108 patients with liver cancer and11270 healthy controls. The logistic regression analysis revealed that exposure to nine types of PAEs was positively correlated with liver cancer (OR > 1, P < 0.05). The network toxicology analysis indicated that the association between PAEs exposure and liver cancer was related to three independent prognostic genes: uridine-cytidine kinase 2 (UCK2), glucose-6-phosphate dehydrogenase (G6PD), and albumin (ALB). These three independent prognostic genes were significantly associated with the tumor immune microenvironment, tumor pathway activation, and tumor drug resistance, and exhibited complex interactions with each other. All three independent prognostic genes showed significant differential expression in the validation datasets GSE58043 and GSE115469 (P < 0.05). The results of both molecular docking and molecular dynamics simulations confirmed that these three independent prognostic genes can freely bind to PAEs and form stable complexes. Conclusion Exposure to PAEs is positively correlated with liver cancer. The intrinsic association between the two may involve metabolic disorders, immunosuppression, and activation of inflammatory and tumor-related pathways.
