Identification of Core Pathways in Perfluorooctane Sulfonamide-Induced Liver Injury Using a Network Toxicology Approach

Perfluorooctane sulfonamide (PFOSA) is an environmentally persistent compound that poses a threat to human health, but its hepatotoxicity mechanism remains unclear. This study integrated the National Health and Nutrition Examination Survey (NHANES) epidemiological data, network toxicology, bioinformatics analysis, and molecular docking simulation to systematically explore the hepatotoxicity mechanism of PFOSA from multiple levels. Potential targets of PFOSA and disease targets related to liver injury were screened through multiple databases, a protein-protein interaction (PPI) network was constructed, core targets were identified, and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis was conducted. Meanwhile, external validation was conducted through the Gene Expression Omnibus (GEO) dataset, and molecular docking was used to evaluate the affinity between PFOSA and key targets. Data from 2,476 NHANES participants (1999-2012) showed that there was a significant association between PFOSA exposure and liver function markers (aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), etc.), establishing an association between the population level and liver injury. Through multi-database screening (CHEMBL, Search Tool for Interactions of Chemicals (STITCH), GeneCards, etc.), 623 intersection targets were identified, and 37 core targets were screened out. Among them, the top five were MDM2, HSP90AB1, HIF1A, MMP9, and TP53. The Gene Ontology (GO) and KEGG analyses highlighted the enrichment of cancer-related pathways, oxidative phosphorylation, and non-alcoholic fatty liver disease (NAFLD). The molecular docking of PFOSA with the core target shows a strong binding affinity. Overall, PFOSA may induce liver steatosis, fibrosis, and carcinogenic risks by disrupting the apoptosis regulation of MDM2-TP53, HIF1A-mediated oxidative stress, and MMP9-driven extracellular matrix degradation. These findings emphasize the necessity of stricter PFOSA regulations and enhanced environmental monitoring in areas where NAFLD is prevalent, providing a framework for toxicity assessment and intervention strategies.