Integrated In Silico and Network Toxicology Analysis of Perfluorononanoic Acid-Induced Hepatotoxicity in Humans

Perfluorononanoic acid (PFNA) is a long-chain perfluorocarboxylic acid that was recently listed as a persistent organic pollutant under the Stockholm Convention. Growing toxicological and epidemiological evidence associates PFNA exposure with multiple adverse health outcomes, including hepatotoxicity; however, the molecular mechanisms underlying PFNA-induced hepatotoxicity in humans remain unclear. In this study, the molecular mechanisms and targets associated with PFNA-induced hepatotoxicity in humans were investigated using in silico hepatotoxicity prediction, network toxicology, multi-level bioinformatics approaches, molecular docking, and differential gene expression (DEG) analysis. Through comprehensive database screening, 107 potential targets associated with PFNA-induced hepatotoxicity were identified. Protein-protein interaction network construction and topological analysis using STRING, Cytoscape, and the MCODE algorithm identified six hub targets (SRC, EGFR, ESR1, FN1, MAPK1, and JAK2). Gene-gene interaction analysis revealed enrichment in peptidyl-tyrosine phosphorylation, while Gene Ontology analysis demonstrated significant enrichment in the positive regulation of phosphatidylinositol 3-kinase/protein kinase B signaling. KEGG pathway analysis highlighted pathways associated with proteoglycan-mediated signaling and chemical carcinogenesis-receptor activation. Molecular docking indicated weak binding affinities between PFNA and the identified hub targets. DEG analysis further showed downregulation of SRC, EGFR, and JAK2, whereas ESR1, FN1, and MAPK1 were upregulated. Collectively, these findings suggest that PFNA may perturb key regulatory signaling networks involved in tyrosine kinase activity, PI3K/Akt signaling, and extracellular matrix-associated pathways, which are frequently implicated in carcinogenesis and liver pathophysiology. This study provides mechanistic insights into PFNA-induced hepatotoxicity and establishes a foundation for future experimental validation in vitro and in vivo.