Investigation of the toxicological effects of PFAS on cholangiocarcinoma based on network toxicology, bioinformatics, and molecular docking.

Previous studies have identified an association between per- and polyfluoroalkyl substances (PFAS) and the occurrence of intrahepatic cholangiocarcinoma (ICC), but the specific mechanisms remain unclear. This study aims to analyze the toxicological mechanisms of PFAS, particularly perfluoroctanoic acid (PFOA) and perfluorooctane sulfonate (), on ICC through network toxicology and bioinformatics. Relevant targets for PFOS and PFOA were retrieved from the CTD, ChEMBL, and Super-PRED databases. Targets related to ICC were gathered from the GeneCards, NCBI, and OMIM databases. Common targets between ICC and PFOS, PFOA were identified and subjected to median filtering in CytoHubba to select core targets, which were then analyzed for protein-protein interaction using the STRING database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on core targets to elucidate the biological processes affected by PFAS in ICC. The intersection of the targets for ICC and those from PFOS/PFOA was compared with the differentially expressed genes in ICC from the TCGA database. LASSO regression was applied to filter prediction targets, and bioinformatics analysis was conducted to assess the differential expression of these targets in ICC, constructing a risk assessment model. Molecular docking was utilized to evaluate the binding affinity of PFOA and PFOS to the predicted targets. A total of 1,838 and 2,616 targets were predicted for PFOA and PFOS, respectively; whereas, for ICC, 2,044 targets were identified, with 345 and 459 common targets for PFOA and PFOS, respectively. GO and KEGG enrichment analyses revealed that these processes were primarily associated with biological functions such as cell proliferation and apoptosis, potentially mediated by the PI3K-Akt and HIF-1 signaling pathways. The integrated analysis of differentially expressed genes from the TCGA database and the intersection of targets from PFOA/PFOS with those from ICC yielded five core genes (TP53, ESR1, CDH1, BCL2, and MMP9) that formed an ICC prognostic score with robust predictive capability for survival, classifying ICC patients into high-risk and low-risk groups (p < 0.05). Molecular docking simulations demonstrated strong binding affinities between PFAS and these core targets, supporting their potential roles in PFAS-induced ICC development. This study explores the potential key mechanisms underlying PFAS-induced ICC and highlights core biomarkers that could serve as therapeutic targets. These results are expected to offer novel perspectives on strategies for the prevention and treatment of ICC.