Multi-omics investigation of per- and polyfluoroalkyl substances in lung adenocarcinoma: comprehensive network...

Growing concerns regarding per- and polyfluoroalkyl substances (PFAS) as pervasive environmental contaminants have prompted increasing scrutiny regarding their potential contributions to pulmonary diseases. Therefore, this study specifically investigates their implications in lung adenocarcinoma (LUAD) pathogenesis. We utilized the Comparative Toxicogenomics Database (CTD), GeneCards, and OMIM databases to collect LUAD-related targets, while PFAS-related targets were independently predicted from ChEMBL, SwissTargetPrediction, and PharmMapper databases using stringent criteria. The intersecting targets were subjected to protein-protein interaction (PPI) network construction, functional enrichment analysis and molecular docking. We then integrated multi-omics data using ten clustering algorithms to identify the consensus LUAD subtypes, which were subsequently employed in three machine learning algorithms to develop a consensus per- and polyfluoroalkyl substance-related signature (CPFASRS) for LUAD patients. Consequently, we identified six hub toxicological targets: HSP90AA1, EGFR, AKT1, ALB, SRC, and ESR1, highlighting their potential central roles in PFAS-driven LUAD pathogenesis. These targets are enriched in PPAR signaling pathway, chemical carcinogenesis-receptor, and thyroid hormone signaling pathway. The PFAS-toxicity classifiers and CPFASRS prognostic model serve as valuable tools for clinical stratification and personalized management of LUAD patients. Molecular docking suggested that Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) bind tightly to core targets and weakly to other proteins, which may imply a potential role in PFAS-related LUAD toxicity. Therefore, this study clarifies how PFAS contribute to the development of LUAD and explores the molecular pathways involved, providing crucial insights into the toxicological effects of PFAS. Furthermore, it establishes a theoretical basis for devising preventive strategies and therapeutic approaches for pulmonary diseases related to PFAS exposure.