Identifying the Toxicological Effects of Per- and Polyfluoroalkyl Substances Exposure on Osteoarthritis and Verifying through Molecular Docking

Per- and polyfluoroalkyl substances (PFAS) pose a significant challenge due to their persistence, bioaccumulation, and multi-system toxicity. Their impact on degenerative diseases, particularly osteoarthritis (OA), remains understudied, necessitating comprehensive toxicity assessment. Multiple databases identified targets between PFAS and OA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to elucidate the underlying mechanisms. Machine learning further screened targets, and molecular docking confirmed strong binding affinities between PFAS and core targets. 31 targets between PFAS and OA were identified through the multiple databases, with GO analysis revealing enrichment in inflammatory response, nuclear receptor activity, and oxidative stress. KEGG pathway enrichment analyses implicated PI3K-Akt, interleukin-17 (IL-17), and peroxisome proliferator-activated receptor (PPAR) signaling in cartilage homeostasis disruption. Machine learning further prioritized 9 hub genes, and molecular docking confirmed strong PFAS-core target binding, suggesting PFAS exacerbates OA by impairing ABCB1 detoxification, antagonizing ESR1 mediated cartilage protection, and activating FGFR2 driven matrix degradation. PFAS may influence OA progression through mechanisms such as antioxidant disruption, inflammatory activation, and key gene modulation. This study provides new insights into the potential impact of PFAS on OA and highlights the need for further investigation.