Abstract
Perfluoroalkyl 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 identified nine hub genes, and molecular docking confirmed strong binding affinities between PFAS and these core targets. RT-qPCR analyses indicated that PFAS may exacerbate OA via the following mechanisms: impairing ABCB1-mediated detoxification, antagonizing ESR1-mediated cartilage protection, down-regulating FGFR2 to suppress chondrocyte survival, and inhibiting DNMT1-mediated methylation to disrupt chondrocyte phenotypic stability. This study provides new insights into the potential impact of PFAS on OA and highlights the need for further investigation.