Deciphering the toxicological mechanisms of per- and polyfluoroalkyl substances (PFAS) in musculoskeletal disorders via integrated network toxicology and molecular docking

Per- and polyfluoroalkyl substances (PFAS) have been extensively used in everyday products; however, their effects on human health remain largely unknown. This study aimed to investigate the potential mechanisms by which PFAS may contribute to functional disorders in the human musculoskeletal system. Four representative musculoskeletal disorders were selected, which included intervertebral disc degeneration, myositis, osteoarthritis, and osteoporosis. Advanced network toxicology approaches integrating data from the Comparative Toxicogenomics Database (CTD) and GeneCards identified potential PFAS-associated targets for each disorder. Molecular docking simulations were employed to assess interactions between PFAS and target proteins. Molecular docking of a series of PFAS molecules against multiple protein targets revealed strong binding affinities. Prioritization based on average binding energies highlighted the targets with the greatest PFAS-binding potential. A subsequent comprehensive analysis further discussed these findings by integrating the functional roles of the targets and the classification of the various PFAS compounds. Evidence synthesis confirmed that these core targets are critically involved in key pathological processes common to musculoskeletal diseases, including chronic inflammation, oxidative stress, apoptosis, extracellular matrix degradation, and impaired bone remodeling. This study provides innovative insights into the mechanisms by which environmental pollutants contribute to human diseases, thereby establishing a theoretical foundation for disease prevention and therapeutic strategies.