Exploration of potential targets and toxicological mechanisms of microplastic exposure-induced osteoarthritis based on network toxicology, molecular docking and experimental validation

Microplastics (MPs), ubiquitous environmental pollutants, enter the human body via dietary and respiratory pathways and impair bone and joint tissues, but their toxicological mechanisms in the onset and progression of osteoarthritis (OA) remain elusive. Herein, four common MPs—polyethylene (PE), polyethylene terephthalate (PET), polypropylene (PP), and polystyrene (PS)—were selected as research subjects. Core OA-related targets responsive to MPs exposure were screened using the Gene Expression Omnibus (GEO), SwissTargetPrediction, and Comparative Toxicogenomics Database (CTD), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Weighted gene co-expression network analysis (WGCNA) combined with three machine learning algorithms (random forest, SVM-RFE, LASSO) was employed for cross-validation to identify key targets, whose diagnostic efficacy was validated via nomograms and receiver operating characteristic (ROC) curves. Molecular docking assays assessed the binding affinity between quercetin and the identified targets, while in vitro experiments preliminarily verified the chondrocyte toxicity of PS-MPs and the protective effects of quercetin. A total of 95 core targets were identified, primarily involved in oxidative stress, inflammatory responses, cartilage matrix metabolism, and cell proliferation/apoptosis. DDIT4 and CDKN1A (area under the curve [AUC] > 0.7) were identified as key diagnostic targets for OA. Quercetin stably bound to DDIT4 (binding energy: −7.8 kcal/mol) and CDKN1A (binding energy: −6.1 kcal/mol), preliminarily mitigating PS-MPs-induced chondrocyte damage. This study clarifies the role of MPs in OA progression, identifies DDIT4 and CDKN1A as core regulatory targets, and provides preliminary evidence that quercetin is a potential natural agent against MPs-induced OA.