MMP9 mediates 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced osteoarthritis cartilage damage via regulating the p38 MAPK pathway: A mechanistic study based on network toxicology and multi-omics.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic persistent organic pollutant (POP), is associated with musculoskeletal disorders, yet its molecular mechanisms in osteoarthritis (OA)-related cartilage damage remain unclear. This study aimed to explore this mechanism and identify key functional targets. Core genes were screened by integrating network toxicology and OA cartilage transcriptome data, validated via independent cohorts and machine learning, and further identified using SHAP combined with WGCNA. RT-qPCR verified the core target's gene expression in chondrocytes; zebrafish jaw cartilage transcriptome data (GSE11893) confirmed its expression changes after TCDD exposure; Western Blot (WB) validated protein expression and enriched pathways; and a rat OA model with proteomics further verified the target. Molecular docking and dynamics simulations assessed TCDD-target binding affinity. Bioinformatics analysis identified MMP9 as a key candidate gene, and experimental validation confirmed elevated MMP9 expression and increased p38 MAPK phosphorylation under OA-like cartilage injury conditions. Supplementary Western blot analysis in the IL-1β-induced OA-like injury model further showed increased phosphorylation of ERK and JNK, suggesting broader MAPK branch activation under inflammatory OA-like injury conditions. TCDD exposure time-dependently upregulated MMP9 in the zebrafish jaw cartilage transcriptome dataset, and molecular docking/dynamics simulation suggested a potential TCDD-MMP9 interaction. These findings indicate that MMP9 may be associated with TCDD-related OA cartilage damage and may participate in cartilage ECM dysregulation through MAPK signaling, particularly the p38 MAPK branch. Further human biomonitoring and low-dose chronic exposure studies are required to validate the clinical relevance of this mechanism.