The Role of Myeloperoxidase in Osteoarthritis and Its Potential Modulation by Resveratrol: An Integrated Study

ABSTRACT To utilize bioinformatics to trace the neutrophil extracellular traps (NETs) pathway to its core downstream mediator, myeloperoxidase (MPO), in osteoarthritis (OA), and to experimentally validate resveratrol's (RE) local intervention effects on MPO within the joint microenvironment. Using the GEO dataset, bioinformatics analysis was done. OA candidate genes were obtained and analyzed by GO and KEGG enrichment, and key pathways were selected for correlation analysis. Unsupervised clustering and single‐cell analysis of OA cartilage tissues were carried out. The LASSO model was used to identify key genes, reverse‐predict related compounds, and perform molecular docking and dynamics simulation. An OA rat model was constructed for validation. Eight hundred eight differentially expressed genes (DEGs) were found in OA. Eleven types of immune cells were differentially expressed, with lower levels in the OA group. Neutrophil extracellular trap formation was a key pathway. The LASSO model identified MPO as a key target. Molecular docking predicts a close binding between RE and MPO. In OA rats, MPO was up‐regulated, and RE reduced its expression. Bioinformatics identified the NETs‐related gene MPO as a core target in OA. Subsequent in vitro experiments revealed a novel mechanism whereby stressed chondrocytes locally express MPO, which RE effectively suppresses. This provides a scientific basis for targeting local MPO activity, extending beyond its traditional role in systemic NETs.