Bioinformatics analysis of GEO datasets identified 808 differentially expressed genes in osteoarthritis (OA), with neutrophil extracellular trap (NET) formation emerging as a key pathway. LASSO modeling pinpointed myeloperoxidase (MPO) as the central downstream target. Molecular docking confirmed tight binding between resveratrol (RE) and MPO, and in vivo rat OA models showed MPO was upregulated in diseased joints while RE administration reduced its expression. Crucially, in vitro experiments revealed that stressed chondrocytes — not just infiltrating neutrophils — locally express MPO, a mechanistically novel finding.
MPO has long been studied as a systemic inflammatory enzyme released by neutrophils into NETs, but its chondrocyte-intrinsic expression in OA reframes it as a joint-autonomous damage amplifier, not merely a bystander of systemic immune infiltration. This distinction matters clinically: it suggests intra-articular MPO suppression could be therapeutic independent of systemic anti-inflammatory strategies. Resveratrol's documented pleiotropic activity — SIRT1 activation, NF-κB suppression, and now direct MPO binding — reinforces its relevance to cartilage biology, though bioavailability remains a persistent translational obstacle. The study is rodent-based and relies heavily on computational predictions, limiting direct clinical inference. Human synovial tissue validation and dose-response characterization are needed. Still, the chondrocyte-MPO axis represents a genuinely underexplored mechanism in OA pathogenesis, making this an incremental but directionally significant contribution to joint longevity research.