Wine‐Processed <i>Cornus officinalis</i> Ameliorates Osteoarthritis via Modulating <scp>M1</scp> / <scp>M2</scp> Macrophage Polarization

Cornus officinalis (CO) is a traditional herbal medicine renowned in Traditional Chinese Medicine (TCM) for its properties of tonifying the liver and kidney and replenishing vital essence. Meanwhile, wine-processed CO (pCO) exhibits superior pharmacological effects, including anti-inflammatory, antioxidant and anti-fibrotic activities. However, the immunomodulatory mechanism of pCO in osteoarthritis (OA) remains unclear. OA models were established in Sprague-Dawley rats via anterior cruciate ligament transection (ACLT). Network pharmacology and molecular docking were used to predict potential targets of pCO against OA, which were validated through behavioural tests, histomorphological staining and immunohistochemistry. HPLC-Q-Orbitrap-MS analysis identified key differential compounds between raw and wine-processed CO. The immunomodulatory effects of pCO were further confirmed by ELISA, immunofluorescence staining and RT-qPCR. pCO ameliorated joint pain and cartilage damage in OA rats by reducing pro-inflammatory factors (IL-1β, COX-2, IL-12) and promoting anti-inflammatory factors (IL-10, TGF-β1) in serum and synovial fluid. Network pharmacology combined with in vivo experiments revealed that pCO attenuated chondrocyte degeneration and apoptosis. Mechanistically, pCO modulated macrophage polarization by suppressing the M1 phenotype (CD86, iNOS) while promoting the M2 phenotype (CD206, TGF-β1, Arg-1), which revealed the key mechanism underlying its therapeutic effects against OA. pCO improved joint function and attenuated cartilage degeneration and synovial lesions, which were associated with the promotion of articular cartilage protection via the modulation of M1/M2 macrophage polarization.