Pterostilbene Attenuates Osteoarthritis Progression Through p53-Dependent Autophagy Activation: Evidence from Network Pharmacology and Experimental Validation

Background and Purpose: Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by cartilage deterioration and pain. Autophagy dysfunction represents a critical mechanism in OA pathogenesis. This study aimed to investigate the molecular mechanism by which pterostilbene (PT) protects chondrocytes through autophagy activation and its potential therapeutic application in OA. Methods: Network pharmacology analysis identified key targets and signaling pathways related to PT and OA. In vitro, IL-1β-stimulated C28/I2 chondrocytes were used to evaluate PT's effects on extracellular matrix metabolism, autophagy activity, and underlying mechanisms, while p53 transcriptional inhibitor pifithrin-α verified mechanism specificity. In vivo, a monosodium iodoacetate-induced OA rat model validated PT's therapeutic efficacy. Results: Network pharmacology identified 238 shared targets between PT and OA, predominantly enriched in p53 signaling and autophagy-related pathways. PT significantly ameliorated IL-1β-induced ECM metabolic imbalance by promoting cartilage-specific proteins while inhibiting matrix-degrading enzymes. PT enhanced autophagy through promoting p53 nuclear accumulation, activating AMPK phosphorylation, and inhibiting mTOR. In vivo, PT treatment significantly improved joint pathological changes (OARSI scores decreased from 14.9±0.9 to 7.3±0.7, P<0.001) and enhanced cartilage autophagy. Autophagy inhibitor 3MA partially reversed PT's protective effects. Conclusion: PT protects chondrocytes from degenerative changes by promoting p53 nuclear accumulation and regulating AMPK/mTOR signaling to activate autophagy, providing evidence for PT as a potential OA therapeutic agent.