Puerarin Attenuates Osteoarthritis via Multi-Target Regulation of Inflammation, Apoptosis, and ECM Degradation

Osteoarthritis (OA) is a degenerative joint disease characterised by cartilage breakdown, leading to pain and reduced quality of life. This study aims to investigate the therapeutic potential of Puerarin (PUE), a natural compound derived from Pueraria lobata, in modulating OA progression. Employing a multifaceted approach that included bioinformatics analysis, molecular docking, in vitro assays, and in vivo experiments, we identified 57 overlapping targets between PUE and OA-related genes, suggesting a multi-target interaction model. Our findings revealed that PUE effectively inhibited inflammatory cytokine production and protected chondrocytes from apoptosis at non-cytotoxic concentrations (5 and 10 μM), promoting extracellular matrix synthesis by reversing IL-1β-induced degradation of Aggrecan and Collagen II while reducing MMP-13 and ADAMTS5 expression. Furthermore, PUE was shown to attenuate IL-1β-induced apoptosis by restoring BCL-2 levels and decreasing cleaved caspase-3 levels. In vivo, PUE administration in a destabilisation of the medial meniscus (DMM) mouse model significantly slowed OA progression, preserving cartilage structure and reducing osteophyte formation. Moreover, PUE activated the PI3K-AKT signalling pathway, underscoring its anti-inflammatory and anti-apoptotic mechanisms. Collectively, these results support Puerarin's potential as a disease-modifying agent in OA treatment, warranting further clinical exploration and consideration of its application in combination therapies to enhance cartilage protection and repair.