Ginsenoside Rg3 attenuates osteoarthritis progression by modulating the Nrf2-mediated autophagy pathway

Purpose Osteoarthritis (OA) is a chronic and progressive joint disorder characterized by persistent inflammation, extracellular matrix (ECM) disruption, and chondrocyte apoptosis. This study aimed to investigate the protective effects of ginsenoside Rg3 (Rg3), a natural steroidal saponin from Panax ginseng, on OA and to elucidate its underlying molecular mechanisms.Methods The effects of Rg3 were evaluated using a combination of network pharmacology, molecular docking, and experimental validation in vitro and in vivo. IL-1β–stimulated chondrocytes and a mouse OA model induced by destabilization of the medial meniscus (DMM) served as experimental platforms. Inflammatory mediators, ECM-associated markers, and proteins related to apoptosis and autophagy were analyzed by qPCR, Western blot, immunofluorescence, and flow cytometry. Molecular docking was performed to predict potential targets and signaling pathways involved.Results Rg3 significantly inhibited IL-1β–induced inflammation by downregulating iNOS, COX-2, and IL-6 expression. It alleviated ECM degradation through suppression of MMP-13 and ADAMTS-5 and preservation of collagen II and aggrecan. Rg3 reduced chondrocyte apoptosis via modulation of Bcl-2, Bax, and cleaved caspase-3, while enhancing autophagic activity by regulating LC3-II, ATG7, and Beclin1. Molecular docking and protein analyses indicated activation of the Nrf2/HO-1 pathway, implicating its role in the observed protective effects.Conclusions Rg3 exerts therapeutic effects in OA by activating Nrf2/HO-1 signaling, promoting autophagy, inhibiting inflammation, and protecting cartilage from degeneration, highlighting its potential as a candidate for OA management.