Astragaloside IV Alleviates Osteoarthritis by Inhibiting Chondrocyte Ferroptosis via the p53/SLC7A11/GPX4 Axis.

PURPOSE: Osteoarthritis (OA) is a chronic joint disease characterized by articular cartilage damage. Astragaloside IV (AS-IV), a cyclic triterpenoid saponin extracted from Astragalus membranaceus, exhibits antioxidant and cartilage-protective activities. However, its mechanism of action in OA remains unclear. To study the efficacy and mechanism of action of AS-IV in the treatment of OA. METHODS: In the SW1353 cell model treated with IL-1β, cell viability was detected by CCK-8, and the ultrastructure of mitochondria was observed by transmission electron microscopy. Multiple methods such as flow cytometry, immunofluorescence, Western blotting, and fluorescent probe method were used to evaluate the effects of AS-IV on chondrocyte ferroptosis and extracellular matrix degradation, and the results were verified by rescue experiments. An OA rat model was established, and multiple methods such as histopathology were used to evaluate the therapeutic effect of AS-IV on OA cartilage injury. RESULTS: In vitro experiments have shown that IL-1β can induce ferroptosis in chondrocytes. Overexpression of p53 promotes ferroptosis in chondrocytes and exacerbates the progression of OA. AS-IV can downregulate the expression of p53 and MMP13, while upregulating the expression of SLC7A11, GPX4, SOX9, Col II, and GSH. Additionally, AS-IV reduces intracellular levels of ROS, MDA, and Fe(2+). In an OA rat model, AS-IV significantly reduces the Osteoarthritis Research Society International (OARSI) score and Mankin score, alleviating cartilage damage. Furthermore, AS-IV inhibits extracellular matrix degradation and lipid peroxidation in cartilage tissue. CONCLUSION: AS-IV inhibits chondrocyte ferroptosis by modulating the p53/SLC7A11/GPX4 axis, thereby alleviating cartilage damage and OA. This suggests that AS-IV has therapeutic potential for OA treatment.