Semaglutide alleviates osteoarthritis independent of weight loss via GLP-1R–mediated activation of autophagy through AKT/mTOR inhibition

Objective: The development of osteoarthritis (OA) is closely associated with systemic metabolic disorders, yet there remains a lack of disease-modifying therapeutic strategies that simultaneously target metabolic abnormalities and inflammatory responses. This study aims to systematically evaluate the therapeutic potential of semaglutide, a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist used for diabetes management, in OA and to elucidate its underlying molecular mechanisms. Methods: . RNA sequencing was performed to explore the regulator effects of semaglutide on extracellular matrix metabolism, associated signaling pathways, and autophagy in IL-1β-stimulated primary mouse chondrocytes. To verify the functional loss, the GLP-1R antagonist Exendin (9-39) and the autophagy inhibitor Bafilomycin A1 were employed. Results: gene deficiency exacerbated cartilage degeneration and bone structural damage, indicating that GLP-1R signaling is indispensable for maintaining cartilage homeostasis. Mechanistically, semaglutide inhibited the AKT/mTOR pathway through GLP-1R activation, thereby reversing IL-1β- and DMM-induced autophagy suppression and restoring the balance of extracellular matrix metabolism in chondrocytes. Conclusion: : This study demonstrates, for the first time, that semaglutide exerts protective effects against OA independent of weight loss by directly activating chondrocyte GLP-1R, inhibiting the AKT/mTOR pathway, and enhancing autophagy. These findings provide robust preclinical evidence supporting the repositioning of semaglutide as a disease-modifying therapy, particularly for patients with OA and comorbid metabolic disorders such as diabetes. Furthermore, they indicate that GLP-1R and its downstream signaling pathways may represent potential therapeutic targets for OA, thereby opening new avenues for drug repurposing and precision interventions in metabolic OA.