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Osteoarthritis (OA) is a heterogeneous disease that is consistently difficult to treat due to the complexity of the regulatory network involved in OA pathogenesis, especially in terms of cartilage degeneration. As a C-2 epimer of glucose, d-mannose can alleviate bone loss and repress immunopathology by upregulating regulatory T cells; however, the role of d-mannose in OA-related cartilage degeneration remains unknown. In this study, we investigated the chondroprotective effect of d-mannose in vitro and in vivo on OA. We found that incuba