Hyperglycemia Exacerbates Osteoarthritis through CD11b Lactylation-Mediated Impairment of Macrophage Efferocytosis

Osteoarthritis (OA) and diabetes predominantly affect middle-aged and elderly populations, with OA patients frequently presenting with comorbid diabetes. Despite evidence that diabetes aggravates OA progression, underlying mechanisms remain elusive. Here, we demonstrate that hyperglycemia exacerbates OA progression through CD11b lactylation-mediated impairment of macrophage efferocytosis. Mechanistically, hyperglycemia enhances glycolysis in synovial macrophages, leading to lactate accumulation and CD11b K575 lactylation. This post-translational modification alters CD11b protein conformation, impairing recognition of apoptotic cells and compromising synovial macrophage efferocytosis, thereby exacerbating inflammation and accelerating OA progression. Additionally, we identify CBP as a lactylation transferase whose targeted knockdown in synovial macrophages effectively reduces lactylation levels, restores efferocytosis function, and delays hyperglycemia-associated OA progression. Collectively, our findings elucidate the molecular mechanism by which hyperglycemia aggravates OA and suggest that targeting CBP represents a potential therapeutic strategy for mitigating hyperglycemia-associated OA.