Hyperglycemia exacerbates osteoarthritis by impairing macrophage efferocytosis through modulation of CD11b lactylation

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, the underlying mechanisms are not fully understood. Here, we demonstrate that hyperglycaemia exacerbates OA progression through CD11b lactylation-mediated impairment of macrophage efferocytosis. Mechanistically, hyperglycemia enhances glycolysis in synovial macrophages, leading to lactate accumulation and CD11b lactylation at K575. This post-translational modification alters the conformation of the CD11b protein, impairing recognition of apoptotic cells and compromising synovial macrophage efferocytosis, thereby exacerbating inflammation and accelerating OA progression. Additionally, we identify CBP as a lactyl-transferase whose targeted knockdown in synovial macrophages effectively reduces lactylation levels, restores efferocytosis function, and delays hyperglycemia-associated OA progression. Collectively, our findings represent an important molecular mechanism by which hyperglycemia aggravates OA and suggest that targeting CBP could be utilized as therapeutic strategy for mitigating hyperglycemia-associated OA.