Metabolic stress and macrophage efferocytosis in osteoarthritis: mechanisms and therapeutic implications

Metabolic disturbances contribute to osteoarthritis through mechanisms that extend beyond increased mechanical loading, yet their effects on inflammatory resolution remain incompletely understood. Macrophage efferocytosis—the recognition, engulfment, and degradation of apoptotic cells—provides a potential link between metabolic stress and persistent synovitis. This Mini Review examines how obesity and hyperglycemia disrupt synovial macrophage clearance and evaluates the rationale for therapeutic restoration. Human observations and experimental osteoarthritis studies implicate reduced growth arrest-specific 6 signaling and hyperglycemia-associated CD11b lactylation in defective apoptotic-cell recognition and uptake. Complementary evidence from other inflammatory conditions identifies membrane trafficking, mitochondrial adaptation, and lysosomal cargo processing as additional determinants of clearance competence. Importantly, glycolysis and lactate have context-dependent effects: although lactylation can impair recognition, adaptive lactate signaling supports repeated engulfment and expansion of pro-resolving macrophages. This distinction challenges indiscriminate glycolytic inhibition and favors interventions matched to the affected clearance step. Defective efferocytosis may amplify synovitis through persistence of cellular debris and loss of resolution-promoting signals, thereby creating an environment unfavorable to cartilage homeostasis. Emerging receptor-directed, metabolic, and intra-articular delivery strategies offer opportunities to restore clearance, but clinical validation remains necessary. Translation will require identification of susceptible macrophage populations, functional assessment of the complete efferocytic process, and demonstration that clearance recovery mediates meaningful improvements in joint structure and symptoms.