MIF-CD74 orchestrates synovial macrophage metabolic-inflammatory reprogramming by ENO2 interaction to drive osteoarthritis pathogenesis.

A pathogenic CD74+ macrophage subset expands in murine synovium and human OA tissues, localizing at the synovial-cartilage interface and depending on glycolysis to sustain inflammation.

• Why it matters: Synovitis drives osteoarthritis progression, but the cellular and molecular mechanisms maintaining inflammatory circuits in the synovium are not fully understood.
• What they did: Time-resolved single-cell RNA sequencing in murine synovium and spatial transcriptomics in human OA identified CD74+ macrophages; multiomics and mechanistic work showed CD74 interacts with ENO2 to promote nuclear HIF-1α/β-catenin dimers and coactivate glycolytic and inflammatory programs.
• The result: Genetic ablation of CD74 in myeloid cells or pharmacological blockade mitigated synovitis and cartilage degradation in murine OA models, and synovium-targeted PcLNPs delivering CD74 siRNA attenuated inflammatory and glycolytic phenotypes and ameliorated OA progression in vivo.