Targeting the macrophage mechanosensing regulator CKAP4 accelerates the inflammatory-to-proliferative transition in...

Wound healing requires a timely transition from inflammation to proliferation, yet chronic wounds often stall in prolonged inflammation. An unresolved question is how physical cues in injured tissue influence macrophages to orchestrate this transition. Here, we find that loss of cytoskeleton-associated protein 4 (CKAP4) in macrophages accelerates wound closure and inflammation resolution in mice. CKAP4-deficient wounds exit the inflammatory state earlier, show higher expression of reparative genes, and promote faster angiogenesis and tissue regrowth. Mechanistically, CKAP4 binds Talin1 to restrain adhesion-associated signaling and STAT6 nuclear translocation. Its deficiency heightens macrophage sensitivity to matrix stiffness, triggering cytoskeletal remodeling and a pro-regenerative program at lower stiffness thresholds. In a diabetic wound model, local silencing of Ckap4 in macrophages restores their mechanoresponsiveness, advances the inflammation-to-proliferation transition, and improves healing. Thus, CKAP4 acts as a negative regulator of macrophage mechanosensing, and targeting this pathway offers a mechanotherapeutic avenue for wound treatment.