Abstract
Diabetic periodontitis is a refractory complication of diabetes with limited therapeutic options. Here, we identify excessive fibrin deposition as a key perpetuator of chronic inflammation in diabetic periodontitis. Through single-cell transcriptomics and functional studies, we demonstrate that fibrin-Mac-1 interaction promotes M1 macrophage polarization via the NF-κB pathway, amplifying gamma delta T (γδ T) cell-derived IL-17A production and disrupting epithelial barrier integrity. Targeting this axis with a novel fibrin-blocking peptide (377 P) suppressed M1 macrophage and IL-17A signaling, restored claudin-1–dependent tight junctions, and promoted periodontal bone healing in diabetic mice. Clinical validation in human periodontal tissues revealed fibrin-M1 macrophage co-localization correlating with disease severity. Our findings establish fibrin as a druggable target for diabetic complications and propose 377 P as a translatable therapy to resolve chronic mucosal inflammation.