Inhibiting Nampt signaling promotes M2 macrophage polarization to enhance bone regeneration in periodontitis

Background Dysregulated macrophage polarization is a fundamental cause of bone loss in periodontitis. However, the role of nicotinamide phosphoribosyltransferase (NAMPT) in macrophage regulation within periodontitis remains unclear. This study aimed to elucidate the function of NAMPT signaling in macrophage polarization and its effects on periodontal bone regeneration. Methods Single-cell RNA sequencing (scRNA-seq) data from periodontitis tissues were analyzed to characterize NAMPT + macrophages. Murine macrophages (RAW264.7) were treated with the NAMPT inhibitor FK866 or the enzymatic product of NAMPT and NAD + precursor nicotinamide mononucleotide to assess polarization status and were co-cultured with MC3T3-E1 osteoblasts to evaluate osteogenic potential. The therapeutic effects of local FK866 injection were further examined in a ligature-induced rat periodontitis model using micro-computed tomography (micro-CT), hematoxylin-eosin Staining H&E, Tartrate-resistant acid phosphatase (TRAP), and immunofluorescence staining. Results The M2 macrophage subpopulation with low NAMPT expression exhibited strong bone repair–promoting properties. In vitro , FK866 treatment reduced M1 polarization and increased M2 polarization, significantly increasing the macrophage-mediated promotion of mineralization. In vivo , local FK866 administration decreased osteoclast formation and inflammatory infiltration while promoting alveolar bone regeneration mediated by M2 macrophages. Conclusion Inhibition of the NAMPT signaling pathway induces M2 macrophage polarization, alleviating inflammation and facilitating osteogenesis within periodontal bone defects. These findings identify NAMPT as a promising therapeutic target for modulating the host response and promoting bone regeneration in periodontitis.