Bergapten Alleviates Periodontitis by Suppressing NLRP3 Inflammasome Activation via Mitophagy-Induced Disruption of NEK7-NLRP3 Interaction

Abstract

Periodontitis is a prevalent chronic inflammatory disease characterized by gingival inflammation and progressive alveolar bone loss. The NLRP3 inflammasome functions as a molecular mediator that drives its pathogenesis. Bergapten (BeG), a natural furanocoumarin, exhibits anti-inflammatory properties and bone-protective effects. This study demonstrates that BeG alleviates experimental periodontitis in mice by inhibiting the NLRP3 inflammasome. Mechanistically, BeG does not affect NLRP3 priming, dispersed trans-Golgi network (dTGN) localization, or oligomerization; instead, it induces mitophagy by inhibiting the AKT–mTOR axis and consequently suppresses the mtROS-dependent NEK7–NLRP3 interaction. Notably, BeG also suppressed cytosolic release of oxidized mitochondrial DNA (ox-mtDNA), a known endogenous ligand for NLRP3. This effect was attributed to BeG-mediated inhibition of NLRP3 activation, likely via blockade of GSDMD-NT mitochondrial localization. These findings deepen our understanding of the anti-inflammatory mechanisms of BeG and position it as a promising candidate for periodontitis treatment.