Jiao Cao

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.

Exosome-based therapy is emerging as a promising strategy to promote bone regeneration due to exosomal bioactive cargos, among which circular RNA (circRNA) has recently been recognized as the key effector. The role of exosomal circRNA derived from bone marrow mesenchymal stem cells (BMSCs) has not been well-defined. The present study aimed to clarify the regulatory function and molecular mechanism of BMSC-derived exosomal circRNA in osteogenesis. Exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) were isolated and identified. BMSC-Exos’ pro-osteogenic effect on MC3T3-E1 cells was validated by alkaline phosphatase (ALP) activity and Alizarin Red staining. Through bioinformatic analysis and molecular experiments, circHIPK3 was selected and verified as the key circRNA of BMSC-Exos to promote osteoblast differentiation of MC3T3-E1 cells. Mechanistically, circHIPK3 acted as an miR-29a-5p sponge and functioned in mitophagy via targeting miR-29a-5p and PINK1. Additionally, we showed that the mitophagy level of MC3T3-E1 cells were mediated by BMSC-Exos, which promoted the osteogenic differentiation. Collectively, our results revealed an important role for BMSC-derived exosomal circHIPK3 in osteogenesis. These findings provide a potentially effective therapeutic strategy for bone regeneration.