METTL3-mediated m6A modifications of NLRP3 accelerate alveolar bone resorption through enhancing macrophage pyroptosis.

Periodontitis (PD) is twice as prevalent in diabetics compared to nondiabetics, and diabetes-associated PD is characterized by increased inflammation and aggravated tissue damage. Pyroptosis has recently been implicated in diabetes-associated PD; however, the underlying mechanisms remain largely unknown, resulting in a lack of effective treatments. In this study, we investigated the role of methyltransferase-like 3 (METTL3) in macrophage pyroptosis and found that it inhibits the osteogenic differentiation of osteoblasts via pyroptotic macrophages in a diabetes-associated periodontitis mouse model. Further analysis and validation revealed that nod-like receptor family pyrin domain-containing 3 (NLRP3) is a target of METTL3, with its mRNA stability regulated through a binding of insulin-like growth factor 2 binding protein 3 (IGF2BP3)-dependent pathway. Additionally, local injection of adeno-associated virus 9 (AAV9) demonstrated that METTL3 deficiency in macrophages significantly ameliorates periodontal inflammation and alveolar bone loss in diabetes-associated PD mice. Collectively, our findings indicate that METTL3-mediated modulation of NLRP3 expression is a crucial factor in macrophage pyroptosis during diabetes-associated PD progression. This suggests that the METTL3/IGF2BP3/NLRP3 axis is a novel and promising target for the improvement of periodental inflammation and alveolar bone loss in diabetes-associated PD.