N6‐methyladenosine (m6A) modification, installed by METTL3‐METTL14 complex, is abundant and critical in eukaryotic mRNA. However, its role in oral mucosal immunity remains ambiguous. Periodontitis is a special but prevalent infectious disease characterized as hyperinflammation of oral mucosa and bone resorption. Here, it is reported that genetic deletion of Mettl3 alleviates periodontal destruction via suppressing NLRP3 inflammasome activation. Mechanistically, the stability of TNFAIP3 (also known as A20) transcript is significantly attenuated upon m6A modification. When silencing METTL3, accumulated TNFAIP3 functioning as a ubiquitin‐editing enzyme facilitates the ubiquitination of NEK7 [NIMA (never in mitosis gene a)‐related kinase 7], and subsequently impairs NLRP3 inflammasome assembly. Furtherly, Coptisine chloride, a natural small‐molecule, is discovered as a novel METTL3 inhibitor and performs therapeutic effect on periodontitis. The study unveils a previously unknown pathogenic mechanism of METTL3‐mediated m6A modifications in periodontitis and indicates METTL3 as a potential therapeutic target.

中文翻译：

---

METTL3 的抑制通过增加 NEK7 的泛素化来减轻 NLRP3 炎症小体的激活

N6-甲基腺苷（m6A) 由 METTL3-METTL14 复合物安装的修饰在真核 mRNA 中丰富且关键。然而，它在口腔粘膜免疫中的作用仍然不明确。牙周炎是一种特殊但普遍的感染性疾病，其特征是口腔粘膜过度炎症和骨吸收。据报道，基因缺失梅特尔3通过抑制 NLRP3 炎性体激活来减轻牙周破坏。从机制上讲，稳定性TNFAIP3（也称为 A20）转录物在 m 时显着减弱6一个修改。当沉默 METTL3 时，积累的 TNFAIP3 作为泛素编辑酶促进 NEK7 [NIMA（不在有丝分裂基因 a）相关激酶 7] 泛素化，并随后损害 NLRP3 炎性体组装。此外，天然小分子氯化黄连碱被发现是一种新型 METTL3 抑制剂，对牙周炎具有治疗作用。该研究揭示了 METTL3 介导的 m 的先前未知的致病机制6牙周炎的改变表明 METTL3 作为潜在的治疗靶点。