Inhibition of METTL3 Alleviates NLRP3 Inflammasome Activation via Increasing Ubiquitination of NEK7

Adv Sci (Weinh). 2024 Jul;11(26):e2308786. doi: 10.1002/advs.202308786. Epub 2024 May 2.


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.

Keywords: METTL3; m6A modification; periodontitis; pyroptosis; small‐molecule inhibitor.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Humans
  • Inflammasomes* / genetics
  • Inflammasomes* / metabolism
  • Methyltransferases* / genetics
  • Methyltransferases* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NIMA-Related Kinases* / genetics
  • NIMA-Related Kinases* / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Periodontitis / drug therapy
  • Periodontitis / genetics
  • Periodontitis / metabolism
  • Ubiquitination* / drug effects
  • Ubiquitination* / genetics


  • NIMA-Related Kinases
  • Methyltransferases
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Mettl3 protein, mouse
  • Nek7 protein, mouse