Inhibition of METTL3 alleviates NLRP3 inflammasome activation via increasing ubiquitination of NEK7. Periodontitis, a common oral disease, is characterized by hyperinflammation and bone resorption. This study shows that genetic deletion of Mettl3 alleviates periodontal destruction by suppressing NLRP3 inflammasome activation. Mechanistically, METTL3 deficiency reduces the degradation of TNFAIP3 transcripts, leading to increased ubiquitination of NEK7 and impaired NLRP3 inflammasome assembly. A natural small-molecule inhibitor, Coptisine chloride, was identified as a novel METTL3 inhibitor with therapeutic effects on periodontitis. The study reveals a previously unknown pathogenic mechanism of METTL3-mediated m⁶A modifications in periodontitis and indicates METTL3 as a potential therapeutic target. METTL3-mediated m⁶A modification regulates TNFAIP3 degradation, which in turn affects NEK7 ubiquitination and NLRP3 inflammasome activation. TNFAIP3 inhibits pyroptosis by ubiquitinating NEK7. Disulfiram, a pyroptosis inhibitor, alleviates periodontitis in mice. Coptisine chloride reduces NEK7 expression and suppresses NLRP3 inflammasome activation, thereby ameliorating periodontitis. The study highlights the role of METTL3 in periodontitis and suggests that targeting METTL3 could be a promising therapeutic strategy for periodontal diseases.Inhibition of METTL3 alleviates NLRP3 inflammasome activation via increasing ubiquitination of NEK7. Periodontitis, a common oral disease, is characterized by hyperinflammation and bone resorption. This study shows that genetic deletion of Mettl3 alleviates periodontal destruction by suppressing NLRP3 inflammasome activation. Mechanistically, METTL3 deficiency reduces the degradation of TNFAIP3 transcripts, leading to increased ubiquitination of NEK7 and impaired NLRP3 inflammasome assembly. A natural small-molecule inhibitor, Coptisine chloride, was identified as a novel METTL3 inhibitor with therapeutic effects on periodontitis. The study reveals a previously unknown pathogenic mechanism of METTL3-mediated m⁶A modifications in periodontitis and indicates METTL3 as a potential therapeutic target. METTL3-mediated m⁶A modification regulates TNFAIP3 degradation, which in turn affects NEK7 ubiquitination and NLRP3 inflammasome activation. TNFAIP3 inhibits pyroptosis by ubiquitinating NEK7. Disulfiram, a pyroptosis inhibitor, alleviates periodontitis in mice. Coptisine chloride reduces NEK7 expression and suppresses NLRP3 inflammasome activation, thereby ameliorating periodontitis. The study highlights the role of METTL3 in periodontitis and suggests that targeting METTL3 could be a promising therapeutic strategy for periodontal diseases.