The study investigates the role of METTL3 in oral mucosal immunity, particularly in periodontitis, a common infectious disease characterized by hyperinflammation and bone resorption. Genetic deletion of Mettl3 is found to alleviate periodontal destruction by suppressing NLRP3 inflammasome activation. Mechanistically, METTL3-mediated m6A modification on TNFAIP3 transcripts leads to their accelerated degradation, which in turn upregulates NLRP3 inflammasome activation and pyroptosis. Accumulating TNFAIP3 facilitates the ubiquitination of NEK7, impairing NLRP3 inflammasome assembly. The study also identifies Coptisine chloride, a natural small-molecule inhibitor of METTL3, which shows therapeutic effects on periodontitis. These findings uncover a novel pathogenic mechanism of METTL3-mediated m6A modifications in periodontitis and suggest METTL3 as a potential therapeutic target.The study investigates the role of METTL3 in oral mucosal immunity, particularly in periodontitis, a common infectious disease characterized by hyperinflammation and bone resorption. Genetic deletion of Mettl3 is found to alleviate periodontal destruction by suppressing NLRP3 inflammasome activation. Mechanistically, METTL3-mediated m6A modification on TNFAIP3 transcripts leads to their accelerated degradation, which in turn upregulates NLRP3 inflammasome activation and pyroptosis. Accumulating TNFAIP3 facilitates the ubiquitination of NEK7, impairing NLRP3 inflammasome assembly. The study also identifies Coptisine chloride, a natural small-molecule inhibitor of METTL3, which shows therapeutic effects on periodontitis. These findings uncover a novel pathogenic mechanism of METTL3-mediated m6A modifications in periodontitis and suggest METTL3 as a potential therapeutic target.