METTL3-mediated m6A on nascent RNA coordinates translational and transcriptional programs to activate the NLRP3 inflammasome in macrophages

Summary NLRP3 inflammasome activation requires both transcriptional priming and complex assembly, but how RNA m 6 A methylation coordinates these steps remains unclear. Here, we show that m 6 A levels increase during macrophage NLRP3 inflammasome activation and that METTL3 loss suppresses this activation. Myeloid-specific Mettl3 knockout mice display reduced inflammation and improved metabolic outcomes in lipopolysaccharide (LPS)-induced sepsis, monosodium urate (MSU)-induced arthritis, and diet-induced obesity. Integrated chromatin-associated RNA sequencing (chrRNA-seq), kethoxal-assisted single-stranded DNA sequencing (KAS-seq), and chrRNA-methylated RNA immunoprecipitation (MeRIP)-seq analyses show that METTL3 installs m 6 A co-transcriptionally on nascent Jak1 , Nlrp3 , and Il1β RNAs and that METTL3 regulates dynamic transcription and chromatin accessibility while selectively maintaining Nlrp3 / Il1β transcription. YTHDF1-driven translation of Jak1 activates the JAK1-STAT3-C/EBPβ axis to initiate Nlrp3 / Il1β transcription, and m 6 A-YTHDF1 translation of Nlrp3 / Il1β amplifies protein output, forming a coupled transcriptional-translational circuit. Pharmacologic STAT3 inhibition and METTL3 catalytic rescue validate this pathway and identify METTL3-mediated m 6 A as a therapeutic target for inflammasome-driven diseases.