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Updated: Jan 13, 2026

Activation and Measurement of NLRP3 Inflammasome Activity Using IL-1β in Human Monocyte-derived Dendritic Cells
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METTL3-mediated m6A on nascent RNA coordinates translational and transcriptional programs to activate the NLRP3

Jie Fu1, Xin Zong2, Hong Zhang2

  • 1National Engineering Research Center of Green Feeds and Healthy Livestock Industry, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Zhejiang University, Hangzhou 310058, China; Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, Zhejiang University, Hangzhou 310058, China; Zhejiang Key Laboratory of Nutrition and Breeding for High-quality Animal Products, Zhejiang University, Hangzhou 310058, China; Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.

Cell Reports
|January 11, 2026
PubMed

Insights

RNA m6A methylation, regulated by METTL3, is crucial for NLRP3 inflammasome activation. METTL3 loss reduces inflammation and improves metabolic health in various disease models, highlighting its therapeutic potential.

Area of Science:

  • Molecular Biology
  • Immunology
  • Epigenetics

Background:

  • NLRP3 inflammasome activation requires priming and assembly.
  • The role of RNA m6A methylation in coordinating these steps is not well understood.

Purpose of the Study:

  • To investigate how RNA m6A methylation, specifically by METTL3, regulates NLRP3 inflammasome activation.
  • To explore the therapeutic potential of targeting METTL3-mediated m6A in inflammasome-driven diseases.

Main Methods:

  • Myeloid-specific Mettl3 knockout mice models.
  • Lipopolysaccharide (LPS)-induced sepsis, monosodium urate (MSU)-induced arthritis, and diet-induced obesity models.
  • Chromatin-associated RNA sequencing (chrRNA-seq), kethoxal-assisted single-stranded DNA sequencing (KAS-seq), and MeRIP-seq.
  • Pharmacologic STAT3 inhibition and METTL3 catalytic rescue.

Main Results:

  • m6A levels increase during NLRP3 inflammasome activation; METTL3 loss suppresses activation.
  • METTL3 installs m6A on nascent Jak1, Nlrp3, and Il1β RNAs, regulating transcription and chromatin accessibility.
  • A coupled transcriptional-translational circuit involving JAK1-STAT3-C/EBPβ and m6A-YTHDF1 amplifies Nlrp3/Il1β expression.
  • METTL3 inhibition reduces inflammation and improves metabolic outcomes in vivo.

Conclusions:

  • METTL3-mediated m6A is a key regulator of NLRP3 inflammasome activation through a coupled transcriptional-translational circuit.
  • Targeting METTL3-mediated m6A offers a promising therapeutic strategy for inflammasome-driven diseases.
Keywords:
CP: ImmunologyCP: Molecular biologyMETTL3NLRP3 inflammasomem(6)A methylationmacrophagetranscriptiontranslation

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