Molecular mechanisms of NLRP3 inflammasome activation

Exp Mol Med. 2026 Mar;58(3):650-663. doi: 10.1038/s12276-026-01656-9.

Hyo Jung Shin ¹, In Soo Kim ² ³ ⁴, Jin Kyung Kim ⁵, Eun-Kyeong Jo ⁶ ⁷ ⁸

Affiliations

1 Department of Biochemistry and Cell Biology, Eulji University School of Medicine, Daejeon, Republic of Korea.
2 Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea.
3 Department of Pharmacology, Chungnam National University College of Medicine, Daejeon, Republic of Korea.
4 Biomedical Research Institute, Chungnam National University Hospital, Daejeon, Republic of Korea.
5 Department of Microbiology, Keimyung University School of Medicine, Daegu, Republic of Korea.
6 Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea. [email protected].
7 Biomedical Research Institute, Chungnam National University Hospital, Daejeon, Republic of Korea. [email protected].
8 Department of Microbiology, Chungnam National University College of Medicine, Daejeon, Republic of Korea. [email protected].

PMID: 41876821 DOI: 10.1038/s12276-026-01656-9

Abstract

The NOD-like Receptor protein 3 (NLRP3) inflammasome is among the most extensively studied multiprotein complexes, driving the maturation of pro-interleukin-1β (pro-IL-1β) and pro-IL-18-into their active forms, IL-1β and IL-18, respectively. The activation of the NLRP3 inflammasome is a multifaceted process triggered by a diverse array of stimuli, including pathogens, environmental particles and endogenous stress signals. Previously, NLRP3 inflammasome activation was considered a straightforward two-step process: signal 1, which induces the expression of NLRP3 and proinflammatory cytokines, and signal 2, which promotes the assembly of the inflammasome complex through mechanisms such as ionic fluxes, mitochondrial dysfunction and lysosomal damage. However, more intricate mechanisms have now been elucidated, particularly regarding the 'priming' step, involving the regulation of its post-translational modifications. Recent studies have comprehensively identified the core components of the NLRP3 inflammasome complex, its interacting complex partners, and regulatory mechanisms. Here we delve into the current understanding of the NLRP3 inflammasome activation mechanisms and explore its regulatory networks. Enhanced insights into the molecular and signaling pathways controlling this specialized inflammasome activation may pave the way for novel applications of NLRP3 inflammasome regulation to advance human health and prevent numerous diseases linked to the NLRP3 inflammasome.

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