Nrf2 promotes NLRP3 inflammasome assembly and activation by Klf9-TXNIP axis.

IF 10.4 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2026-06-26 DOI:10.1038/s41420-026-03219-3

You Zhou, Hui You, Xin-Yu Xia, Ke Zhang, Hui Jiang, Liang-Hua Liu, Hong-Ping Liu, Ming-Cai Zhao, Su-Yu He

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引用次数: 0

Abstract

NLRP3 inflammasome activation shows a crucial role in the innate immune response that triggers inflammation. Activation is controlled by two sequential steps: a priming step, followed by an assembly step. Nrf2 has been shown to promote NLRP3 inflammasome activation; however, the underlying mechanisms remain elusive. This study identifies Nrf2 as an encourager of NLRP3 inflammasome activation. We show that Nrf2 inhibition suppresses NLRP3 inflammasome activation in macrophages, including THP-1 cells and BMDMs. In addition, Nrf2 facilitates NLRP3 inflammasome assembly. Mechanically, Nrf2 increases Klf9 expression by binding to the Klf9 promoter. Klf9 stabilizes TXNIP by deubiquitination, thereby enhancing the TXNIP-NLRP3 interaction, which is required for NLRP3 inflammasome assembly and full activation. Finally, Nrf2 deficiency exerts a protective effect and alleviates NLRP3 inflammasome activation in mouse models of DSS-induced colitis and MSU crystals-induced acute gouty arthritis. Our study reveals a novel regulatory mechanism of NLRP3 inflammasome by Nrf2 and indicates Nrf2 may be a promising target for treating NLRP3 inflammasome-driven diseases.

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Nrf2通过Klf9-TXNIP轴促进NLRP3炎性体的组装和激活。

NLRP3炎性小体的激活在触发炎症的先天免疫反应中起着至关重要的作用。激活由两个连续步骤控制：启动步骤，然后是组装步骤。Nrf2已被证明可促进NLRP3炎性体的激活；然而，潜在的机制仍然难以捉摸。本研究确定Nrf2是NLRP3炎性体激活的促进因子。我们发现Nrf2抑制可抑制巨噬细胞（包括THP-1细胞和BMDMs）中NLRP3炎性体的激活。此外，Nrf2促进NLRP3炎性小体的组装。机械地，Nrf2通过结合Klf9启动子来增加Klf9的表达。Klf9通过去泛素化稳定TXNIP，从而增强TXNIP-NLRP3的相互作用，这是NLRP3炎症小体组装和充分激活所必需的。最后，Nrf2缺乏在dss诱导的结肠炎和MSU晶体诱导的急性痛风性关节炎小鼠模型中发挥保护作用，减轻NLRP3炎性体的激活。我们的研究揭示了Nrf2对NLRP3炎症小体的一种新的调控机制，并提示Nrf2可能是治疗NLRP3炎症小体驱动疾病的一个有希望的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.