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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月26日

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

摘要

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.