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<p>Excessive activation of the NLRP3 inflammasome drives the pathogenesis of diverse inflammatory diseases. However, the clinical application of NLRP3 inflammasome inhibitors remains a significant challenge. Here, we screen a natural product library of 126 compounds and identify Nimbolide (NIM), a triterpenoid from <i>Azadirachta indica</i>, as a potent suppressor of IL-1β secretion. Cellular studies reveal that NIM dose-dependently suppresses NLRP3 inflammasome activation, thereby the blocking Caspase-1 cleavage, IL-1β release, and pyroptosis in macrophages. Importantly, NIM exhibits high selectivity for NLRP3 inflammasome, showing no significant inhibition of non-NLRP3 inflammasomes. Mechanistically, NIM exerts dual effects by suppressing both NF-κB-dependent priming and NLRP3 inflammasome assembly. Molecular investigations reveal that NIM directly targets the Lys565 within the NLRP3 NACHT domain, thereby hindering inflammasome assembly. Using male C57BL/6 and <i>Nlrp3</i>-knockout mice, we demonstrate that NIM administration effectively alleviates inflammation and pathological damage in models of LPS-induced acute respiratory distress syndrome (ARDS) and DSS-induced ulcerative colitis. Collectively, our findings highlight NIM as a natural inhibitor that targets both the priming and assembly phases of NLRP3 inflammasome activation, offering a dual-modulatory strategy for treating NLRP3-driven inflammatory disorder.</p><p></p>

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Nimbolide ameliorates ARDS and ulcerative colitis by disrupting NLRP3 inflammasome activation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月11日

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  • Haowen Xu,
  • Yao Lin,
  • Weiwei Luo,
  • Shiying Sheng,
  • Yongan Xu,
  • Zhaocai Zhang

摘要

Excessive activation of the NLRP3 inflammasome drives the pathogenesis of diverse inflammatory diseases. However, the clinical application of NLRP3 inflammasome inhibitors remains a significant challenge. Here, we screen a natural product library of 126 compounds and identify Nimbolide (NIM), a triterpenoid from Azadirachta indica, as a potent suppressor of IL-1β secretion. Cellular studies reveal that NIM dose-dependently suppresses NLRP3 inflammasome activation, thereby the blocking Caspase-1 cleavage, IL-1β release, and pyroptosis in macrophages. Importantly, NIM exhibits high selectivity for NLRP3 inflammasome, showing no significant inhibition of non-NLRP3 inflammasomes. Mechanistically, NIM exerts dual effects by suppressing both NF-κB-dependent priming and NLRP3 inflammasome assembly. Molecular investigations reveal that NIM directly targets the Lys565 within the NLRP3 NACHT domain, thereby hindering inflammasome assembly. Using male C57BL/6 and Nlrp3-knockout mice, we demonstrate that NIM administration effectively alleviates inflammation and pathological damage in models of LPS-induced acute respiratory distress syndrome (ARDS) and DSS-induced ulcerative colitis. Collectively, our findings highlight NIM as a natural inhibitor that targets both the priming and assembly phases of NLRP3 inflammasome activation, offering a dual-modulatory strategy for treating NLRP3-driven inflammatory disorder.