INF39 is a nontoxic, irreversible, acrylate-based NLRP3 inhibitor and a further optimization of ethyl 2-((2-chlorophenyl) hydroxyl) methyl) acrylate (INF4E). However, the detail mechanism and the direct target of its anti-inflammatory activity is not clear. Here, we show that INF39 is a specific inhibitor for NLRP3 inflammasome activation. INF39 specifically suppresses NLRP3 activation but not the NLRC4 or AIM2 inflammasomes. INF39 has no effect on K+ efflux, ROS generation or mitochondrial membrane potential, which are the upstream events of NLRP3 inflammasome activation. In addition, INF39 has no direct inhibitory effect on GSDMD, which is the downstream event of inflammasomes. More importantly, INF39 inhibits the interaction of NEK7-NLRP3, and subsequently inhibits interaction of NLRP3-NLRP3, NLRP3-ASC, ASC oligomerization and speckle formation. Altogether, our study unveils a deeper anti-inflammatory mechanism for INF39 and suggests it could serve as a lead for developing novel therapeutics combating NLRP3-driven diseases.

中文翻译：

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NLRP3 炎症小体抑制剂 INF39 减弱了巨噬细胞中 NLRP3 的组装。

INF39 是一种无毒、不可逆、基于丙烯酸酯的 NLRP3 抑制剂，是 2-((2-氯苯基) 甲基) 丙烯酸乙酯 (INF4E) 的进一步优化。然而，其抗炎活性的详细机制和直接靶点尚不清楚。在这里，我们表明 INF39 是 NLRP3 炎症小体激活的特异性抑制剂。INF39 特异性抑制 NLRP3 激活，但不抑制 NLRC4 或 AIM2 炎症小体。INF39 对 K+ 外流、ROS 生成或线粒体膜电位没有影响，这些都是 NLRP3 炎症小体激活的上游事件。此外，INF39 对炎症小体下游事件 GSDMD 没有直接抑制作用。更重要的是，INF39抑制NEK7-NLRP3的相互作用，进而抑制NLRP3-NLRP3、NLRP3-ASC、ASC寡聚化和斑点形成的相互作用。