Aberrant activation of Nod-like receptor family pyrin domain-containing-3 (NLRP3) inflammasome is implicated in a variety of inflammatory diseases. Targeting NLRP3 inflammasome represents a promising therapy to cure such diseases. We and others recently demonstrated that acetylation of NLRP3 promotes the inflammasome activity and also suggested lysine acetyltransferases inhibitors could be a kind of promising agents for treating NLRP3 associated disorders. In this study, by searching for kinds of lysine acetyltransferases inhibitors, we showed that SI-2 hydrochloride (SI-2), a specific inhibitor of lysine acetyltransferase KAT13B (lysine acetyltransferases 13B), specifically blocks NLRP3 inflammasome activation both in mice in vivo and in human cells ex vivo. Intriguingly, SI-2 does not affect the acetylation of NLRP3. Instead, it disrupts the interaction between NLRP3 and adaptor apoptosis-associated speck-like protein containing CARD (ASC), then blocks the formation of ASC speck. Thus, our study identified a specific inhibitor for NLRP3 inflammasome and suggested SI-2 as a potential inhibitory agent for the therapy of NLRP3-driven diseases.

包含Nod样受体家族的含吡喃域的3（NLRP3）炎性小体的异常激活与多种炎性疾病有关。靶向NLRP3炎性体代表了治愈此类疾病的有前途的疗法。我们和其他人最近证明，NLRP3的乙酰化可促进炎性体的活性，并且还提出赖氨酸乙酰转移酶抑制剂可能是治疗NLRP3相关疾病的一种有前途的药物。在这项研究中，通过搜索各种赖氨酸乙酰基转移酶抑制剂，我们发现SI-2盐酸盐（SI-2）是赖氨酸乙酰基转移酶KAT13B的特异性抑制剂（赖氨酸乙酰基转移酶13B）在小鼠体内和体外均能特异性阻断NLRP3炎性体的活化。离体人类细胞。有趣的是，SI-2不会影响NLRP3的乙酰化。相反，它破坏了NLRP3与适配器凋亡相关的含有CARD（ASC）的斑点样蛋白之间的相互作用，然后阻止了ASC斑点的形成。因此，我们的研究确定了NLRP3炎性体的特异性抑制剂，并建议SI-2作为治疗NLRP3驱动的疾病的潜在抑制剂。