Insitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China; Wuxi School of Medicine, Jiangnan University, Jiangsu, China.
Wuxi School of Medicine, Jiangnan University, Jiangsu, China.
Cell Rep Med. 2023 Dec 19;4(12):101310. doi: 10.1016/j.xcrm.2023.101310.
Excessive inflammation caused by abnormal activation of the NLRP3 inflammasome contributes to the pathogenesis of multiple human diseases, but clinical drugs targeting the NLRP3 inflammasome are still not available. In this study, we identify entrectinib (ENB), a US Food and Drug Administration (FDA)-approved anti-cancer agent, as a target inhibitor of the NLRP3 inflammasome to treat related diseases. ENB specifically blocks NLRP3 without affecting activation of other inflammasomes. Furthermore, we demonstrate that ENB directly binds to arginine 121 (R121) of NEK7 and blocks the interaction between NEK7 and NLRP3, thereby inhibiting inflammasome assembly and activation. In vivo studies show that ENB has a significant ameliorative effect on mouse models of NLRP3 inflammasome-related diseases, including lipopolysaccharide (LPS)-induced systemic inflammation, monosodium urate (MSU)-induced peritonitis, and high-fat diet (HFD)-induced type 2 diabetes (T2D). These data show that ENB is a targeted inhibitor of NEK7 with strong anti-NLRP3 inflammasome activity, making it a potential candidate drug for the treatment of inflammasome-related diseases.
异常激活 NLRP3 炎性体引起的过度炎症是多种人类疾病发病机制的原因，但针对 NLRP3 炎性体的临床药物仍尚未问世。在这项研究中，我们鉴定出恩曲替尼（ENB），一种美国食品和药物管理局（FDA）批准的抗癌药物，是治疗相关疾病的 NLRP3 炎性体的靶向抑制剂。ENB 特异性地阻断 NLRP3，而不影响其他炎性体的激活。此外，我们证明 ENB 直接结合 NEK7 的精氨酸 121（R121）并阻断 NEK7 与 NLRP3 之间的相互作用，从而抑制炎性体的组装和激活。体内研究表明，ENB 对 NLRP3 炎性体相关疾病的小鼠模型具有显著的改善作用，包括脂多糖（LPS）诱导的全身炎症、单钠尿酸盐（MSU）诱导的腹膜炎和高脂肪饮食（HFD）诱导的 2 型糖尿病（T2D）。这些数据表明，ENB 是一种具有强大抗 NLRP3 炎性体活性的 NEK7 靶向抑制剂，使其成为治疗炎性体相关疾病的潜在候选药物。
