Dehydrocostus Lactone Effectively Alleviates Inflammatory Diseases by Covalently and Irreversibly Targeting NLRP3

作者：Qi Lv, Yishu Zhang, Juan Wang, Weijiang Lin, Yingbai Xie, Hongqiong Yang, Xunkai Yin, Zhenzhen Zhu, Yifan Cui, Yang Hu, Li Zeng, Yinan Zhang, Xubing Chen, Jian Liu, Lihong Hu · 发表于：MedComm · 年份：2025 · DOI：10.1002/mco2.70367 · 被引用次数：5 · 研究领域：Inflammasome and immune disorders、Diet, Metabolism, and Disease、Medicinal Plants and Bioactive Compounds

The activation of nucleotide oligomerization domain-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the pathogenesis of various inflammatory diseases. The natural product oridonin possesses a novel mechanism for NLRP3 inhibition and a unique binding mode with NLRP3, but its poor anti-inflammatory activity limits further application. After virtual screening of diverse natural product libraries, dehydrocostus lactone (DCL) was considered as a potential NLRP3 inhibitor. DCL effectively inhibited caspase-1 cleavage and release of IL-1β in mouse and human macrophages at an extremely low concentration of 10 nM, comparable to MCC950. Mechanistically, our study assigned DCL a novel role in disrupting NLRP3 inflammasome assembly and ASC oligomerization. Excluding the influence on potassium/chloride ion efflux, calcium ion influx, and production of mitochondrial ROS, DCL formed a covalent bond with cysteine 280 in NACHT domain of NLRP3, thereby inhibiting the interaction between NLRP3 and NEK7. Furthermore, DCL exhibited protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including dextran sulfate sodium-induced colitis, 2,4,6-trinitrobenzenesulfonic acid-induced Crohn's disease, LPS-induced septic shock, and monosodium urate-induced peritonitis. Our findings identify NLRP3 as the direct target of DCL, positioning DCL as a promising lead compound for treatment of NLRP3 inflammasome-related diseases.