New applications of clioquinol in the treatment of inflammation disease by directly targeting arginine 335 of NLRP3.
10.1016/j.jpha.2024.101069
- Author:
Peipei CHEN
1
;
Yunshu WANG
1
;
Huaiping TANG
1
;
Chao ZHOU
1
;
Zhuo LIU
1
;
Shenghan GAO
1
;
Tingting WANG
2
;
Yun XU
1
;
Sen-Lin JI
1
Author Information
1. Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
2. State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing, 210008, China.
- Publication Type:Journal Article
- Keywords:
Clioquinol;
Colitis;
NACHT domain;
NLRP3 inflammasome;
Peritonitis;
Sepsis
- From:
Journal of Pharmaceutical Analysis
2025;15(1):101069-101069
- CountryChina
- Language:English
-
Abstract:
The NOD-like receptor protein 3 (NLRP3) inflammasome is essential in innate immune-mediated inflammation, with its overactivation implicated in various autoinflammatory, metabolic, and neurodegenerative diseases. Pharmacological inhibition of NLRP3 offers a promising treatment strategy for inflammatory conditions, although no medications targeting the NLRP3 inflammasome are currently available. This study demonstrates that clioquinol (CQ), a clinical drug with chelating properties, effectively inhibits NLRP3 activation, resulting in reduced cytokine secretion and cell pyroptosis in both human and mouse macrophages, with a half maximal inhibitory concentration (IC50) of 0.478 μM. Additionally, CQ mitigates experimental acute peritonitis, gouty arthritis, sepsis, and colitis by lowering serum levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α). Mechanistically, CQ covalently binds to Arginine 335 (R335) in the NACHT domain, inhibiting NLRP3 inflammasome assembly and blocking the interaction between NLRP3 and its component protein. Collectively, this study identifies CQ as an effective natural NLRP3 inhibitor and a potential therapeutic agent for NLRP3-driven diseases.
