Guang Xu1,2, Shubin Fu1,3,4, Xiaoyan Zhan1,2, Zhilei Wang1,5, Ping Zhang1,2, Wei Shi1,3, Nan Qin1,3, Yuanyuan Chen1, Chunyu Wang1, Ming Niu1, Yuming Guo2, Jiabo Wang1, Zhaofang Bai1, Xiaohe Xiao1. 1. Military Institute of Chinese Materia, the Fifth Medical Centre, General Hospital of PLA, Beijing, China. 2. Integrative Medical Centre, the Fifth Medical Centre, General Hospital of PLA, Beijing, China. 3. School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China. 4. Jiujiang Institute for Food and Drug Control, Jiujiang, China. 5. School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Abstract
Aberrant activation of NLRP3 inflammasome has been implicated in a variety of human inflammatory diseases, but currently, no pharmacological NLRP3 inhibitor has been approved. In this study, we showed that echinatin, the ingredient of the traditional herbal medicine licorice, effectively suppresses the activation of NLRP3 inflammasome in vitro and in vivo. Further investigation revealed that echinatin exerts its inhibitory effect on NLRP3 inflammasome by binding to heat-shock protein 90 (HSP90), inhibiting its ATPase activity and disrupting the association between the cochaperone SGT1 and HSP90-NLRP3. Importantly, in vivo experiments demonstrated that administration of echinatin obviously inhibits NLRP3 inflammasome activation and ameliorates LPS-induced septic shock and dextran sodium sulfate-induced (DSS-induced) colitis in mice. Moreover, echinatin exerted favorable pharmacological effects on liver inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis (NASH). Collectively, our study identifies echinatin as a potentially novel inhibitor of NLRP3 inflammasome, and its use may be developed as a therapeutic approach for the treatment of NLRP3-driven diseases.
Aberrant activation of NLRP3 inflammasome has been implicated in a variety of pan class="Species">humaninflammatory diseases, but currently, no pharmacological NLRP3 inhibitor has been approved. In this study, we showed that echinatin, the ingredient of the traditional herbal medicine licorice, effectively suppresses the activation of NLRP3 inflammasome in vitro and in vivo. Further investigation revealed that echinatin exerts its inhibitory effect on NLRP3 inflammasome by binding to heat-shock protein 90 (HSP90), inhibiting its ATPase activity and disrupting the association between the cochaperone SGT1 and HSP90-NLRP3. Importantly, in vivo experiments demonstrated that administration of echinatin obviously inhibits NLRP3 inflammasome activation and ameliorates LPS-induced septic shock and dextran sodium sulfate-induced (DSS-induced) colitis in mice. Moreover, echinatin exerted favorable pharmacological effects on liver inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis (NASH). Collectively, our study identifies echinatin as a potentially novel inhibitor of NLRP3 inflammasome, and its use may be developed as a therapeutic approach for the treatment of NLRP3-driven diseases.
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