Tivantinib alleviates inflammatory diseases by directly targeting NLRP3

Yi Huang; Yun Guo; Yan Zhou; Qian Huang; Yi Ru; Yingli Luo; Wen Xu

doi:10.1016/j.isci.2023.106062

Tivantinib alleviates inflammatory diseases by directly targeting NLRP3

iScience. 2023 Feb 1;26(3):106062. doi: 10.1016/j.isci.2023.106062. eCollection 2023 Mar 17.

Authors

Yi Huang¹, Yun Guo², Yan Zhou³, Qian Huang¹, Yi Ru¹, Yingli Luo¹, Wen Xu⁴

Affiliations

¹ Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.
² Department of Respiratory Medicine, The Affiliated Wuxi Children's Hospital of Jiangnan University, 214023 Wuxi, Jiangsu, China.
³ Department of Child Health Care, Anhui Provincial Children's Hospital/ Children's Hospital of Fudan University Anhui Hospital, Hefei 230051, China.
⁴ Neurology Department, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

Abstract

NLRP3 inflammasome-mediated immune responses are involved in the pathogenesis of multiple inflammatory diseases, but few clinical drugs are identified that directly target the NLRP3 inflammasome to treat these diseases to date. Here, we show that the anticancer agent tivantinib is a selective inhibitor of NLRP3 and has a strong therapeutic effect on inflammasome-driven disease. Tivantinib specifically inhibits canonical and non-canonical NLRP3 inflammasome activation without affecting AIM2 and NLRC4 inflammasome activation. Mechanistically, Tivantinib inhibits NLRP3 inflammasome by directly blocking NLRP3 ATPase activity and subsequent inflammasome complex assembly. In vivo, Tivantinib reduces IL-1β production in mouse models of lipopolysaccharide (LPS)-induced systemic inflammation, monosodium urate (MSU)-induced peritonitis and Con A-induced acute liver injury (ALI), and also has remarkable preventive and therapeutic effects on experimental autoimmune encephalomyelitis (EAE). In conclusion, our study identifies the anticancer drug tivantinib as a specific inhibitor of NLRP3 and provides a promising therapeutic agent for inflammasome-driven disease.

Keywords: Biological sciences; Health sciences; Immunology.