Tabersonine, a natural NLRP3 inhibitor, suppresses inflammasome activation in macrophages and attenuate NLRP3-driven diseases in mice

Hao-wen Xu1,2, Wei-feng Li2, Shan-shan Hong1,2, Jing-jing Shao2,3, Jia-hao Chen2, Nipon Chattipakorn4, Di Wu2, Wu Luo1, Guang Liang1,2,3
1 Department of Cardiology and Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
3 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 311399, China
4 Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
Correspondence to: Di Wu:, Wu Luo:, Guang Liang:,
DOI: 10.1038/s41401-022-01040-z
Received: 25 August 2022
Accepted: 6 December 2022
Advance online: 10 January 2023


Aberrant activation of NLRP3 inflammasome causes the progression of various inflammation-related diseases, but the small-molecule inhibitors of NLRP3 are not currently available for clinical use. Tabersonine (Tab) is a natural product derived from a traditional Chinese herb Catharanthus roseus that is usually used as an anti-tumor agent. In this study we investigated the anti-inflammatory effects and molecular targets of Tab. We first screened 151 in-house natural compounds for their inhibitory activity against IL-1β production in BMDMs. We found that Tab potently inhibited NLRP3-mediated IL-1β production with an IC50 value of 0.71 μM. Furthermore, we demonstrated that Tab suppressed the assembly of NLRP3 inflammasome, especially the interaction between NLRP3 and ASC. Interestingly, we found that Tab directly bound to NLRP3 NACHT domain, thereby reducing the self-oligomerization of NLRP3. In addition, we showed that administration of Tab significantly ameliorated NLRP3-driven diseases, such as peritonitis, acute lung injury, and sepsis in mouse models. The preventive effects of Tab were not observed in the models of NLRP3 knockout mouse. In conclusion, we have identified Tab as a natural NLRP3 inhibitor and a lead compound for the design and discovery of novel NLRP3 inhibitors.
Keywords: tabersonine; NLRP3 inflammasome; NACHT domain; acute lung injury; peritonitis; sepsis

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