Tabersonine, a natural NLRP3 inhibitor, suppresses inflammasome activation in macrophages and attenuate NLRP3-driven diseases in mice
Aberrant activation of the NLRP3 inflammasome contributes to the progression of various inflammation-related diseases, but small-molecule inhibitors of NLRP3 are not yet available for clinical use. Tabersonine (Tab), a natural product derived from the traditional Chinese herb Catharanthus roseus, is commonly used as an anti-tumor agent. In this study, we investigated the anti-inflammatory effects and molecular targets of Tab. We screened 151 in-house natural compounds for their inhibitory activity against IL-1β production in BMDMs and found that Tab significantly inhibited NLRP3-mediated IL-1β production with an IC50 value of 0.71 μM. Further analysis revealed that Tab suppressed the assembly of the NLRP3 inflammasome, particularly the interaction between NLRP3 and ASC. Notably, Tab directly bound to the NACHT domain of NLRP3, thereby reducing NLRP3 self-oligomerization. Additionally, administration of Tab significantly ameliorated NLRP3-driven diseases such as peritonitis, acute lung injury, and sepsis in mouse models. These preventive effects were not observed in NLRP3 knockout mouse models. In conclusion, we identified Tab as a natural NLRP3 inhibitor and a promising lead compound for the development of novel NLRP3 inhibitors.