Sennoside A is a novel inhibitor targeting caspase-1

caspase-1 inhibition. Mechanistically, Sen A not only suppressed the assembly of both NLRP3 and AIM2 inflammasome but also affected the priming process of NLRP3 inflammasome by blocking NF-κB signaling. Sen A significantly ameliorated the pathophysiological effect in LPS-, MSU- and carrageenan-challenged rodent models by suppressing inflammasome activation. Furthermore, P2X7 was indispensable for Sen A inhibiting NLRP3 inflammasome since it failed to further decrease IL-1β and IL-18 production in LPS plus ATP-stimulated BMDMs that were transfected with P2X7 siRNA. Sen A also restrained the large pore-forming functionalities of the P2X7R as verified by the YO-PRO-1 uptake assay. Taken together, Sen A inactivates caspase-1 to inhibit NLRP3 and AIM2 inflammasome-involved inflammation in a P2X7-dependent manner, making it an attractive candidate as a caspase-1 small-molecular inhibitor.