The Selective 3-MST Inhibitor I3MT-3 Works as a Potent Caspase-1 Inhibitor.

I3MT-3 (HMPSNE) has been identified as a selective inhibitor of the supersulfide-producing enzyme 3-MST. In this study, we found that I3MT-3 inhibits inflammatory responses, including the secretion of the pro-inflammatory cytokine interleukin-1β (IL-1β) and inflammatory cell death pyroptosis, induced by the activation of the inflammasomes composed of NLRP1, NLRP3, or AIM2. However, interestingly, the knockdown of 3-MST did not affect the activation of the inflammasomes, suggesting that the inhibitory effect of I3MT-3 on inflammasome activation is mediated by alternative ways rather than the inhibition of 3-MST. Interestingly, an in vitro caspase assay revealed that I3MT-3 directly inhibits caspase-1 activation, and molecular docking simulations raised the possibility that the pyrimidone ring in I3MT-3 stabilizes direct interaction of I3MT-3 with caspase-1. Taken together, our data suggest that I3MT-3 inhibits inflammasome activation by targeting caspase-1, and show I3MT-3 as a potent inhibitor of caspase-1.