Nitrosonisoldipine is a selective inhibitor of inflammatory caspases and protects against pyroptosis and related septic shock

Pyroptosis is a type of acute cell death that mainly occurs in immune cells. It characterized with robust release inflammatory cytokines and has emerged to play critical role the pathogenesis sepsis-associated disorders. In this study, we screened for pyroptotic inhibitors ultimate goal benefit sepsis treatments. Accidentally, identified nitrosonisoldipine (NTS), photodegradation product calcium channel inhibitor nisoldipine, inhibits noncanonical pyroptosis. Using murine immortalized BM-derived macrophage human THP-1 line, further discovered NTS not only pyroptosis mediated by caspase-11 or caspase-4 but also canonical caspase-1. Mechanistically, directly enzyme activities these caspases, inhibitory effects persist despite extensive washout drug. By contrast, apoptosis caspase-3/-7 was affected NTS. Mice pretreated intraperitoneally displayed improved survival rate extended time LPS- polymicrobe-induced septic models, respectively. conclusion, selective caspases blocks both pathways. safe intraperitoneal administration might be used as prototype develop drugs