Ethyl pyruvate confers protection against endotoxemia and sepsis by inhibiting caspase-11-dependent cell pyroptosis

•Ethyl pyruvate(EP) inhibits caspase-11-dependent cell pyroptosis.•EP suppresses intracellular LPS-induced Caspase-11 dependent cleavage of Gsdmd and release of IL-1α/β.•EP inhibits Caspase-11-related pyroptosis by impeding the interaction between LPS and Caspase-11.•EP protects the mice against lethal endotoxemia and sepsis. Ethyl pyruvate exertsa special protectiveeffecton endotoxin-induced endotoxemia and experimental sepsis, but the underlying mechanism remains elusive. Werecently demonstrated that ethyl pyruvate inhibited caspase-11-mediated macrophage pyroptotic cell death. GasderminDis akeymolecule incaspase-11 mediated non-canonical inflammasome-inducedpyroptosis. We proved that ethyl pyruvate significantly decreased caspase-11 and gasdermin D-mediated pyroptosis induced by cytoplasmic lipopolysaccharide (LPS) and bacterial outer membrane vesicles (OMVs). Ethyl pyruvate treatment offered effective protection against lethal endotoxemia and reduced the release of IL-1α and IL-1β. Similarresults were observed in the mousececal ligation and puncture (CLP)peritonitissepsismodel. These findings identified ethyl pyruvate as an inhibitor against LPS-mediated activation of cytoplasmic caspase-11 and gasdermin D. This mechanism is believed to contribute tothe further explanation of theprotectiveactionof ethyl pyruvate in experimental sepsis and endotoxemia and the potential application of ethyl pyruvate for rescuing sepsis.