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Programmed cell death(PCD),including apoptosis,apoptotic necrosis,and pyroptosis,is involved in various organ dysfunction syndromes.Recent studies have revealed that a substrate of caspase-3,gasdermin E(GSDME),functions as an effector for pyroptosis;however,few inhibitors have been reported to prevent pyroptosis mediated by GSDME.Here,we developed a class of GSDME-derived inhibitors containing the core structure of DMPD or DMLD.Ac-DMPD-CMK and Ac-DMLD-CMK could directly bind to the catalytic domains of caspase-3 and specifically inhibit caspase-3 activity,exhibiting a lower IC50 than that of Z-DEVD-FMK.Functionally,Ac-DMPD/DMLD-CMK substantially inhibited both GSDME and PARP cleavage by caspase-3,preventing apoptotic and pyroptotic events in hepatocytes and macrophages.Furthermore,in a mouse model of bile duct ligation that mimics intrahepatic cholestasis-related acute hepatic failure,Ac-DMPD/DMLD-CMK significantly alleviated liver injury.Together,this study not only identified two specific inhibitors of caspase-3 for investigating PCD but also,more importantly,shed light on novel lead compounds for treating liver failure and organ dysfunctions caused by PCD.