Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure

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.