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

Wan-feng Xu1, Quan Zhang1, Chu-jie Ding1, Hui-yong Sun1, Yuan Che1, Hai Huang1, Yun Wang1, Jia-wei Wu1, Hai-ping Hao1, Li-juan Cao1
1 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing 210009, China
Correspondence to: Hai-ping Hao:, Li-juan Cao:,
DOI: 10.1038/s41401-020-0434-2
Received: 6 January 2020
Accepted: 9 May 2020
Advance online: 26 May 2020


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.
Keywords: caspase-3 inhibitor; gasdermin E; apoptosis; pyroptosis; acute hepatic failure

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