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

  
@article{APS10251,
	author = {Wan-feng Xu and Quan Zhang and Chu-jie Ding and Hui-yong Sun and Yuan Che and Hai Huang and Yun Wang and Jia-wei Wu and Hai-ping Hao and Li-juan Cao},
	title = {Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure},
	journal = {Acta Pharmacologica Sinica},
	volume = {42},
	number = {1},
	year = {2021},
	keywords = {},
	abstract = {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.},
	url = {http://www.chinaphar.com/article/view/10251}
}