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Updated: Dec 20, 2025
Author Spotlight: Evaluating Therapeutic Strategies to Enhance Liver Regeneration
Published on: May 24, 2024
Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure
Wan-Feng Xu1, Quan Zhang1, Chu-Jie Ding1
1State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism, China Pharmaceutical University, Nanjing, 210009, China.
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.
Insights
Researchers developed new caspase-3 inhibitors, Ac-DMPD-CMK and Ac-DMLD-CMK, to block programmed cell death (PCD) effectors like gasdermin E (GSDME). These compounds show promise in treating liver failure and other organ dysfunctions.
Area of Science:
- Molecular Biology
- Biochemistry
- Pathology
Background:
- Programmed cell death (PCD), encompassing apoptosis, apoptotic necrosis, and pyroptosis, is implicated in diverse organ dysfunction syndromes.
- Gasdermin E (GSDME) acts as a pyroptosis effector, but specific inhibitors for GSDME-mediated pyroptosis are scarce.
Purpose of the Study:
- To develop novel inhibitors targeting caspase-3 to prevent GSDME-mediated pyroptosis.
- To evaluate the efficacy of these inhibitors in cellular models and a mouse model of acute liver failure.
Main Methods:
- Design and synthesis of GSDME-derived inhibitors (Ac-DMPD-CMK and Ac-DMLD-CMK) based on DMPD or DMLD structures.
- In vitro assessment of caspase-3 inhibition kinetics (IC50 values) and substrate cleavage (GSDME, PARP).
- In vivo evaluation in a mouse model of bile duct ligation-induced acute hepatic failure.
Main Results:
- Ac-DMPD-CMK and Ac-DMLD-CMK demonstrated potent and specific inhibition of caspase-3 activity with lower IC50 values compared to Z-DEVD-FMK.
- These inhibitors effectively blocked GSDME and PARP cleavage in hepatocytes and macrophages, preventing apoptotic and pyroptotic cell death.
- Treatment with Ac-DMPD/DMLD-CMK significantly reduced liver injury in a mouse model mimicking intrahepatic cholestasis-related acute hepatic failure.
Conclusions:
- Ac-DMPD-CMK and Ac-DMLD-CMK are effective caspase-3 inhibitors useful for studying PCD.
- These compounds represent promising lead candidates for developing therapeutics against PCD-driven organ failures, particularly liver failure.
