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Updated: Jul 4, 2026

Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Caspase-3 activation is a brake in GSDMD-mediated pyroptosis
Guangyuan Li1, Mingyu Peng2, Mengxue Li2
1Department of Oncology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China; The Fifth Clinical Medical College of Zhengzhou University, Zhengzhou, China.
None:
Pyroptosis is a form of programmed cell death mediated by gasdermin proteins, with GSDMD and GSDME being the most extensively studied. Inflammatory caspase-1/4/5/11 cleave GSDMD to release the pore-forming fragment GSDMD-NT, whereas the apoptotic caspase-3 cleaves GSDME to release the pore-forming fragment GSDME-NT. In this study, we observed that caspase-3 is activated during GSDMD-mediated pyroptosis. Interestingly, downregulation of caspase-3 activity through RNAi or the caspase-3 inhibitor Z-DEVD-FMK significantly increased cell death. Furthermore, we found that caspase-3 physically interacts with GSDMD-NT and cleaves it at a site distinct from those targeted by caspase-1 or caspases-4/5/11. This alternative cleavage generates a non-functional fragment, thereby disrupting the integrity of GSDMD-NT. Collectively, we demonstrate that caspase-3 activation serves as a negative feedback mechanism to regulate the intensity of GSDMD-mediated pyroptosis.
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