Related Experiment Video
Updated: Sep 24, 2025
Isolation of Regenerating Hepatocytes after Partial Hepatectomy in Mice
Published on: December 2, 2022
Gasdermin D-mediated pyroptosis suppresses liver regeneration after 70% partial hepatectomy
Xingyu Lv1,2, Jiang Chen1,2, Jiayan He1,2
1Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
Pyroptosis is a kind of programmed cell death primarily mediated by gasdermin D (GSDMD) and shown to regulate multiple diseases. However, its contribution to liver regeneration, a fine-tuned tissue repair process mediated primarily by hepatocytes after mass loss, remains unclear. Herein, we found that caspase-11/GSDMD-mediated pyroptosis was activated in regenerating liver after 70% partial hepatectomy. Impeding pyroptosis by deleting GSDMD significantly reduced liver injury and accelerated liver regeneration. Mechanistically, GSDMD deficiency up-regulates the activation of hepatocyte growth factor/c-Met and epidermal growth factor receptor mitogenic pathways at the initiation phase. Moreover, activin A and glypican 3 (GPC3), two terminators of liver regeneration, were inhibited when GSDMD was absent. In vitro study suggested the expressions of activin A and GPC3 were induced by interleukin (IL)-1β and IL-18, whose maturations were regulated by GSDMD-mediated pyroptosis. Similarly, pharmacologically inhibiting GSDMD recapitulates these phenomena. Conclusion: This study characterizes the role of GSDMD-mediated pyroptosis in liver regeneration and lays the foundation for enhancing liver restoration by targeting GSDMD in liver patients with impaired regenerative capacity.
Insights
Gasdermin D (GSDMD)-mediated pyroptosis hinders liver regeneration. Inhibiting GSDMD reduces liver injury and promotes liver repair by activating growth pathways and suppressing regeneration terminators.
Area of Science:
- Molecular Biology
- Cellular Biology
- Hepatology
Background:
- Pyroptosis, a programmed cell death form, is regulated by gasdermin D (GSDMD) and implicated in various diseases.
- The role of pyroptosis in liver regeneration, a critical hepatocyte-mediated repair process, is not well understood.
Purpose of the Study:
- To investigate the involvement of caspase-11/GSDMD-mediated pyroptosis in liver regeneration following partial hepatectomy.
- To elucidate the molecular mechanisms by which GSDMD influences liver repair and regeneration.
Main Methods:
- Utilized a mouse model of 70% partial hepatectomy to study liver regeneration.
- Employed genetic deletion of GSDMD and pharmacological inhibition to impede pyroptosis.
- Analyzed key signaling pathways, including hepatocyte growth factor/c-Met and epidermal growth factor receptor, and regeneration terminators like activin A and glypican 3 (GPC3).
- Investigated the role of interleukin (IL)-1β and IL-18 in vitro.
Main Results:
- Caspase-11/GSDMD-mediated pyroptosis is activated during liver regeneration.
- GSDMD deficiency significantly reduced liver injury and accelerated liver regeneration.
- GSDMD absence enhanced hepatocyte growth factor/c-Met and epidermal growth factor receptor signaling and inhibited activin A and GPC3 expression.
- Interleukin-1β and IL-18 maturation, regulated by GSDMD pyroptosis, influenced activin A and GPC3 expression.
Conclusions:
- GSDMD-mediated pyroptosis plays a crucial inhibitory role in liver regeneration.
- Targeting GSDMD presents a potential therapeutic strategy for enhancing liver restoration in patients with compromised regenerative capacity.
