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Sublethal executioner caspase activation in hepatocytes promotes liver regeneration through the JAK/STAT3 pathway

  • 0The Key Laboratory of Experimental Teratology of the Ministry of Education, State Key Laboratory of Reproductive Medicine and Offspring Health, and Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Plos Biology +

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August 28, 2025

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August 28, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Executioner caspase activation (ECA) promotes liver regeneration without causing cell death. This process enhances hepatocyte proliferation via JAK/STAT3 signaling, revealing a key role for caspases beyond apoptosis in tissue repair.

Area Of Science

  • Cell Biology
  • Molecular Biology
  • Regenerative Medicine

Background

  • Apoptosis, mediated by executioner caspases, is known to drive regeneration in various species.
  • Executioner caspases release pro-regenerative signals from apoptotic cells, but their role independent of apoptosis is unclear.

Purpose Of The Study

  • To investigate the role of executioner caspase activation (ECA) in liver regeneration.
  • To determine if ECA can promote regeneration without inducing apoptosis.

Main Methods

  • Generation of transgenic mice with a lineage tracing system for cells experiencing ECA.
  • Induction of liver regeneration via partial hepatectomy (PHx) and carbon tetrachloride (CCl4) treatment.
  • Analysis of hepatocyte proliferation, apoptosis, and JAK/STAT3 signaling pathways.

Main Results

  • ECA occurs in a small fraction of hepatocytes in homeostatic livers and expands significantly during liver regeneration.
  • The majority of hepatocytes with ECA survive and proliferate, rather than undergoing apoptosis.
  • Inhibition of ECA impairs hepatocyte proliferation and regeneration, while excessive ECA impedes regeneration.
  • ECA enhances hepatocyte proliferation by activating the JAK/STAT3 pathway.

Conclusions

  • Executioner caspase activation plays a crucial, apoptosis-independent role in liver regeneration.
  • Sublethal levels of ECA are essential for promoting hepatocyte proliferation and effective liver repair.
  • ECA acts through the JAK/STAT3 signaling pathway to drive regenerative processes.

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