Caspase-3/7 deficiency results in enhanced intestinal inflammation and reduced tumorigenesis

  • Sci Adv. 2026 Mar 20;12(12):eadz5906. doi: 10.1126/sciadv.adz5906.
Wei Xie  1  2 ,  Laura Wyckaert  1  2 ,  Mike Vadi  1  2 ,  Bruno Verstraeten  1  2 ,  Tatyana Divert  1  2 ,  Jef Haerinck  2  3  4 ,  Riet De Rycke  2  5 ,  Femke Baeke  2  5 ,  Mohamed Lamkanfi  6 ,  Geert Berx  2  3  4 ,  Adam Wahida  1  2  7 ,  Peter Vandenabeele  1  2
Affiliations
  • 1. Molecular Signaling and Cell Death Unit, VIB-UGent Center for Inflammation Research, Flanders Institute for Biotechnology, Ghent, Belgium.
  • 2. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • 3. Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium.
  • 4. Molecular and Cellular Oncology Laboratory, Ghent University, Ghent, Belgium.
  • 5. VIB BioImaging Core, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent, 9052, Belgium.
  • 6. Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
  • 7. Institute of Metabolism and Cell Death, Molecular Targets and Therapeutics Center, Helmholtz Munich, Neuherberg, Germany.
PMID: 41861024 DOI: 10.1126/sciadv.adz5906
Abstract

Aberrant intestinal epithelial cell (IEC) death is common in inflammatory bowel disease (IBD) and related animal models. While various cell death pathways contribute to disease, the dominant modalities and their regulatory mechanisms in intestinal inflammation remain ill defined. Using the DSS colitis model, we examined the contribution of Apoptosis (Casp3/7ΔIEC), Necroptosis (MlklΔIEC), Pyroptosis (GsdmeΔIEC, Gsdmd-/-), and Ferroptosis (Gpx4iΔIEC) in IECs. Mice lacking Caspase-3/7 in IECs showed worsened colitis, higher mortality, and impaired regeneration, not seen in the Other transgenic mice. Caspase-3/7 deficiency in IECs hindered stem cell proliferation and increased inflammatory cell death, disrupting barrier integrity and delaying recovery. Despite heightened inflammation, Casp3/7ΔIEC mice had reduced tumor formation in the AOM/DSS-induced colorectal Cancer model. These findings highlight a protective role for Caspase-3/7 in controlling inflammation and tissue regeneration, while promoting tumorigenesis following intestinal injury, and suggest modulation of Caspase-3/7 as a promising therapeutic strategy in IBD and colorectal Cancer.

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