Caspases 3 and 7 restrict intestinal inflammation by regulating stem cell function and gsdmd-mediated pyroptosis

Aberrant intestinal epithelial cell (IEC) death is a hallmark of inflammatory bowel disease (IBD), observed in patient samples and animal models of colitis. While multiple cell death pathways contribute to disease pathogenesis, the dominant modalities and their regulatory mechanisms in IBD remain poorly defined. In this study, we demonstrate that mice with intestinal epithelial cell-specific deletion of caspase-3 and -7 (Casp3/7 Tg) exhibit exacerbated colitis, increased mortality, and impaired epithelial regeneration, phenotypes not observed in other cell death-related knockout models. These findings highlight a previously unrecognized protective role of caspase-3/7 in controlling inflammation and tissue regeneration following intestinal injury. Mechanistically, caspase-3/7 deficiency negatively affects intestinal stem cell proliferation and promotes GSDMD-dependent pyroptosis, compromising barrier integrity and return to steady state conditions. Together, our results identify caspase-3/7 as key regulators of epithelial integrity and inflammation and suggest their modulation as a promising therapeutic strategy in IBD and colorectal cancer. Overall design: Two sets of mRNA seq samples: The first set of samples are mural colon tissue samples from 4 conditions (0 or 8 days post DSS treatment of Casp3/7 transgenic and wild type mice). The second set of samples were derived from mural intestinal epithelial cells of Casp3/7 transgenic and wild type mice. The samples were taken 0 or 3 days post DSS treatment.