Radiation is one of the most efficient cancer treatments. Even so, gastrointestinal (GI) syndrome MAO is usually a big limiting element in abdominal and pelvic radiotherapy. The loss of crypt stem cells or villus endothelial cells is suggested to be accountable for radiation-induced intestinal harm. We report here a crucial role with the BH3-only protein p53 upregulated ABT-199 modulator of apoptosis (PUMA) inside the radiosensitivity of intestinal epithelium and pathogenesis of GI syndrome. PUMA was induced in the p53-dependent method and mediated radiation-induced apoptosis by way of the mitochondrial pathway during the intestinal mucosa. PUMA-deficient mice exhibited blocked apoptosis within the intestinal progenitor and stem cells, enhanced crypt proliferation and regeneration, and prolonged survival following lethal doses of radiation. Unexpectedly, PUMA deficiency had very little effect on radiation-induced intestinal endothelial apoptosis. Suppressing PUMA expression by antisense oligonucleotides offered significant intestinal radioprotection. Consequently, PUMA-mediated apoptosis within the progenitor and stem cell compartments is vital for radiation-induced intestinal harm.