PIKfyve Deficiency Exacerbates Radiation-Induced Intestinal Toxicity

Intestinal acute radiation sickness (IARS) is a life-threatening component of the acute radiation syndrome characterized by severe vomiting, diarrhea, and gastrointestinal bleeding, for which no effective prophylaxis or therapy currently exists. Despite intensive investigation, the molecular determinants that govern intestinal epithelial resilience to ionizing radiation remain poorly defined, and strategies to mitigate radiation-induced gut injury are still lacking. To address this gap, we generated an inducible intestinal-epithelial-specific PIKfyve-knockout mouse model (PIKfyve cKO); mice were subjected to 10 Gy abdominal irradiation, and intestinal tissues, serum, and small-intestinal organoids were analysed by histopathology, apoptosis assays, barrier-permeability tests (FD4), multiplex immunoassays, and RNA sequencing.PIKfyve deletion alone did not perturb normal gut architecture, but after irradiation it precipitated villous atrophy, crypt hypoplasia, and massive crypt-cell apoptosis, resulting in impaired epithelial renewal. Barrier dysfunction was evidenced by elevated serum FD4 and heightened systemic levels of pro-inflammatory cytokines, which culminated in markedly increased post-irradiation mortality. Transcriptomic profiling further revealed that PIKfyve loss potentiated DNA-damage signalling and amplified inflammatory cascades following radiation exposure.These findings identify PIKfyve as a previously unrecognized guardian of intestinal epithelial integrity after irradiation and position PIKfyve as a tractable molecular target for the prevention or treatment of intestinal acute radiation sickness.