Distinct molecular responses of human intestinal organoids to proton and photon radiation.

Radiation exposure impairs rapidly renewing tissues like the intestinal epithelium, yet translational insights from murine models have been limited by species-specific responses. Here, we use human intestinal organoids (HIOs) derived from jejunal epithelium to evaluate human epithelial responses to low-dose proton and photon (γ) radiation. γ irradiation induces a unique developmental and metabolic shift in crypt-like organoids, including enrichment of amino acid metabolism pathways and activation of fetal-associated transcription factors and morphology. Integrated multiomic profiling reveals serotonin biosynthesis as a central regenerative node. HIOs can complement animal models and are emerging as a powerful tool in modeling human radiation responses and identifying candidate biomarkers for intestinal injury.NEW & NOTEWORTHY Radiation damages the intestinal epithelium, but murine models often fail to capture human-specific responses. Using human intestinal organoids, we show that γ irradiation triggers a distinct developmental and metabolic reprogramming, including enrichment of amino acid metabolism and induction of fetal-associated transcription factors and morphology. These findings highlight human organoids as a translational platform to model radiation injury and uncover candidate biomarkers for intestinal damage.