BACKGROUND: Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) and is considered a Th1-mediated disease, supported by the over-expression of interferon-gamma (IFN-gamma) in the intestinal lamina propria. IFN-gamma has a pleiotropic effect on the intestinal epithelial cells (IECs), suggesting that IFN-gamma-induced responses may differ between epithelial cell types. METHODS: We established human small intestinal organoids (enteroids) derived from non-IBD controls and CD patients. Using human enteroids, the major response of IECs induced by IFN-gamma was evaluated, focusing on the IFN-gamma-induced programmed cell death (PCD) pathway. Identified IFN-gamma-induced responses were validated in surgically resected intestinal samples and publicly available single-cell RNA-sequencing datasets. RESULTS: IFN-gamma stimulated programmed cell death (PCD) of IECs in both control and CD enteroids in a dose-dependent manner. Pyroptosis, apoptosis. and necroptosis were activated in enteroids, suggesting that PANoptosis was the main process of IFN-gamma-induced PCD in IECs. The response to IFN-gamma depends on the cell type of the IECs. IFN-gamma induced depletion of enterocytes with upregulation of PANoptosis-associated genes, while leading to expansion of goblet cells without significant change in PANoptosis-associated gene expression. Individual PCD inhibitors were insufficient to block IFN-gamma-induced cytotoxicity, whereas the selective JAK1 inhibitor (upadacitinib) effectively blocked IFN-gamma-induced cytotoxicity and PANoptosis. Furthermore, PANoptosis was significantly activated in surgically resected tissues and in publicly available single-cell RNA-sequencing datasets of intestinal tissues from patients with CD. CONCLUSION: IFN-gamma induces PANoptosis in enterocytes, which can be treated with a selective JAK1 inhibitor in patients with CD.