Interferon driven epithelial stress responses are a central pathogenic feature of celiac disease (CeD) and refractory CeD (RCeD). We aim to clarify how intestinal homeostasis is disrupted through JAK/STAT pathway and to determine whether selective JAK inhibition can suppress the interferon induced epithelial responses in advanced three‑dimensional human intestinal organoids derived from duodenal biopsies of CeD, RCeD, and non‑celiac individuals. As several JAK inhibitors are already approved for immune mediated diseases such as rheumatoid arthritis and ulcerative colitis, they represent a rational strategy to dampen pathological cytokine signalling.
We previously demonstrated that IFNγ induces TG2 expression in a JAK/STAT dependent manner and sustains a positive inflammatory feedback loop, contributing to the chronicity of the autoimmune response1. Building on this, we examined the effects of clinically approved and next‑generation JAK inhibitors on interferon regulated pathways. In our unpublished work, IFNγ exposure robustly induced STAT1 phosphorylation and downstream transcriptional activation of TGM2 and NOS2, while downregulating HMGCS2. Baricitinib, momelotinib, and tofacitinib showed the strongest inhibition of STAT1 phosphorylation and effectively suppressed the associated transcriptional responses at clinically relevant concentrations.
Given the emerging role of type I interferons in viral triggered CeD onset, we further assessed responses to IFNα and IFNβ. Both cytokines induced epithelial STAT1 activation and TG2 upregulation comparable to IFNγ. These responses were efficiently blocked by tofacitinib and the TYK2‑selective inhibitor deucravacitinib, highlighting the therapeutic potential of targeting both type I and type II IFN pathways.
Collectively, our findings demonstrate that JAK inhibitors can prevent IFN mediated epithelial stress, metabolic reprogramming, and autoantigen induction, suggesting a potential strategy to halt early disease amplification before mucosal injury occurs. This work provides proof-of-concept for combining a large cohort of patient-derived organoids and biopsies to enable mechanistic and therapeutic insights into cytokine responses across disease stages and cell types.