Enteropathy in STAT3 GOF syndrome: Insights into the role of the JAK/STAT pathway

: The term enteropathy refers to any disease affecting the small intestine. In the past, celiac disease (CeD) was the only well-established atrophic enteropathy, but the spectrum of non-celiac enteropathies with villous atrophy has been expanded, as has knowledge about the underlying pathogenic mechanisms. Kinases within the JAK-STAT3 pathway are essential in transducing signals from various pro-inflammatory cytokines. Uncontrolled activation of these pathways promotes the development and progression of different diseases such as inflammatory and autoimmune diseases, lymphomas, and solid tumors. Therefore, inhibition of JAK-STAT3 represents a promising therapeutic option for patients with these disorders. Gain-of-function mutations in the STAT3 gene cause a rare syndrome characterized by enteropathy and a wide range of immune-mediated manifestations, including lymphoproliferation, autoimmune cytopenias and growth delay. In this narrative review we introduce signalling via the JAK-STAT3 pathway, focusing on potential mechanisms contributing to immune deficiencies in the constellation of a STAT3 gain of function. Furthermore, through an emblematic clinical case on the efficacy of anti-JAK therapy in STAT3 enteropathy, we review different enteropathies which recognize alterations in the JAK-STAT pathway and discuss the role of JAK inhibitors in this setting.