Niu, X.; Fink, C.; Kallsen, K.; Shi, L.; Mincheva, V.; Franzenburg, S.; Prange, R. D.; Bruchhaus, I.; Heine, H.; Bossen, J. M.; Roeder, T.

Respiratory epithelial cells must dynamically adapt to continuous environmental challenges, yet the molecular pathways that govern their stress responses remain incompletely understood. This study demonstrates that the JAK/STAT signaling pathway is a crucial regulator of airway epithelial cell survival and homeostasis in Drosophila melanogaster. Our findings reveal that JAK/STAT activity is continuously required throughout development and adulthood, with environmental factors like cigarette smoke and hypoxia further intensifying pathway activation. Disrupting JAK/STAT signaling in airway epithelia during development is lethal, triggers apoptosis, and in adults, reduces lifespan while increasing vulnerability to chronic smoke exposure. Conversely, chronic hyperactivation of JAK/STAT signaling induces significant cell-autonomous epithelial remodeling, evidenced by epithelial thickening, tracheal narrowing, and impaired barrier structure, mirroring the pathological features of chronic lung disease. Pharmacological inhibition of this pathway effectively reverses these defects. Comprehensive transcriptomic analyses further reveal that maintaining a balance in JAK/STAT signaling is essential for preserving cellular junctions and secretory functions. These findings underscore the importance of tightly regulated JAK/STAT signaling for the integrity of airway epithelium and present a valuable in vivo model for exploring the mechanisms underlying inflammatory lung diseases and for preclinical drug testing.