FoxO factors preserve airway epithelial homeostasis by coordinating adaptive stress responses

Airway epithelia must maintain functional and structural homeostasis despite exposure to diverse environmental stressors. FoxO transcription factors are well suited to this task, acting as integration hubs that translate extrinsic and intrinsic signals into appropriate physiological responses. We show that FoxO factors in Drosophila, mouse, and human airway epithelial cells (AECs) undergo nuclear translocation in response to stressors including hypoxia, temperature, and oxidative stress. In human airway epithelial cell lines, individual hFOXO factors show distinct, cell-type-specific activation patterns. In Drosophila, hypoxia was the only stressor among those tested that triggered a dfoxo-dependent innate immune response. Because Drosophila possesses a single FoxO ortholog, loss-of-function analysis directly demonstrated that dfoxo is required for stress resistance in the airway epithelium. Reduced FoxO expression was similarly observed in mouse models of asthma and in airway samples from asthma patients, paralleling the increased stress sensitivity seen upon FoxO loss in flies. While our data do not establish that reduced FOXO levels cause asthma, they indicate that FoxO-dependent stress pathways are altered in diseased airways across species. Together, these findings support a model in which FoxO coordinates adaptive epithelial stress responses that maintain airway homeostasis under environmental challenge.

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Publication Details

Journal
eLife
Published
2026-11-11
DOI
https://doi.org/10.7554/elife.96385.2
Primary Topic
FOXO transcription factor regulation
Type
preprint
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preprint

FoxO factors preserve airway epithelial homeostasis by coordinating adaptive stress responses

Ahmed Abdelsadik, Christina Wagner, Ruben D. Prange, Xiao Niu et al.
eLife
FOXO transcription factor regulation
preprint

FoxO factors preserve airway epithelial homeostasis by coordinating adaptive stress responses

Ahmed Abdelsadik, Christina Wagner, Ruben D. Prange, Xiao Niu, Christine Fink, Judith Bossen, Holger Heine, Mario Pieper, Iris Bruchhaus, Ulrich M. Zissler, Karin Uliczka, Thomas Roeder, Michael Wegmann, Christina Vock, Carsten B. Schmidt‐Weber, Mirjam Knop, Peter König, Soren Franzenburg, Petra Pfefferle
preprint en

Abstract

Airway epithelia must maintain functional and structural homeostasis despite exposure to diverse environmental stressors. FoxO transcription factors are well suited to this task, acting as integration hubs that translate extrinsic and intrinsic signals into appropriate physiological responses. We show that FoxO factors in Drosophila, mouse, and human airway epithelial cells (AECs) undergo nuclear translocation in response to stressors including hypoxia, temperature, and oxidative stress. In human airway epithelial cell lines, individual hFOXO factors show distinct, cell-type-specific activation patterns. In Drosophila, hypoxia was the only stressor among those tested that triggered a dfoxo-dependent innate immune response. Because Drosophila possesses a single FoxO ortholog, loss-of-function analysis directly demonstrated that dfoxo is required for stress resistance in the airway epithelium. Reduced FoxO expression was similarly observed in mouse models of asthma and in airway samples from asthma patients, paralleling the increased stress sensitivity seen upon FoxO loss in flies. While our data do not establish that reduced FOXO levels cause asthma, they indicate that FoxO-dependent stress pathways are altered in diseased airways across species. Together, these findings support a model in which FoxO coordinates adaptive epithelial stress responses that maintain airway homeostasis under environmental challenge.

eLife
Philipps University of Marburg (DE), Universitätsklinikum Gießen und Marburg (DE), Helmholtz Zentrum München (DE), Christian-Albrechts-Universität zu Kiel (DE), Research Center Borstel - Leibniz Lung Center (DE), German Center for Lung Research (DE), Universities of Giessen and Marburg Lung Center (DE), Rosenheim Technical University of Applied Sciences (DE), Technical University of Munich (DE), Aswan University (EG), University of Lübeck (DE), Bernhard Nocht Institute for Tropical Medicine (DE)
FOXO transcription factor regulation
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