Gut-derived Unpaired-3 cytokine signaling promotes systemic hypoxia tolerance in <i>Drosophila</i>

Systemic hypoxia - a reduction in oxygen supply to all tissues and organs - occurs in many physiological and pathological conditions, including fetal development, high altitude exposure, and disorders such as sleep apnea and respiratory disease. Under these conditions, whole-body physiology must adapt to ensure proper tissue functioning and survival. While extensive research has characterized how individual cells sense and adapt to low oxygen conditions, the mechanisms that coordinate whole-body responses to systemic hypoxia remain poorly understood. In this study, we uncover an inter-organ signaling response mediated by the cytokine Unpaired-3 (upd3), a functional homolog of human interleukin-6 (IL-6), that is important for systemic hypoxia tolerance in Drosophila. We demonstrate that hypoxia rapidly induces upd3 expression and activates JAK/STAT signaling in both larvae and adults. Interestingly, we discovered a sex-specific requirement for this pathway, with females requiring upd3 for hypoxia survival while males do not. We also identify the intestine as a critical source of hypoxia-induced upd3 and show that gut-derived upd3 signals to the fat body and oenocytes to mediate hypoxia tolerance by promoting expression of nitric oxide synthase, the FGF ligand Branchless, and the kinase Hipk. Furthermore, we reveal an unexpected role for the canonical hypoxia response transcription factor HIF-1α/sima as a molecular brake, which prevents lethal upd3 overproduction, revealing that hypoxia survival requires precise cytokine dosage control. Our findings define a gut-to-fat body signaling axis that coordinates systemic hypoxia adaptation, highlighting cytokine-mediated inter-organ communication as a mechanism for whole-body adaptation to low oxygen, with potential relevance to hypoxia-related human pathologies.