Drosophila blood cells bridge distant injury and gut homeostasis through Upd3-mediated inter-organ signaling

Abstract Inter-organ communication is a central feature of host defence and tissue repair. In Drosophila, hemocytes secrete the cytokine-like ligand Unpaired 3 (Upd3, an IL-6 homolog) to activate JAK/STAT signaling in the gut, yet why this axis is essential for survival after injury has remained unclear. Here we show that loss of hemocyte activation by reactive oxygen species (ROS) and the consequent failure to produce Upd3 leads to adherens junction disruption, intestinal barrier dysfunction, and increased lethality following clean injury. Hemocyte-derived Upd3 drives sustained STAT activation in the gut epithelium, promoting enterocyte turnover and survival after injury. Chronic STAT activity further modulates intestinal stem cell fate and differentiation, indicating that hemocyte–gut signaling shapes long-term epithelial homeostasis. Notably, hemocytes home to the gut after distant wounding, where their localized presence enhances resistance to enteric infection. Taken together, these findings reveal that Drosophila blood cells bridge distant injury and gut homeostasis through Upd3-mediated inter-organ signaling that links wound sensing to epithelial integrity and host survival.