CircRNA-encoded protein fine-tunes ROS homeostasis and engages conserved JAK-STAT antiviral defenses in <i>Drosophila</i>

Antiviral immunity depends on the balance between host defenses and viral countermeasures. In fruit flies, RNA interference (RNAi) represents the primary barrier to viral infection, but viruses often disable this pathway. We show that the circRNA-encoded protein CRAV provides a backup defense by directly binding the NADPH oxidase Nox to generate moderate reactive oxygen species (ROS). Unlike damaging oxidative stress, these ROS serve as signaling cues that activate p38 and JAK-STAT pathways, which in turn drive antiviral cytokine production. This study uncovers how a circRNA-derived protein engages conserved redox-sensitive immune signaling, illustrating an adaptive strategy that ensures protection when RNAi is compromised. The results provide fundamental insights into the evolutionary diversification of circRNA-encoded proteins and broaden our understanding of how finely tuned ROS signaling contributes to innate antiviral immunity.