ZNFX1 functions as an compensatory dsRNA recognition receptor to exert antiviral effectin orange-spotted grouper

Many Actinopterygii fish lack the canonical dsRNA receptor RIG-I, leaving open questions about their antiviral capacity, alternative receptors, and fish-virus immune interactions. This study identifies A—a compensatory dsRNA sensor upregulated by OGNNV infection. By binding viral dsRNA, A exerts dual immunoregulation in different cells to modulate viral inflammation and inhibit replication. Mechanistically, it reduces brain cell neurotoxicity via suppressing IFN-I/pyroptosis, while activating TBK1-dependent IFN-I signaling in splenocytes. The study confirms A as a compensatory antiviral receptor in RIG-I-deficient fish, aiding NNV control strategies and illuminating innate immunity in RIG-I-lacking Actinopterygii.