RIG-I–MAVS–IFN–NOXA axis coordinates antiviral innate response and apoptosis during parahenipavirus infection

Gamak virus (GAKV) is a recently identified shrew-borne paramyxovirus belonging to the genus Parahenipavirus , which also includes the zoonotic Langya virus (LayV). Despite the growing recognition of shrew-associated paramyxoviruses, the host pathways that detect infection and regulate antiviral responses remain poorly understood. In this study, we characterized host responses to GAKV infection using integrated in vitro and in vivo approaches. GAKV infection induced robust innate immune responses in A549 cells, characterized by activation of interferon regulatory factor 3 (IRF3) and signal transducer and activator of transcription 1 (STAT1), together with induction of type I interferon (IFN) and interferon-stimulated genes (ISGs). Transcriptomic analysis further revealed coordinated enrichment of antiviral and intrinsic apoptosis-associated pathways, suggesting a link between innate immune signaling and apoptosis during GAKV infection. Genetic analyses identified retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signaling protein (MAVS) as essential mediators of antiviral signaling and apoptosis during GAKV infection. Furthermore, disruption of type I IFN-STAT1 signaling attenuated apoptosis. NOXA knockdown reduced apoptosis and enhanced viral replication. Consistent with these in vitro findings, intranasal GAKV inoculation in six-week-old female immunocompetent BALB/c mice was associated with viral RNA detection in lungs and induction of antiviral responses without overt disease. Together, these findings identify a RIG-I–MAVS–IFN–NOXA signaling axis that integrates antiviral and apoptotic responses during GAKV infection, providing a mechanistic framework for understanding host defense against parahenipaviruses.