Host long non-coding RNAs (lncRNAs) are emerging as critical regulators of influenza A virus (IAV) pathogenesis. Still, the functional landscape of avian host lncRNAs remains largely unexplored. In this study, we identified a novel H9N2-induced transcript lncRNA, lncGVRP1, which serves as a conserved positive regulator of IAV replication across H9N2, H1N1, and H3N2 subtypes. In addition, we discovered that lncGVRP1 acts as a functional lncRNA containing a hidden open reading frame (ORF). This ORF encodes a novel 74-amino acid micro-peptide, named GVRP1-ORF. Functional rescue experiments demonstrated that the enhancement of viral activity by the lncGVRP1 is strictly dependent on the peptide it encodes. Overexpression of the GVRP1-ORF recapitulated the pro-viral effect achieved by overexpressing the lncRNA. In contrast, an ORF-deleted mutant entirely failed to promote viral replication. Mechanistically, lncGVRP1 facilitates viral propagation by significantly suppressing the host type I interferon (IFN) response and downstream interferon-stimulated genes (ISGs). Furthermore, transcriptome-wide analysis indicated that lncGVRP1 modulates critical cellular machineries, including FoxO signaling and lysosomal trafficking. Collectively, our findings reveal a unique mechanism in which a lncRNA-derived micro-peptide hijacks host immunity to support viral persistence. Moreover, this micro-peptide may serve as a potential therapeutic target against influenza infection.

To Cite This Article: Fan M, Liu Z, Zeng Y, Qiao Y, Wang C, Rushanov A, Zhang Y, Su J and Ping J, 2026. The avian host lncGVRP1 encodes a novel micro-peptide that facilitates influenza a virus replication by suppressing antiviral interferon response. Pak Vet J, 46(4): 899-909. http://dx.doi.org/10.29261/pakvetj/2026.086