A novel role of circCPSF6 regulating antiviral innate immunity via miR-665 and PCBP2-IPS-1 axis in IAV infection

Innate immunity plays a vital role in subverting viral infections via dynamic regulatory networks that calibrate antiviral response and prevent excessive inflammation. These networks are coordinately regulated by coding and non-coding elements of the genome. The non-coding elements, particularly circular RNAs (circRNAs), have emerged as a key modulator of various biological processes, yet their precise function in innate immune response during influenza A virus (IAV) infection remains insufficiently defined. Here, we identified circCPSF6, a conserved circRNA that remains suppressed during IAV infection, in vitro and in vivo. Functional analyses revealed that circCPSF6 acts as an antiviral regulator through a dual regulatory mechanism of RNA-RNA and RNA-protein interactions. circCPSF6 sponges proviral miR-665, thereby alleviating the repression of key antiviral mediators such as MyD88, STAT2, and IKKε via RNA-RNA interactions. At RNA-protein level, circCPSF6 directly interacts with the RNA-binding protein PCBP2, which is a negative regulator of IPS-1, and sustains IPS-1-mediated antiviral signaling. These interactions enhance cytokines and interferon-stimulated genes expression, which strengthen antiviral response. Our findings report circCPSF6 as a crucial regulator of host innate immune response and highlight circRNA-mediated networks as potential therapeutic targets in viral infection.