All-Trans Retinoic Acid Inhibits Canine Influenza Virus Replication Through Keratin 27-Mediated Autophagy Modulation.

The influenza A virus (IAV) poses a significant threat to public health. Thus, antiviral drug research is a hotspot for IAV. All-trans retinoic acid (ATRA), a bioactive metabolite of vitamin A, exhibits different effects on different subtypes of IAV. In this study, ATRA was found to inhibit canine influenza virus (CIV) replication in Madin-Darby canine kidney (MDCK) and mink lung cells. Furthermore, the transcriptomic analysis revealed that ATRA significantly upregulated keratin 27 (KRT27), a cytoskeletal protein not previously associated with antiviral immunity. Overexpression of KRT27 suppressed CIV replication, while its knockdown enhanced viral load. Mechanistically, ATRA and KRT27 promoted autophagy, counteracting CIV-mediated autophagy hijacking. Notably, ATRA's antiviral effect was species-specific, showing no inhibition in human BEAS-2B or A549 cells. These findings identify ATRA-induced KRT27 as a novel regulator of autophagy and innate immunity against CIV, offering a potential host-directed therapeutic strategy against influenza viruses.