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.