The Hemagglutinin of Influenza A Virus Induces Ferroptosis to Facilitate Viral Replication

Abstract Ferroptosis is a novel form of cell death caused by the accumulation of lipid peroxides in an iron‐dependent manner. However, the precise mechanism underlying the exploitation of ferroptosis by influenza A viruses (IAV) remains unclear. The results demonstrate that IAV promotes its own replication through ferritinophagy by sensitizing cells to ferroptosis, with hemagglutinin identified as a key trigger in this process. Hemagglutinin interacts with autophagic receptors nuclear receptor coactivator 4 (NCOA4) and tax1‐binding protein 1 (TAX1BP1), facilitating the formation of ferritin‐NCOA4 condensates and inducing ferritinophagy. Further investigation shows that hemagglutinin‐induced ferritinophagy causes cellular lipid peroxidation, inhibits aggregation of mitochondrial antiviral signaling protein (MAVS), and suppresses the type I interferon response, thereby contributing to viral replication. Collectively, a novel mechanism by which IAV hemagglutinin induces ferritinophagy resulting in cellular lipid peroxidation, consequently impairing MAVS‐mediated antiviral immunity, is revealed.