Novel Duck Orthoreovirus Induces Ferroptosis in HD11 Cells by Hijacking Cellular Iron Metabolism and Promoting Iron Accumulation

Novel duck orthoreovirus (NDRV) infection induces severe splenic necrosis in ducks, resulting in a cascade of detrimental consequences, including immunosuppression, secondary infections, and diminished vaccine efficacy. Avian orthoreovirus (ARV) exhibits high tropism for macrophages, with splenic macrophages being identified as the primary target cells of NDRV. Although ferroptosis has been implicated in this pathological process, the molecular mechanism underlying NDRV‐induced cellular damage remains poorly elucidated. In this study, an in vitro model of NDRV infection was established using HD11 cells to systematically investigate its effect on ferroptosis and the associated mechanisms. Our results indicate that NDRV infection triggers ferroptosis and markedly elevates intracellular Fe 2+ levels. Mechanistically, NDRV upregulates transferrin receptor 1 (TfR1), thereby enhancing iron uptake, promoting iron accumulation, and ultimately inducing ferroptosis. This study is the first to reveal that NDRV induces macrophage ferroptosis by hijacking cellular iron metabolism, providing a theoretical foundation for understanding the mechanism through which NDRV infection mediates splenic necrosis and immune cell injury.