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Summary A number of new cell death processes have been discovered in recent years, including ferroptosis, which is characterized by the accumulation of lipid peroxidation products derived from iron metabolism. The evidence suggests that ferroptosis has a tumor-suppressor function. However, the mechanism by which ferroptosis mediates the response of tumor cells to oncolytic viruses remains poorly understood. The Newcastle disease virus (NDV) can selectively replicate in tumor cells. We show that NDV-induced ferroptosis acts through p53-SLC7A11-GPX4 pathway. Meanwhile, the levels of intracellular reactive oxygen species and lipid peroxides increased in tumor cells. Ferritinophagy was induced by NDV promotion of ferroptosis through the release of ferrous iron and an enhanced Fenton reaction. Collectively, these observations demonstrated that the NDV can kill tumor cells through ferroptosis. Our study provides novel insights into the mechanisms of NDV-induced ferroptosis and highlights the critical role of viruses in treating therapy-resistant cancers., Graphical abstract, Highlights • Oncolytic viruses NDV caused tumor cells death through ferroptosis • NDV-induced ferroptosis acts through nutrient deprivation by suppression of System Xc− • P53 activation is required for NDV-induced ferroptosis initiation • Ferritinophagy induced by NDV promotes ferroptosis through release of ferrous iron, Biological sciences; Virology; Cell biology; Cancer