Newcastle disease virus induced ferroptosis through p53-SLC7A11-GPX4 axis mediated nutrient deprivation in tumor cells

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. Newcastle disease virus can selectively replicate in tumor cells. We show that NDV-induced ferroptosis acts through p53-SLC7A11-GPX4 pathway. The expression of tumor suppressor gene p53 increased after NDV infection, and the expressions of SLC7A11 and SLC3A2 were down-regulated, leading to the inhibition of glutathione synthesis and a decrease in glutathione peroxidase 4 expression. The chemical compound erastin, which induces ferroptosis, also down-regulated glutathione synthase expression and caused lipid peroxide accumulation and cell death. 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 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. ### Competing Interest Statement The authors have declared no competing interest. * NDV : Newcastle disease virus NP : Nucleocapsid protein NCOA4 : nuclear receptor coactivator 4 FTH1 : ferritin heavy chain 1 FTL : ferritin light chain TFR1 : transferrin receptor protein 1 qPCR : quantitative polymerase chain reaction AMPK : AMP-activated protein kinase PUFAs : polyunsaturated fatty acids BAP1 : BRCA1-associated protein 1 ACSL4 : acyl-CoA synthetase long-chain family member 4 ALOX 12 : 12-lipoxygenase DCFDA : 2′,7′-dichlorofluorescin diacetate TBHP : tert-butyl hydroperoxide MDA : malondialdehyde LDH : lactate dehydrogenase ROS : reactive oxygen species LPO : lipid peroxidation GSH : glutathione LIP-1 : liproxstain-1 PFTα : pifithrin-α Baf-A1 : bafilomycin A.