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.

中文翻译：

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新城疫病毒通过p53-SLC7A11-GPX4轴介导的肿瘤细胞营养剥夺诱导肥大

近年来发现了许多新的细胞死亡过程，包括铁结节病，其特征是源自铁代谢的脂质过氧化产物的积累。有证据表明，肥大症具有肿瘤抑制功能。然而，铁氧体肥大介导肿瘤细胞对溶瘤病毒的反应的机制仍知之甚少。新城疫病毒可以在肿瘤细胞中选择性复制。我们显示NDV诱导的肥大病通过p53-SLC7A11-GPX4途径起作用。NDV感染后，抑癌基因p53的表达增加，而SLC7A11和SLC3A2的表达下调，导致谷胱甘肽合成受到抑制，谷胱甘肽过氧化物酶4表达下降。引起铁锈病的化学化合物雌激素，还下调了谷胱甘肽合酶的表达，并导致脂质过氧化物的积累和细胞死亡。同时，肿瘤细胞中细胞内活性氧和脂质过氧化物的水平增加。NDV通过释放亚铁和增强Fenton反应来促进肥大症来诱导铁蛋白吞噬。总体而言，这些观察结果表明，NDV可以通过肥大病杀死肿瘤细胞。我们的研究为NDV引起的肥大症的发病机理提供了新颖的见解，并强调了病毒在治疗耐药性癌症中的关键作用。NDV通过释放亚铁和增强Fenton反应来促进肥大症来诱导铁蛋白吞噬。总体而言，这些观察结果表明，NDV可以通过肥大病杀死肿瘤细胞。我们的研究为NDV引起的肥大症的发病机理提供了新颖的见解，并强调了病毒在治疗耐药性癌症中的关键作用。NDV通过释放亚铁和增强Fenton反应来促进肥大症来诱导铁蛋白吞噬。总体而言，这些观察结果表明，NDV可以通过肥大病杀死肿瘤细胞。我们的研究为NDV引起的肥大症的发病机理提供了新颖的见解，并强调了病毒在治疗耐药性癌症中的关键作用。