TNF-α inhibits Epstein Barr virus reactivation through the GPX4 mediated glutathione pathway

Epstein-Barr virus (EBV) is a carcinogenic γ-herpesvirus that remains latent in more than 95% of adults. The virus can undergo lytic activation when immune function is suppressed or when stimulated by drugs or pathogens. EBV reactivation poses a significant threat to human health and is closely associated with various cancers, such as Burkitt's lymphoma and nasopharyngeal carcinoma. Inhibiting EBV reactivation is a current clinical challenge. Tumour necrosis factor-α (TNF-α), an important cytokine, has different effects on various viruses. It also exerts varying effects on the same virus depending on the type of infected cell. This study aimed to investigate the impact of TNF-α on EBV reactivation and its underlying mechanisms. Our experimental research revealed that TNF-α significantly inhibits EBV reactivation and that this inhibitory effect is mediated primarily through its receptor TNFR1. Furthermore, TNF-α affects the expression of the GPX4 protein and regulates the potential ferroptosis state of cells. Using transmission electron microscopy and other methods, we observed typical characteristics of ferroptosis, such as changes in mitochondrial morphology and Fe2 + accumulation. Additionally, we established stable GPX4-knockdown cell lines, which demonstrated the crucial role of GPX4 in the process of TNF-α-mediated inhibition of EBV reactivation. Overall, TNF-α acts on the TNFR1 receptor, thereby affecting the GPX4 protein and the ferroptosis pathway to achieve its inhibitory effect on EBV reactivation. These findings provide new insights into the mechanisms of EBV reactivation and may offer new perspectives for the early treatment of EBV-related diseases.