EBV infection-induced GPX4 promotes chemoresistance and tumor progression in nasopharyngeal carcinoma

Epstein-Barr virus (EBV) was the first oncogenic virus identified in humans. It is primarily associated with multiple lymphoid and epithelial cancers, including nasopharyngeal carcinoma (NPC). However, its association with ferroptosis and its role in cancer therapy resistance have not been fully elucidated. Here, we show that EBV infection reduces the sensitivity of NPC cells to ferroptosis by activating the p62-Keap1-NRF2 signaling pathway in conjunction with upregulation of SLC7A11 and GPX4 expression. Knockdown of endogenous GPX4 or blockade of GPX4 using a specific inhibitor enhanced the chemosensitivity of EBV-infected NPC cells. Functional studies revealed that GPX4 knockdown suppresses the proliferation and colony formation of NPC cells. Mechanistically, GPX4 interacts with the TAK1-TAB1/TAB3 complex, regulates TAK1 kinase activity, and further activates downstream MAPK-JNK and NF kappa B pathways. High GPX4 expression is correlated with poor clinical outcomes in patients with NPC and other cancer types. Taken together, our findings suggest that EBV infection has important effects on redox homeostasis, revealing a previously unappreciated role for GPX4 in tumor progression. This novel mechanism provides a potential new target for the treatment of EBV-related tumors.

Automated summary

This study found that Epstein-Barr virus (EBV) infection reduces the sensitivity of nasopharyngeal carcinoma (NPC) cells to ferroptosis by activating the p62-Keap1-NRF2 signaling pathway and upregulating SLC7A11 and GPX4 expression. Inhibition of GPX4 enhances the chemosensitivity of EBV-infected NPC cells. High GPX4 expression is associated with poor clinical outcomes in NPC and other cancer types.