Epstein-Barr virus modulates iron metabolism and ferritin expression to promote tumorigenesis in gastric cancer.

Iron is crucial for cell survival and maintaining normal physiological functions. Viral infections can disrupt cellular iron metabolism, leading to inflammation and cancer. Ferritin, a key iron-binding protein, consists of ferritin heavy chain 1 (FTH1) and ferritin light chain (FTL) and helps regulate systemic iron balance, both implicated in various tumor developments. Epstein-Barr virus (EBV), the first oncogenic virus discovered in humans, can induce the development of EBV-associated gastric cancer (EBVaGC). However, the regulatory mechanisms and functions of FTH1 and FTL in EBVaGC are poorly understood. This study aimed to investigate how EBV regulates FTH1 and FTL and their roles in the development of EBVaGC. We show that EBV is able to remodel intracellular iron metabolism, affecting the expression of FTH1 and FTL. EBV-encoded LMP2A promotes the expression of FTH1 and FTL by up-regulating p62 and blocking the autophagy degradation pathway, thus participating in the occurrence and development of EBVaGC. Knocking down FTL inhibits cell migration and proliferation, and promotes apoptosis, whereas FTH1 knockdown has negligible effects on these cellular functions. Additionally, we found that ferritin enhanced the inflammatory state of gastric cancer cells. Overall, our findings highlight the significant impact of EBV on ferritin, underscoring a previously unrecognized role of ferritin in the progression of EBVaGC. This novel pathway could offer new therapeutic targets for the treatment of EBVaGC.