ZIP8 modulates ferroptosis to drive esophageal carcinoma progression

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy, and a better understanding of its molecular drivers is crucial for developing targeted therapies. Through bioinformatic analyses of gene expression data and immunohistochemistry, we identified the zinc transporter ZIP8 as being overexpressed in ESCC tumors compared to normal esophageal tissue. Functional studies revealed that ZIP8 knockdown impaired ESCC cell proliferation and anchorage-independent growth. Mechanistically, elevated ZIP8 expression enhanced zinc-dependent phosphorylation of CREB, leading to upregulation of the ferroptosis suppressor GPX4 and inhibition of this iron-dependent cell death modality. Significantly, we discovered that the natural compound nobiletin targeted ZIP8, inhibiting ESCC cell growth in vitro and in vivo. Our findings demonstrate ZIP8 as a potential therapeutic target in ESCC and suggest that promoting ferroptosis through ZIP8 inhibition may represent a novel anti-cancer strategy for ESCC therapy.