Coxsackievirus B3 suppresses oral squamous cell carcinoma by inducing ferroptosis through the circ_0010074/miR-214-3p/GPX4 pathway.

Oral squamous cell carcinoma (OSCC) exhibits aggressive invasion with limited treatment options. This study investigates the oncolytic potential of coxsackievirus B3 (CVB3) against OSCC and explores its ability to induce ferroptosis. Gene Set Enrichment Analysis (GSEA) highlighted CVB3's efficacy in initiating ferroptosis, placing the pathogen as a hopeful option in cancer treatment. We demonstrated CVB3 infection significantly inhibited OSCC cell proliferation and tumor growth in mouse models. Biochemical tests verified ferroptosis activation, marked by increased Fe2+, lipid reactive oxygen species (ROS), and malondialdehyde (MDA) levels, alongside decreased glutathione (GSH). These effects were reversed by ferroptosis inhibitors. Mechanistically, CVB3 downregulated circ_0010074 and its target Glutathione peroxidase 4 (GPX4), while upregulating miR-214-3p. Using fluorescence in situ hybridization (FISH) and luciferase assays, we found circ_0010074 sequesters miR-214-3p to regulate GPX4 expression. Our research demonstrates that CVB3 acts as a highly effective oncolytic virus in targeting OSCC, inducing ferroptosis via the previously unrecognized circ_0010074/miR-214-3p/GPX4 pathway. This discovery opens new doors for treating this particularly aggressive form of cancer, offering a potentially groundbreaking therapeutic approach.