The current study explored the potential of metformin as a therapeutic drug for IL-1RA-associated OSCC malignancy in an orthotopic xenograft mouse model, showing that IL-1RA-promoted tumor growth and activation of EGFR/JNK and SOX2 expression in tumor tissues was reduced by metformin or cisplatin treatment, and the inhibitory effect was further augmented by combination therapy. The gene discussed is MAPK8; the disease is neoplasm.