In our study, we found that MFSD4A expression was regulated by methylation of its promoter region in NPC and that MFSD4A could degrade EPH receptor A2 (EPHA2) by recruiting ring finger protein 149 (RNF149), leading to the suppression of the phosphatidylinositol-4,5-Bisphosphate 3-Kinase (PI3K)/protein kinase B (AKT)/extracellular regulated kinase 1/2 (ERK1/2) pathway and epithelial-mesenchyme transition (EMT), thereby inhibiting the proliferation, invasion, and migration of NPC cells. This evidence concerns the gene MAPK3 and nasopharyngeal carcinoma.