In summary, we have presented evidence showing that the EGFR-STAT3 pathway is the main downstream effector of NNMT in iCCA, and NNMT activates the EGFR–STAT3 signaling axis to regulate glycolysis in iCCA cells by reducing the levels of H3K9me3 and H3K27me3 at the EGFR promoter region, which is a unique mechanism to promote the proliferation of iCCA cells. This evidence concerns the gene STAT3 and infantile convulsions and choreoathetosis.