The carcinogenic metabolite D-2-hydroxyglutarate (D-2-HG) produced by IDH mutations induces DNA and histone hypermethylation by competitively inhibiting the activity of α-KG-dependent epigenetic regulatory enzymes, thereby driving tumorigenesis and development, becoming the core mechanism of CCA malignant transformation44. The gene discussed is IDH1; the disease is cholangiocarcinoma.