Amino acid metabolic reprogramming: future prospects for cholangiocarcinoma therapy

Cholangiocarcinoma (CCA) is a highly heterogeneous disease with a poor prognosis and a 5-year survival rate of less than 20% due to late diagnosis and limited therapeutic options, and the current problems in the treatment of CCA can be mainly attributed to the low rate of early diagnosis, the limited availability of targeted drugs, and the gradual increase in chemoresistance. Metabolic reprogramming in CCA causes the accumulation of large amounts of lactic acid and glycolytic intermediates, exacerbating hypoxia and the formation of an acidic environment at the tumor site, which further reduces the effectiveness of therapeutic drugs. Amino acid metabolic reprogramming promotes the proliferation, metastasis, spreading, and tumor angiogenesis of CCA cells, and some amino acid metabolites, in turn, regulate the metabolic state and gene expression of cells, which in turn regulates the cellular phenotype. Abnormal metabolism of amino acids negatively affects the progression of CCA. In the amino acid metabolism of CCA, the PI3K/AKT/mTOR and AMPK/Nrf2 pathways are two key pathways, and c-Myc plays an important role in glutamine metabolism as a transcription factor. Future studies should design targeted drugs around the abnormal accumulation process of glutamine, arginine and other amino acids to disrupt the amino acid uptake dominance in malignant tumors, as well as design novel drugs according to the changes in the tumor microenvironment.