Activate Bcat1 to increase branched-chain amino acids metabolism to promote intrahepatic cholangiocarcinoma migration and invasion via PI3K-AKT-mTOR

Branched-chain amino acids (BCAAs), known as nutritional supplements, also serve as adjuvants in disease treatment, are involved in the development of intrahepatic cholangiocarcinoma (ICC), although their underlying mechanisms remain unclear. This study thoroughly investigates the role of branched-chain amino acids metabolism in intrahepatic cholangiocarcinoma progression. We identified aberrant branched-chain amino acids metabolism in intrahepatic cholangiocarcinoma using publicly available RNA sequencing data at the population level and metabolomics from animal models. Through dietary intervention with branched-chain amino acids restriction, we evaluated the effect of a low branched-chain amino acids diet on tumor growth. In vitro experiments were conducted to assess the impact of branched-chain amino acids and branched-chain aminotransferase 1 (Bcat1) on the proliferation and metastasis of intrahepatic cholangiocarcinoma cells. Results showed that branched-chain amino acids levels were elevated in the intrahepatic cholangiocarcinoma mouse model, and a low branched-chain amino acids diet controlled tumor growth and progression. branched-chain amino acids and their downstream products, branched-chain α-keto acids, promoted intrahepatic cholangiocarcinoma cell migration and invasion via Bcat1-mediated activation of the PI3K-AKT1-mTOR pathway. This research offers new insights into precision nutrition therapy for intrahepatic cholangiocarcinoma.