GOT2, also known as Glutamic-oxaloacetic transaminase 2, is a highly tissue-specific gene in the liver. It is a key component of the malate-aspartate shuttle, which is crucial for maintaining intracellular NAD(H) redox balance and amino acid metabolism [3,4]. This shuttle mechanism enables cells to transfer reducing equivalents from the cytosol to the mitochondria, and GOT2 is also involved in mutant KRAS-mediated rewiring of glutamine metabolism in pancreatic ductal adenocarcinoma [2].

In hepatocellular carcinoma (HCC), knockdown of GOT2 in HCC cells promoted proliferation, migration, invasion, and in mouse models of HCC, loss of GOT2 promoted tumor growth as well as hematogenous and intrahepatic metastasis. Mechanistically, it enhanced glutaminolysis, nucleotide synthesis, and glutathione synthesis by reprogramming glutamine metabolism, activating the PI3K/AKT/mTOR pathway [1].

In pancreatic cancer, the loss of GOT2 in vitro disturbed redox homeostasis and halted proliferation of pancreatic ductal adenocarcinoma (PDA) cells. However, in xenograft PDA or autochthonous mouse models, loss of GOT2 had no effect on tumor growth as the pancreatic tumor microenvironment, specifically cancer-associated fibroblasts releasing pyruvate, could rescue the proliferation of GOT2-knockdown cells [2].

In conclusion, GOT2 plays a significant role in maintaining cellular redox balance and amino acid metabolism through its involvement in the malate-aspartate shuttle. Gene knockout studies in mouse models have revealed its complex role in cancer development, showing differential effects in vitro and in vivo depending on the tumor microenvironment. These findings provide insights into potential therapeutic and diagnostic applications for HCC and pancreatic cancer [1,2].