GOT2, also known as glutamic-oxaloacetic transaminase 2, is a key enzyme in the malate-aspartate shuttle, which is crucial for transferring reducing equivalents from the cytosol to the mitochondria. It is involved in several critical metabolic pathways, such as glutamine metabolism, and plays an important role in maintaining intracellular NAD(H) redox balance [6]. GOT2 is also relevant in both normal cellular metabolism and dysregulated cancer metabolism [1].

In hepatocellular carcinoma (HCC), knockdown of GOT2 in cells promoted proliferation, migration, and invasion, and in mouse models, loss of GOT2 promoted tumor growth, hematogenous, and intrahepatic metastasis. Mechanistically, GOT2 silencing enhanced glutaminolysis, nucleotide synthesis, and glutathione synthesis by reprogramming glutamine metabolism, activating the PI3K/AKT/mTOR pathway [2].

In pancreatic cancer, the loss of GOT2 in cell lines in vitro disturbed redox homeostasis and halted proliferation. However, in xenograft and 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 [5]. Also, in pancreatic cancer, GOT2 acts as a nuclear fatty acid transporter binding to and activating the PPARδ nuclear receptor, driving immunosuppression by suppressing T cell-mediated antitumor immunity [3,4].

In conclusion, GOT2 is essential for maintaining normal metabolic and redox balance. Through gene knockout and conditional knockout mouse models, its roles in cancer, especially in HCC and pancreatic cancer, have been revealed. In HCC, it acts as a tumor-inhibitory factor, while in pancreatic cancer, it is involved in metabolic regulation and immunosuppression, providing insights into potential therapeutic targets for these diseases.