GPT2, also known as glutamate pyruvate transaminase 2, is a nuclear-encoded mitochondrial enzyme. It catalyzes the reversible transfer of an amino group from glutamate to pyruvate, generating alanine and alpha-ketoglutarate. This reaction is involved in glutamine catabolism and plays a role in replenishing tricarboxylic acid (TCA) cycle intermediates, thus being crucial for cellular metabolism [7].

In glioblastoma, hypoxia-inducible factor (HIF)-2 directly induces GPT2, promoting tumor growth. Genetic or pharmacological inhibition of GPT2 decreases cell growth and migration, and knockout of GPT2 in mice inhibits tumor growth [1]. In triple-negative breast cancer, GPT2 is up-regulated and promotes metastasis. Exosomal GPT2 derived from these cells activates BTRC to enhance metastasis, and GPT2 knockout reduces lung metastasis in mice [2]. In acute myeloid leukemia, IGF2BP2 regulates GPT2 in the glutamine metabolism pathways, and inhibiting IGF2BP2 shows anti-leukemia effects [3]. In the locus coeruleus, GPT2 deficiency in mice causes early neurodegeneration, with loss of tyrosine hydroxylase-positive neurons, abnormal action potentials, and microgliosis and astrogliosis [4]. In breast cancer, GPT2 promotes metastasis through the GABA-GABAA receptor-PKC-CREB signaling pathway, and GPT2 knockout reduces metastasis and prolongs survival in mice [5]. In triple-negative breast cancer, abrogating GPT2 decreases TCA cycle intermediates, impairs mTORC1 activity, and induces autophagy, resulting in decreased tumor growth in xenograft studies [6]. In lung adenocarcinoma, inhibition of GPT2 suppresses tumor growth and increases CD4 and CD8 expression, and shows enhanced antitumor immunity when combined with anti-PD-L1 [8].

In conclusion, GPT2 plays essential roles in various biological processes and disease conditions. Gene knockout mouse models have significantly contributed to understanding its role in cancer, neurodegeneration, and metabolic-related disorders, revealing its potential as a therapeutic target in these disease areas.