Cancers reprogram cellular metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells, supporting their aberrant proliferation and survival (1, 2). These reprogrammed activities are recognized as hallmarks of cancers, as many cancer types exhibit general metabolic alterations (2, 3). Normal cell metabolism generates energy for maintaining physiological activities and cellular functions through complex reactions (4). However, cancer cells reprogram metabolism to acquire necessary nutrients from a frequently nutrient-poor environment and repurpose these nutrients to sustain viability and build new biomass (1, 2, 5, 6). Understanding how metabolism is rewired in cancer cells, and utilizing these metabolic changes for therapeutic benefits are key research areas. Accruing evidence suggests that metabolic regulation plays a predominant role in determining cell states, including proliferation and senescence. Therefore, targeting cell metabolism or the key enzymes involved in these processes may be a new strategy for treating refractory cancers.

GOT1 is a key enzyme in cell metabolism, distributed in the liver, muscle, heart, kidney, brain, and other tissues (7). The GOT1 gene, located on human chromosome 10q24.1–25, consists of 9 exons, and encodes a 46.2 kDa protein composed of 413 amino acids (8). GOT1 exhibits abnormal expression in numerous cancers. The expression of GOT1 was up-regulated in pancreatic ductal adenocarcinoma (PDAC) (9–11), colorectal cancer (12, 13), breast cancer (14–16), lung adenocarcinoma (17), glioblastoma (17), prostate cancer (17–19), acute myeloid leukemia (20), and multiple myeloma (21), while down-regulated in poorly-differentiated hepatocellular carcinoma cells (22). Aberrant expression of GOT1 serves as a candidate biomarker. In most cases, elevated expression of GOT1 in cancer is associated with poor prognosis (23, 24). For example, GOT1 expression could be served as an independent prognostic biomarker in PDAC (9). Additionally, serum GOT1 levels are indicators of liver dysfunction in both liver and non-liver tumors, cardiovascular diseases, type 2 diabetes, and all-cause mortality (25–31).

Cytoplasmic GOT1 and its mitochondrial isozyme GOT2 usually occur together and interact with each other in metabolic processes (32–34). GOT1 is mainly present in the cytoplasm and GOT2 exists in the mitochondrial matrix. GOT1 catalyzes aspartate (Asp) and α-ketoglutarate (α-KG) into oxaloacetate (OAA) and glutamate (Glu) in cytoplasm. Then, Glu can generate Asp or be metabolized into other products through tricarboxylic acid (TCA) cycle. Glu can be converted into α-KG via the deamination of glutamate dehydrogenase 1 (GLUD1) and catalyzed to generate Asp by GOT2 in mitochondrial matrix. And then Asp from mitochondrial matrix is converted to OAA via GOT1 in cytoplasm (35). OAA is catalyzed by malate dehydrogenase 1 (MDH1) to generate malate, which is catalyzed to pyruvate through malic enzyme (ME). In this process, NADPH is produced and NADPH/NADP⁺ ratio is increased to maintain reactive oxygen species (ROS) balance (36). GOT2 reversibly catalyzes OAA and Glu into Asp and α-KG, contributing to the TCA cycle and energy production (37–43) ( Figure 1 ). Both GOT1 and GOT2 are crucial components of the malate-aspartate shuttle (MAS), transferring reducing equivalents from NADH into the mitochondria for oxidative phosphorylation (44). Cancer cells utilize the amino acid Glu to support the anabolic processes and promote cell growth. The expression of GOT1 could be regulated by oncogene KRAS (10, 45) or other regulators (43, 45–47) like non-coding RNAs (24, 48–52), affecting Asp synthesis, NADPH production, glucose metabolism, as well as other metabolic pathways, and then tumor cells rewired metabolism to support their proliferation. This process links the expression of GOT1 closely to cancer progression. This review will dissect GOT1-related metabolic mechanisms and the molecular pathways about how GOT1 influences cancer progression. We also discuss potential limitations, challenges, and practical implications in targeting GOT1 therapeutically.

Cancer cells utilize Asp and glutamine (Gln) to support their metabolic process, producing energy, and promote cell proliferation. GOT1, involved in this process, participates in several critical metabolic functions: Asp synthesis, Gln metabolism, glycolysis pathway regulation, immune cell function regulation, and epigenetic regulation ( Figure 2 ). Therefore, GOT1 has become a key consideration when interrogating cancer metabolism.

The expression of GOT1 can be regulated by non-coding RNAs including circular RNAs (circRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), and then affecting cell proliferation and metabolism (46, 48) ( Table 1 ). In addition, lncRNAs and circRNAs usually affect cancer cell proliferation via sponging miRNAs targeted GOT1 directly. For example, circ-MBOAT2 silencing downregulated the expression of GOT1 via sponging miR-433-3p, modulating the tumor development of PDAC (51). In non-small cell lung cancer, hsa_circRNA_103809 sponged miR-337-3p to upregulate the expression of GOT1, affecting the cisplatin-resistance and cell growth (50). CircGOT1 was generated from exon 8 of its host gene GOT1 via back-splicing and then promoted GOT1 expression. CircGOT1 promoted the expression of GOT1 via sponging miR-606 to exert carcinogenesis including promoting tumor growth, migration, and glycolytic metabolism of esophageal squamous cell cancer cells (24). Furthermore, miR-9-5p could directly bind to the 3’-untranslated region (3’UTR) of GOT1 and then inhibited the expression of GOT1, which stunted the proliferation, invasion, Gln metabolism, and redox homeostasis of pancreatic cancer cells (48). Additionally, exosome-derived lncRNA NEAT1 functioned as a ceRNA of miR-9-5p to facilitate the expression of TFRC and GOT1, and then exacerbated ferroptosis of sepsis-associated encephalopathy (52). lncRNA TMPO-AS1 was highly expressed in HCC cells and expedited HCC progression via promoting cell proliferation, stemness as well as suppressing cell apoptosis. Molecular mechanism showed TMPO-AS1 functioned as a molecular sponge for miR-429 and GOT1 served as a downstream target gene of miR-429 in HCC. miR-429 could directly bind to GOT1 and negatively regulated the expression of GOT1 while TMPO-AS1 positively regulated the expression of GOT1. Additionally, GOT1 overexpression reversed the inhibition effects of TMPO-AS1 deficiency on HCC progression, indicating that the TMPO-AS1/miR-429/GOT1 axis may be an underlying treatment strategy for HCC (49).

GOT1 is also a potential target of transcriptional regulators. Paralogous transcriptional regulators TAZ and YAP are considered as central factors in cancer biology and they play key roles in cell proliferation, survival, and cell fate determination (75). TAZ/YAP reprogram cellular energetics to promote the dependence of breast cancer cell growth on exogenous Gln, and TAZ/YAP induced GOT1 and phosphoserine aminotransferase (PSAT1) expression to promote the conversion of Gln to α-KG, and then to support cell growth (14). Additionally, targeting metabolic vulnerability to block of transamination of GOT1 using AOA suppressed the growth of breast cancer cells in a TAZ/YAP-dependent manner (14). These findings indicate more remains to be investigated regarding the role of GOT1 in transcriptional regulation in cancers.

Recent studies have indicated that GOT1 played critical roles in ferroptosis. For instance, in melanoma, miR-9 targeted GOT1 directly, inhibiting the expression of GOT1, which suppressed ferroptosis of melanoma cells (76). In multiple myeloma, GOT1 expression was inhibited by shikonin, enhancing ferroptosis in multiple myeloma cells by promoting the release of autophagic labile iron (21). Additionally, GOT1 inhibition increased labile iron availability through autophagy, enhancing the activity of ferroptosis and impaired proliferation and promoted cell death of pancreatic cancer cells (74). The expression of GOT1 was also up-regulated in pancreatic cancer cell-derived exosomes, promoting cancer cell proliferation, migration, and invasion (77–79). Experimental evidence found that pancreatic cancer cell-derived exosomes enriched with GOT1 inhibited cellular ferroptosis to promoted pancreatic cancer cell progression through mechanisms like upregulating CCR2 expression and activating the Nrf1/HO2559-1 pathway (80). These findings highlight the importance of GOT1 regulation through ferroptosis in cancer treatment strategies, and the necessity to study how genetic and environmental factors influence ferroptosis susceptibility in vivo.

Cellular metabolic reprogramming is a hallmark of cancer, serving as a therapeutic target to overcome limitations in current therapies of cancers. The body of this work involving GOT1 highlights several key points in cancer metabolism. First, cancer cells exhibit dynamic metabolism to support abnormal growth and functions. Second, the metabolic pathways utilized by cancer cells are influenced by various factors such as endogenous signals, tumor microenvironment, nutritional composition, external signals, and oncogenes. Third, using appropriate disease models in the suitable context and environment is crucial for identifying therapeutic targets in cancer metabolism.

A major challenge in targeting cancer metabolism lies in the rapid adaptability of cancer cells to adjust their metabolic pathways (81). Cancer cells can quickly modify their metabolic strategies to utilize available metabolic intermediates from nutrient-deficient environments, synthesizing the energy necessary for their growth. As a component of MAS, the inhibition of GOT1 leads to a decrease in NADPH production. NADPH is essential for multiple metabolic pathways, including glycolysis, and its reduction results in decreased flux into these metabolic routes. Under such circumstances, tumor cells activate a specific metabolic pathway known as non-canonical Gln metabolism replacing the canonical Gln metabolism (82) to meet their energetic demands. In PDAC, GOT1 inhibition resulted in Gln deprivation, dimethyl α-KG did not restore growth upon Gln deprivation, whereas the combination of α-KG and a non-essential amino acid mixture rescued proliferation, suggesting PDAC cells metabolize Gln in a model that is different from canonical models. Gln deprivation led to decreased Gln-derived malate, and Gln-derived OAA converted by GOT1 was metabolized into malate. Malate was utilized by ME1 to generate NADPH, maintaining cell growth (10). In PDAC cells, tumor Asp availability was maintained by both de novo synthesis and alternative extracellular sources in the absence of GOT1/GOT2 in vivo ( 83). Researchers found that PI3K/mTORC2 pathway promoted GOT1 expression via targeting hypoxia-inducible factor HIF-2α, and then activated the non-canonical Gln metabolism in vitro and in vivo, promoting progression of PDAC (46). GOT1 also plays an important role in an acidic tumor microenvironment. In pancreatic cancer, in response to chronic acidosis stress, the expression of GOT1 was increased in cancer cells to fuel oxidative metabolism by enhancing the non-canonical Gln metabolism (84). Cancer cells adapt to nutrient-deprived tumor microenvironment during progression via adjusting the level and function of metabolic enzymes. Inhibition of GOT1 significantly weakened HCC cell proliferation under high glucose conditions, while silencing of glutamate dehydrogenase 1(GDH1) did not take effect. Deletion of GDH1 impaired HCC cell proliferation under low glucose conditions, yet knock-down of GOT1 did not take effect. Moreover, GDH1 expression was elevated in glucose-poor HCC tissues while GOT1 expression was decreased. However, inhibiting Gln-dependent transaminases including GOT2, GPT-1, GPT-2, and PSAT-1 had essentially no impact on proliferation of cells no matter under high or low glucose conditions, suggesting that liver cancer cells maintained survival under different nutritional conditions through the metabolic flexibility of their Gln-related enzymes (63). Collectively, these studies indicate that in the absence of GOT1, cells possess both endogenous and exogenous compensatory mechanisms that allow cancer cells to survive. Thus, GOT1 may be served as a key source to fuel the rewired metabolic pathways.

Although metabolism-targeted therapy is not yet standard therapy for many cancers, several experimental and clinical trials targeting altered metabolism are currently underway. For example, WZB117, a specific GLUT1 inhibitor, could inhibit the tumor-initiating capacity of the cancer stem cells in vitro and inhibit tumor initiation in vivo ( 85). Adapalene, an approved drug clinically used in the therapy of acne vulgaris, could selectively inhibit the activity of GOT1 in a non-competitive manner and further suppress the proliferation of ovarian cancer ES-2 cells (86). AOA, an inhibitor of pyridoxal 5-phosphate-dependent enzymes, could also inhibit the activity of GOT1, causing amino acid deprivation (87, 88). Although numerous small-molecule drugs have been proven to inhibit the activity of GOT1 in a competitive or non-competitive manner (23, 57, 79, 86, 89–91), further efforts are still required for the development of specific inhibitors targeting GOT1. Moreover, none of these GOT1 inhibitors have progressed to clinical trials yet, necessitating further research to develop effective GOT1 inhibitors for cancer treatment. Considerable work remains to translate the basic research on GOT1-targeted drug therapy into clinical applications.

While attempts to treat cancers by targeting cellular metabolism have achieved some success, the development of drug resistance is still a significant challenge in the design of metabolic targeted therapies. It is worth noting that metabolic networks possess remarkable plasticity, allowing them to reconnect and circumvent targeted treatments. Furthermore, certain tumor cells exhibit heterogeneous metabolic subtypes, which exhibit varying prognoses and metabolic susceptibilities (92–94). Consequently, these factors should be thoroughly considered when designing effective metabolic targeted therapies. As research progresses, it is urgent to develop specific and effective drugs targeting metabolism. In the near future, more efficient metabolism-targeting drugs and treatment regimens are expected to develop to improve patient outcomes and extend survival, yielding clinical benefits for patients.