Besides its mitochondrial role, GOT2 has been identified as a plasma membrane-associated fatty acid-binding protein (FABPpm). Under conditions of cellular stress, organ injury, or lipid accumulation, GOT2/FABPpm regulates fatty acid oxidation and energy metabolism by mediating transmembrane transport of free fatty acids (34). While the role of GOT2 in fatty acid transport is well-established in normal tissues, its biological function in cancer has only recently been uncovered. In pancreatic ductal adenocarcinoma models, Abrego et al. found that GOT2 predominantly localizes to the nucleus, enhancing the transport of fatty acids such as arachidonic acid, thereby facilitating their binding to peroxisome proliferator-activated receptor δ (PPARδ) and significantly activating the PPARδ signaling pathway (35). These findings reveal a novel mechanism by which GOT2 drives tumor progression through regulating fatty acid oxidation and lipid signaling pathways, especially under conditions of stress or metabolic dysregulation ( Table 2 ).

As a key enzyme in the glutamine-aspartate shuttle, GOT2 participates in nitrogen balance regulation and urea cycle metabolism. By directing the transfer of aspartate into the urea cycle, GOT2 promotes excretion and recycling of excess intracellular nitrogen, maintaining nitrogen metabolic homeostasis. Studies have shown that in colorectal cancer (CRC), the HIF-1α–SOX12 signaling axis activates GOT2 expression, driving asparagine biosynthesis, thereby simultaneously regulating the urea cycle and amino acid synthesis pathways. Specific inhibition of this signaling axis significantly reduces asparagine levels, thereby suppressing tumor cell proliferation through metabolic reprogramming (36). In hepatocellular carcinoma (HCC), Li et al. further demonstrated that GOT2 knockdown reprograms glutamine metabolism by enhancing glutaminolysis, nucleotide biosynthesis, and glutathione production, maintaining redox balance and promoting tumor progression via the PI3K/AKT/mTOR signaling pathway (37). Notably, the molecular mechanisms by which cancer cells dynamically allocate aspartate flux between the urea cycle and nucleotide synthesis pathways through GOT2 remain to be systematically elucidated.

GOT2 has a dual role in regulating cellular senescence. During glutamine catabolism, it promotes aspartate production, dynamically modulating glutamate and glutathione synthesis, thereby maintaining ROS homeostasis and preventing lipid peroxidation damage. Abnormal GOT2 expression significantly alters the cellular response to senescence signals, and the resulting disruption of redox homeostasis directly impacts tumor cell proliferation and survival. Yang et al. revealed that mitochondrial GOT2 participates in the regulation of cellular senescence in pancreatic ductal adenocarcinoma (PDAC) by finely controlling ROS levels. Further studies indicated that GOT2 knockdown increases ROS levels in PDAC cells, triggering p27-mediated cellular senescence, a protective effect potentially closely related to chemotherapy resistance (38).

As a mitochondrial transaminase with broad substrate specificity, GOT2 catalyzes the transamination of cysteine sulfinate to generate 3-sulfinylpyruvate, which can subsequently decompose into pyruvate and sulfur dioxide. This reaction potentially links GOT2 to the biosynthesis of taurine and suggests a role in maintaining cellular sulfur metabolic homeostasis (39, 40). Previous studies have shown that aberrant GOT2 expression—such as decreased tissue levels or elevated serum levels—is closely associated with dysregulation of the sulfur oxidation pathway in certain patients with myocardial injury or cardiovascular diseases. This may involve mitochondrial sulfur compound metabolism and lead to oxidative stress and cellular dysfunction (41). Although current research on GOT2-related sulfur metabolism has primarily focused on non-cancerous diseases, whether a similar mechanism operates in tumor cells to affect taurine synthesis or modulate sulfur oxidation remains to be determined. Given the potential roles of taurine and sulfur dioxide in regulating apoptosis, redox balance, and the immune microenvironment, investigating GOT2-mediated sulfur metabolism may offer new insights into cancer metabolic reprogramming.

The multicellular expression pattern and functional heterogeneity of GOT2 within the tumor ecosystem have been progressively elucidated. GOT2 is not only highly expressed in cancer cells but is also broadly expressed in immune cells (such as T cells and macrophages) and stromal cells (such as fibroblasts and endothelial cells) within the tumor microenvironment. For instance, in a spontaneous pancreatic cancer transgenic model (KPC mice), quantitative immunohistochemical analyses revealed that although GOT2 protein expression is markedly downregulated in tumor epithelial cells, cancer-associated fibroblasts (CAFs) retain high levels of GOT2 expression, suggesting a compensatory role in stromal remodeling (12). Single-cell transcriptomic analysis further confirmed that GOT2 is widely expressed in non-malignant cells within the pancreatic tumor microenvironment, including macrophages, CD8⁺ T cells, and endothelial cells, with expression levels positively correlated with metabolic activity (42). Bioinformatic analyses also revealed broad GOT2 expression in immune and stromal compartments of clear cell renal cell carcinoma (43). Moreover, fourth-generation CAR-T cells engineered to stably overexpress GOT2 via lentiviral vectors demonstrated enhanced cytotoxicity against hepatocellular carcinoma cells in both in vitro and in vivo models (44).

By catalyzing glutamine metabolism to produce aspartate and its derivatives, GOT2 not only maintains intracellular nitrogen metabolism and TCA cycle function but also supplies key metabolic substrates for immune cells. Aspartate is essential not only for pyrimidine and nucleotide biosynthesis but also plays an irreplaceable role in the activation, proliferation, and effector function of CD8⁺ T cells. Studies have shown that activated T cells are highly dependent on aspartate; insufficient aspartate availability leads to mitochondrial metabolic dysfunction, suppression of mTOR signaling, and reduced expression of cytotoxic molecules such as granzyme B (GZMB) and interferon-γ (IFN-γ), ultimately impairing T cell cytotoxicity (45). Tumor cells often upregulate GOT2 and associated metabolic pathways to enhance aspartate synthesis and uptake, thereby establishing metabolic competition with immune cells within the tumor microenvironment. Given the nutrient-restricted nature of the tumor microenvironment, preferential aspartate acquisition by tumor cells exacerbates its scarcity, severely limiting the metabolic adaptability and functional status of CD8⁺ T cells. This compromises their antitumor activity and facilitates immune evasion (46). Therefore, GOT2 not only participates in cancer cell metabolic reprogramming but also plays a pivotal role in shaping an immunosuppressive microenvironment.

CAFs support GOT2-mediated metabolic reactions by secreting nutrient substrates such as glutamine, thereby facilitating the production of energy and biosynthetic intermediates in tumor cells. In turn, aspartate or α-KG generated by tumor cell metabolism can regulate CAF metabolism, for example, by enhancing their lactate production capacity, establishing a bidirectional metabolic coupling. This cooperative interaction significantly enhances tumor cell proliferation and invasiveness (35, 47). A study by Kerk et al. further revealed this microenvironment-dependent metabolic complementation. In PDAC, while GOT2 knockdown significantly suppresses tumor cell proliferation in vitro, it does not impair tumor growth in xenograft or orthotopic mouse models. Mechanistically, CAFs—an essential component of the PDAC microenvironment—secrete redox-active pyruvate that provides alternative metabolic support to GOT2-deficient cells. When cultured in CAF-conditioned medium (CM), the proliferation of GOT2-deficient cells is partially restored. However, when pyruvate uptake is blocked or its conversion to lactate is inhibited, neither CAF CM nor exogenous pyruvate can rescue the proliferative capacity of GOT2-deficient cells (12). These findings underscore a functionally complementary metabolic interaction between tumor cells and CAFs, in which GOT2 serves as a critical mediator linking cancer and stromal metabolism.

In addition to interacting with neighboring cells in the local microenvironment through metabolic and signaling pathways, tumor cells can also engage in long-range communication via extracellular vesicles, particularly exosomes (48). Exosomes not only carry bioactive molecules such as miRNAs, proteins, and lipids, but may also encapsulate metabolic enzymes like GOT2 and their associated metabolites for delivery to adjacent or distant recipient cells. Through this mechanism, GOT2 may contribute to the formation of the pre-metastatic niche. For example, GOT2 transferred via exosomes to distant tissues may modulate the intracellular balance of glutamate and aspartate through its transamination activity, thereby influencing glutamine utilization, supporting aspartate biosynthesis, and promoting metabolic reprogramming to enhance the adaptability of recipient cells to new microenvironments. In metastatic lesions, this vesicle-mediated metabolic support mechanism facilitates cancer cell proliferation and survival, enhancing their competitive advantage and accelerating colonization and malignant progression at distant sites (49). Moreover, GOT2-associated metabolites may further modulate immune cell function and stromal remodeling within metastatic sites, contributing to the optimization of the metastatic microenvironment. Collectively, GOT2 not only maintains metabolic homeostasis within primary tumors but also functions as both a bridge and an amplifier of long-range metabolic regulation through exosome-mediated intercellular communication during metastasis.

Various transcription factors dynamically regulate GOT2 transcription by binding to its promoter or enhancer regions. In breast cancer, the BRCA1/ZBRK1 complex represses GOT2 promoter activity, suggesting that BRCA1 loss-of-function may upregulate GOT2 by removing this repression (50). Notably, in diffuse large B-cell lymphoma, inflammation-related signaling pathways (e.g., STAT3 and NF-κB) indirectly enhance GOT2 transcription by upregulating c-Myc, thus meeting the high metabolic demands of tumor cells (51). Further studies revealed that SOX12 forms a metabolic regulatory network in CRC by activating glutaminase (GLS), GOT2, and asparagine synthetase (ASNS). Downregulation of GLS, GOT2, and ASNS effectively blocks SOX12-mediated CRC cell proliferation and metastasis, while ectopic expression of these enzymes reverses the inhibitory effects of SOX12 knockdown on tumor progression (36). Additionally, Stegen et al. identified a novel mechanism by which SOX9 regulates glutamine metabolism through c-MYC, simultaneously increasing expression levels of GLUD1, GLS1, and GOT2 (33).

GOT2 expression is dynamically regulated by epigenetic mechanisms, such as DNA methylation, but this regulation shows significant disease- and environment-dependent variability. In clear cell renal cell carcinoma (ccRCC), reduced GOT2 expression is directly associated with abnormally high methylation of its promoter region (43). Another study indicated that GOT2 expression in ccRCC patients is significantly correlated with methylation levels at multiple CpG sites, suggesting that epigenetic silencing of GOT2 may be a critical factor driving tumorigenesis (52). Notably, DNA methylation exerts opposite effects on GOT2 expression in different tumors. In pheochromocytoma, Remacha et al. found that high GOT2 expression correlates with abnormal accumulation of TCA cycle metabolites. Mechanistic studies demonstrated that mutations in TCA cycle-related genes in this tumor might alter DNA methyltransferase (DNMT) activity, inducing hypermethylation of promoter regions of multiple metabolic enzyme genes, including GOT2 (53).

GOT2 mRNA levels are precisely regulated by a multi-layered network of non-coding RNAs. At the direct interaction level, Runtsch et al. found that ACOD1 lncRNA enhances GOT2 enzymatic activity by directly binding to the GOT2 protein, thereby driving tumor metabolic reprogramming (54). At the competitive regulation level, circRNAs function through a “molecular sponge” mechanism: Tang et al. demonstrated that Circ_0006220 in non-small cell lung cancer (NSCLC) stabilizes GOT2 mRNA and enhances its translation by sequestering miR-342-3p, thus promoting tumor angiogenesis and inhibiting apoptosis (55). Jin’s study showed that silencing circSEC31A releases miR-520a-5p, targeting and inhibiting GOT2, significantly reducing MAS function in NSCLC cells (56). Notably, clinical research has indicated the reversibility of this regulation—Prystupa et al. observed a dramatic decrease in GOT2 mRNA levels in peripheral blood leukocytes of NSCLC patients after radical surgery, highlighting the critical role of the tumor microenvironment in post-transcriptional regulation (57).

GOT2 functions are dynamically regulated by post-translational modifications, including acetylation, phosphorylation, and succinylation, with modification patterns showing significant tumor type specificity. Among metabolism-enhancing modifications, acetylation has been identified as a critical regulatory mechanism. In pancreatic cancer, GOT2 acetylation promotes its interaction with malate dehydrogenase 2, forming a functional complex that activates MAS to maintain NADH/NAD⁺ homeostasis, thus driving tumor proliferation (58). In an inflammatory liver microenvironment, inflammation-induced GOT2 acetylation enhances its catalytic activity, promoting adaptive metabolic remodeling (59). Conversely, ω-3 polyunsaturated fatty acid-induced succinylation inhibits GOT2-mediated aspartate synthesis, disrupting essential metabolic pathways in prostate cancer cells and ultimately suppressing their proliferation (60). Notably, phosphorylation also participates in this regulatory network: activation-induced phosphorylation of GOT2 by protein kinase C epsilon significantly enhances its enzymatic activity, suggesting this modification acts as a key molecular switch regulating MAS functions (61). Although these findings underscore the importance of post-translational modifications in tumor metabolic reprogramming, the specificity and biological effects of these modification patterns across different tumor types still require systematic elucidation.