bims-glucam 2025-05-18 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–05–18
23 papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine modulates stress granule formation in cancer cells through core RNA-binding proteins.
Computational modeling of cancer cell metabolism along the catabolic-anabolic axes.
Mitochondrial HSP90 paralog TRAP1 deletion drives glutamine addiction in tumor cells via destablization of the Cys/Glu antiporter SLC7A11/xCT.
Yuanhuacine suppresses head and neck cancer growth by promoting ASCT2 degradation and inhibiting glutamine uptake.
KLHL7 enhances cell viability and cell cycle progression in glioma via glutamine metabolism by activating the β-catenin signaling pathway.
Tobacco Smoking Rewires Cell Metabolism by Inducing GAPDH Succinylation to Promote Lung Cancer Progression.
Complement C5a promotes human retinal pigment epithelial cell viability and migration through SLC38A1-mediated glutamine metabolism.
Upregulations of SNAT2 and GLS-1 Are Key Osmoregulatory Responses of Human Corneal Epithelial Cells to Hyperosmotic Stress.
Advancing Cancer Treatment: A Review of Immune Checkpoint Inhibitors and Combination Strategies.
Glucose, glutamine, lactic acid and α‑ketoglutarate restore metabolic disturbances and atrophic changes in energy‑deprived muscle cells.
Can arginine, glutamate and glutamine serve as surrogates of intestinal mucosal healing in the patients with celiac disease following gluten-free diet? An NMR based metabolomics study.
Metabolic pathway analysis of tumors using stable isotopes.
Immunometabolism of Innate Immune Cells in Gastrointestinal Cancer.
MYLK-AS1 Enhances Glutamine Metabolism to Promote EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer.
Metabolic Plasticity in Prostate Cancer: The Warburg Effect and Its Clinical Relevance.
Activity Regulation of a Glutamine Amidotransferase Bienzyme Complex by Substrate-Induced Subunit Interface Expansion.
Advances in the mechanisms of HIF-1α-enhanced tumor glycolysis and its relation to dedifferentiation.
A phase I/II study of the safety and efficacy of telaglenastat (CB-839) in combination with nivolumab in patients with metastatic melanoma, renal cell carcinoma, and non-small-cell lung cancer.
Advances in the Study of Metabolic Reprogramming in Gastric Cancer.
The role of glutamine and leucine supplementation in liver metabolic reprogramming during sepsis.
Integrative single-cell RNA sequencing and bulk RNA sequencing reveals the characteristics of glutathione metabolism and protective role of GSTA4 gene in pancreatic cancer.
Protein S-glutathionylation confers cellular resistance to ferroptosis induced by glutathione depletion.
The role of glutamate dehydrogenase in the ageing brain.

J Cell Sci. 2025 May 16. pii: jcs.263679. [Epub ahead of print]

Glutamine modulates stress granule formation in cancer cells through core RNA-binding proteins.

Gabriel P Faber, Gilad Gross, Oz Mualem, Matan Y Avivi, Hiba Waldman Ben-Asher, Orly Yaron, Orit Shefi, Rakefet Ben-Yishay, Dana Ishay-Ronen, Yaron Shav-Tal.

  Cytoplasmic stress granules (SGs) induced by various stresses have been linked to cancer and other disorders. Which active energy pathways are required for SG formation remains unclear. We used nutrient deprivation to show that glutamine is the sole amino acid source governing whether cancer cells form SGs. Metabolic profiling revealed the essential functions of glutamine and glucose in SG formation under limiting metabolic conditions. Providing glutamine during metabolic stress restored ATP levels in cancer cells and revived many essential gene expression patterns. Myc, a known regulator of the shift between glucose and glutamine metabolism, showed increased expression as cells moved to glutamine uptake. Inhibition of MYC prevented SG formation even with glutamine present and increased cell death after arsenite exposure. The RNA-binding proteins G3BP1/2 were required for glutamine utilization, with G3BP1/2 knockout cells displaying a heavier reliance on glucose, yielding reduced cell survival and inability to properly utilize glutamine. Altogether, we show that cancer cells require glutamine for SG formation under nutrient deprivation, and its absence reduces cell survival, lowering ATP levels below an energy threshold required for SG formation.

Keywords:  Glutamine; Myc; RNA FISH; Stress granules

DOI:  https://doi.org/10.1242/jcs.263679
NPJ Syst Biol Appl. 2025 May 10. 11(1): 46

Computational modeling of cancer cell metabolism along the catabolic-anabolic axes.

Javier Villela-Castrejon, Herbert Levine, Benny A Kaipparettu, José N Onuchic, Jason T George, Dongya Jia.

Abnormal metabolism is a hallmark of cancer, this was initially recognized nearly a century ago through the observation of aerobic glycolysis in cancer cells. Mitochondrial respiration can also drive tumor progression and metastasis. However, it remains largely unclear the mechanisms by which cancer cells mix and match different metabolic modalities (oxidative/reductive) and leverage various metabolic ingredients (glucose, fatty acids, glutamine) to meet their bioenergetic and biosynthetic needs. Here, we formulate a phenotypic model for cancer metabolism by coupling master gene regulators (AMPK, HIF-1, MYC) with key metabolic substrates (glucose, fatty acids, and glutamine). The model predicts that cancer cells can acquire four metabolic phenotypes: a catabolic phenotype characterized by vigorous oxidative processes-O, an anabolic phenotype characterized by pronounced reductive activities-W, and two complementary hybrid metabolic states-one exhibiting both high catabolic and high anabolic activity-W/O, and the other relying mainly on glutamine oxidation-Q. Using this framework, we quantified gene and metabolic pathway activity by developing scoring metrics based on gene expression. We validated the model-predicted gene-metabolic pathway association and the characterization of the four metabolic phenotypes by analyzing RNA-seq data of tumor samples from TCGA. Strikingly, carcinoma samples exhibiting hybrid metabolic phenotypes are often associated with the worst survival outcomes relative to other metabolic phenotypes. Our mathematical model and scoring metrics serve as a platform to quantify cancer metabolism and study how cancer cells adapt their metabolism upon perturbations, which ultimately could facilitate an effective treatment targeting cancer metabolic plasticity.

DOI: https://doi.org/10.1038/s41540-025-00525-x
Mol Cancer Res. 2025 May 16.

Mitochondrial HSP90 paralog TRAP1 deletion drives glutamine addiction in tumor cells via destablization of the Cys/Glu antiporter SLC7A11/xCT.

Abhinav Joshi, Li Dai, Marisa Maisiak, Sunmin Lee, Elizabeth Lopez, Takeshi Ito, Len Neckers.

TRAP1, the mitochondrial isoform of HSP90, has emerged as a key regulator of cancer cell metabolism, yet the mechanisms by which it rewires nutrient utilization remain poorly understood. We previously reported that TRAP1 loss increases glutamine dependency of mitochondrial respiration following glucose withdrawal. Here, we investigate how TRAP1 deletion impacts glucose metabolism and the mechanisms enabling glutamine retention to support mitochondrial respiration via reductive carboxylation and the oxidative TCA cycle. TRAP1 knockout (KO) in bladder and prostate cancer cells recapitulates the carbon source-specific metabolic rewiring previously observed. Stable isotope tracing reveals that although glucose oxidation remains functional, TRAP1 KO reduces overall glucose uptake and its contribution to glycolysis and the pentose phosphate pathway. This effect is consistent across multiple cell lines. Concurrently, TRAP1-deficient cells exhibit increased glutamine retention and reliance, potentially due to downregulation of the cystine/glutamate antiporter SLC7A11/xCT. Supporting this, xCT overexpression reduces glutamine-dependent respiration in TRAP1 KO cells. qPCR and proteasome inhibition assays suggest xCT is regulated post-translationally via protein stability. Notably, xCT suppression does not trigger ferroptosis, indicating a selective adaptation rather than induction of cell death. Together, our findings suggest that TRAP1 loss decreases glucose uptake while preserving its metabolic fate, promoting glutamine conservation through xCT downregulation to maintain mitochondrial respiration without inducing ferroptosis. Implications: These results reveal a TRAP1-dependent mechanism of metabolic rewiring in cancer cells and identify xCT-mediated glutamine conservation as a key adaptive response, underscoring TRAP1 as a potential metabolic vulnerability and therapeutic target in tumors with altered nutrient utilization.

DOI: https://doi.org/10.1158/1541-7786.MCR-24-0194
Acta Pharmacol Sin. 2025 May 15.

Yuanhuacine suppresses head and neck cancer growth by promoting ASCT2 degradation and inhibiting glutamine uptake.

Xin-Yi Chen, Xin Chen, Xiao-Hui Liang, Dong Lu, Rong-Rong Pan, Qing-Yi Xiong, Xiao-Xia Liu, Jia-Yi Lin, Li-Jun Zhang, Hong-Zhuan Chen, Jin-Mei Jin, Wei-Dong Zhang, Xin Luan.

  Head and neck squamous cell carcinoma (HNSCC) cells exhibit a high dependency on glutamine metabolism, making it an attractive target. Despite the well-established link between glutamine reliance and tumor progression, the specific role of glutamine transporters in HNSCC remains poorly understood. The alanine-serine-cysteine transporter 2 (ASCT2), a key glutamine transporter, is overexpressed in HNSCC, and its silencing has been shown to reduce intracellular glutamine and glutathione levels, inhibiting tumor growth. These facts suggest that targeting ASCT2-mediated glutamine uptake could offer a promising therapeutic strategy for HNSCC. But no clinically approved drugs directly target ASCT2, and challenges such as the limited stability of antisense oligonucleotides persist. In this study we evaluated the correlation between ASCT2-mediate glutamine metabolism and its impact on HNSCC patients. We established a virtual screening method followed by cytotoxic assays to identify small molecules that specifically target ASCT2. Among the top 15 candidates, we identified yuanhuacine (YC) as the most potent antitumor compound with IC50 values of 1.43, 6.62, and 6.46 μM against HN6, CAL33, and SCC7 cells, respectively. We demonstrated that YC (0.3-5 μM) dose-dependently induced ASCT2 degradation by recruiting the E3 ubiquitin ligase RNF5, inhibiting glutamine uptake in HN6 cells. This disruption led to mitochondrial dysfunction and enhanced the therapeutic efficacy of YC. Our results highlight YC as a promising regulator of ASCT2-mediated glutamine metabolism in HNSCC.

Keywords:  ASCT2; glutamine metabolism; head and neck cancer; yuanhuacine

DOI:  https://doi.org/10.1038/s41401-025-01562-2
Neoplasma. 2025 Apr;pii: 241227N539. [Epub ahead of print]72(1-2):

KLHL7 enhances cell viability and cell cycle progression in glioma via glutamine metabolism by activating the β-catenin signaling pathway.

Rui Liu, Xiaoju Cheng, Peirui Wang, Xiangping Xia, Gang Li, Fuan Zhang, Chong Han, Shengtao Yao.

Kelch-like family member 7 (KLHL7) is associated with cancer development and occurrence, but its role and mechanism in the malignant progression of gliomas remain poorly understood. This study aimed to investigate the regulatory effects and mechanisms of KLHL7 on cell cycle and glutamine metabolism in glioma. Glioma cell lines A172 and U87 and a xenograft mouse model were used to analyze the function of KLHL7 in vitro and in vivo, respectively. Gene expression levels and protein amounts were assessed by quantitative reverse-transcription polymerase chain reaction and western blotting, respectively. Cell viability was assessed using the CCK-8 assay, and the cell cycle was analyzed via flow cytometry. The glutamine content was measured using a biochemical assay. The level of KLHL7 was upregulated in patients with glioma. KLHL7 knockdown reduced cell viability, inhibited cell cycle progression, and decreased the glutamine content in A172 cells. KLHL7 silencing inhibited tumor growth in vivo. Furthermore, KLHL7 overexpression enhanced cell viability, cell cycle progression, and glutamine metabolism and activated the β-catenin signaling pathway in U87 cells. These findings indicate that KLHL7 promotes the malignant progression of glioma via the β-catenin signaling pathway and may serve as a biomolecule for the clinical prediction and treatment of the disease.

DOI: https://doi.org/10.4149/neo_2025_241227N539
Cancer Res. 2025 May 14.

Tobacco Smoking Rewires Cell Metabolism by Inducing GAPDH Succinylation to Promote Lung Cancer Progression.

Kun Wang, Jingzhuo Li, Hai Zhang, Hongyan Ma, Hong-Yong Cui, Huai-Qiang Ju, Jing Zhang, Qing-Zhi Ma, Ming Zhao, Qing-Mei Zeng, Jie Zou, Xiu-Xuan Sun, Gang Nan, Meirui Qian, Lin Jing, Yiming Li, Cai-Feng Xiong, Qiu-Zi Yang, Hao Wang, Jian-Li Jiang, Zhi-Nan Chen, Liang Chen, Wan Huang.

Patient behavior and physiology can directly affect cancer metabolism. Smoking is the leading risk factor for non-small cell lung cancer (NSCLC). Here, we identified that smoking modulates lung cancer cell metabolism through altered protein post-translational modification. Proteomic analyses identified elevated K251 succinylation (K251-Su) of GAPDH, a key enzyme in glycolysis, in NSCLC samples, and GAPDH K251-Su was significantly higher in patients who smoke compared to non-smokers. Exposure of lung cancer cells to cigarette smoke extract led to increased uptake of glutamine and enhanced GAPDH K251-Su. Glutamine uptake by cancer cells in hypoxic and nutrient-deficient microenvironments provided succinyl-CoA donors for GAPDH succinylation at K251, which was catalyzed by acyltransferase p300. K251-Su increased GAPDH stability by suppressing TRIM4-mediated K254 ubiquitination. GAPDH K251-Su enhanced glycolysis and glutamine reductive carboxylation to meet the demands for cell growth and to support survival in hypoxic and nutrient-depleted conditions, promoting tumor growth and metastasis. These findings indicate that tobacco smoking mediates metabolic reprogramming of cancer cells through succinylation of GAPDH to drive NSCLC progression.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3525
Med Microbiol Immunol. 2025 May 13. 214(1): 22

Complement C5a promotes human retinal pigment epithelial cell viability and migration through SLC38A1-mediated glutamine metabolism.

Ye Sun, Yifan Hu, Shasha Luo.

  The pathological basis of many visual disorders involves the abnormal viability and migration of retinal pigment epithelium (RPE) cells. Complement response disorder is a significant pathogenic factor causing some autoimmune and inflammation diseases. The complement activation product anaphylatoxin C5a signaling pathway may be associated with RPE cell dysfunction. This study aimed to analyze the molecular mechanisms by which C5a affects RPE cell viability and migration. Recombinant human complement component C5a protein stimulated RPE cells. Cell biological behavior, including cell viability, invasion, and migration were analyzed with Cell Counting Kit-8 and transwell methods. Bioinformatics analysis identified the differentially expressed genes (DEGs) involved in C5a-treated RPE cells based on RNA sequencing. SLC38A1 was knocked down or overexpressed by vector transfection to investigate its involvement in C5a-stimulated RPE cells. C5a promotes RPE cell viability and migration. C5a-induced DEGs are enriched in migration-associated pathways. C5a increased SLC38A1, and SLC38A1 knockdown or overexpression inhibited or promoted RPE cell viability and migration. Glutaminase inhibition abrogated the promoting effect of C5a and SLC38A1 on cell biological behaviors. METTL3-HNRNPC-mediated m6A modification mediated C5a-induced SLC38A1. C5a, METTL3, and SLC38A1 constituted a signaling axis in regulating cell biological behaviors of C5a-treated RPE cells. C5a promotes RPE cell viability and migration, and SLC38A1-mediated improved glutamine metabolism is the downstream signal pathway of the C5a complement pathway. The C5a complement system may target the SLC38A1 to promote RPE cell migration.

Keywords:  Complement C5a; Glutamine metabolism; METTL3; Retinal pigment epithelium cell; SLC38A1

DOI:  https://doi.org/10.1007/s00430-025-00832-4
J Proteome Res. 2025 May 13.

Upregulations of SNAT2 and GLS-1 Are Key Osmoregulatory Responses of Human Corneal Epithelial Cells to Hyperosmotic Stress.

Kenrick Kai-Yuen Chan, Alan Chun-Kit Lee, Shing-Yan Roy Chung, Man-Sau Wong, Chi-Wai Do, Thomas Chuen Lam, Hang-Kin Kong.

  Dry eye syndrome (DES) affects millions of people worldwide. However, as the cellular responses of the corneal epithelium under hyperosmotic stress remain unclear, this study investigated the proteomic changes between human corneal epithelial cells (HCECs) cultured with isosmotic and hyperosmotic media. Under hyperosmotic stress, HCECs increased expressions of sodium-coupled neutral amino acid transporter (SNAT2), glutaminase (GLS-1), and a few isoforms of heat shock protein and aldo-keto reductase family 1. The expressions of SNAT2 and GLS-1 were increased after 6 h of exposure to hyperosmotic stress but not by glutamine deprivation. The hyperosmotic stress increased intracellular levels of glutamine, mitochondrial superoxide, and mitochondrial membrane potential and induced mitochondrial fission in HCECs. Thus, the intracellular level of glutamine was elevated in the hyperosmotic stressed HCECs via the upregulation of SNAT2. Glutamine can act as an osmolyte to regulate the osmolarity of HCECs or be converted to glutamate by GLS-1 for the tricarboxylic acid cycle and oxidative phosphorylation to maintain ATP production under the hyperosmotic stress-induced mitochondrial fission. Thus, the increases in the expressions of SNAT2 and GLS-1 are key osmoregulations in HCECs upon the hyperosmotic stress and may act as corneal biomarkers for monitoring DES progression.

Keywords:  corneal epithelial cell; dry eye syndrome; glutaminase (GLS-1); glutamine; mitochondria; sodium-coupled neutral amino acid transporter (SNAT2)

DOI:  https://doi.org/10.1021/acs.jproteome.4c01046
Cancers (Basel). 2025 Apr 23. pii: 1408. [Epub ahead of print]17(9):

Advancing Cancer Treatment: A Review of Immune Checkpoint Inhibitors and Combination Strategies.

Valencia Mc Neil, Seung Won Lee.

  A groundbreaking milestone in oncology has been the recognition and targeted elimination of malignant cells through cancer immunotherapy, which harnesses the body's immune system to attack cancer [...].

Keywords:  breast cancer; cancer vaccine; glutamine metabolism; hepatocellular carcinoma melanoma; immune checkpoint inhibitor synergy; lung cancer; microbiota-metabolite-immune; oncolytic virus

DOI:  https://doi.org/10.3390/cancers17091408
Mol Med Rep. 2025 Jul;pii: 197. [Epub ahead of print]32(1):

Glucose, glutamine, lactic acid and α‑ketoglutarate restore metabolic disturbances and atrophic changes in energy‑deprived muscle cells.

Miu Ikeda, Moe Matsumoto, Miki Tamura, Masaki Kobayashi, Kaoruko Iida.

  Skeletal muscle atrophy is often triggered by catabolic conditions such as fasting, malnutrition and chronic diseases; however, the efficacy of nutritional supplementation in maintaining muscle mass and preventing muscle atrophy remains controversial. The present study aimed to compare the inhibitory effects of various nutritional substrates on starvation‑induced catabolic changes and muscle cell atrophy. C2C12 muscle cells were starved for up to 24 h in medium lacking serum and main nutrients (glucose, glutamine and pyruvate). To assess the effects of exogenous substrates, the cells were incubated in starvation medium and individually supplemented with each of the following nutrients: Glucose, amino acids, fatty acids, lactate or ketone bodies. The expression of each gene and protein was analyzed by reverse transcription‑quantitative PCR and western blotting, respectively. Mitochondrial activity was determined by MTT assay and cell morphology was observed by immunofluorescence staining. The results revealed that starvation for >3 h suppressed mitochondrial activity, and after 5 h of starvation, the expression levels of several metabolic genes were increased; however, the levels of most, with the exception of Scot and Cpt‑1b, were suppressed after 24 h. Protein degradation and a decrease in protein synthesis were observed after 5 h of starvation, followed by autophagy with morphological atrophy at 24 h. Supplementation with specific substrates, with the exception of leucine, such as glucose, glutamine, lactic acid or α‑ketoglutarate, attenuated the suppression of mitochondrial activity, and altered gene expression, protein degradation and myotube atrophy in starved myotubes. Furthermore, the decrease in intracellular ATP production after 24 h of starvation was reversed by restoring glycolysis in glucose‑treated cells, and via an increase in mitochondrial respiration in cells treated with glutamine, lactic acid or α‑ketoglutarate. In conclusion, increasing the availability of glucose, glutamine, lactic acid or α‑ketoglutarate may be beneficial for countering muscle atrophy associated with inadequate nutrient intake.

Keywords:  atrophy; metabolism; muscle cells; nutrient substrates; starvation

DOI:  https://doi.org/10.3892/mmr.2025.13562
Magn Reson Imaging. 2025 May 13. pii: S0730-725X(25)00105-5. [Epub ahead of print] 110421

Can arginine, glutamate and glutamine serve as surrogates of intestinal mucosal healing in the patients with celiac disease following gluten-free diet? An NMR based metabolomics study.

Deepti Upadhyay, Prasenjit Das, Siddhartha Dattagupta, Govind K Makharia, Naranamangalam R Jagannathan, Uma Sharma.

  Celiac disease (CeD) is a chronic small intestinal autoimmune disease initiated by dietary gluten in genetically predisposed individuals. Till date, the only effective treatment for CeD is the gluten-free diet (GFD). However, not all patients achieve full histological recovery despite GFD. Thus, it is crucial to assess the treatment response and improvement in the villous architecture following GFD. Therefore, present study investigated the potential of NMR-based metabolomics for identifying non-invasive biomarkers for assessing treatment response. Comprehensive metabolic profiling of 120 biological samples comprising of small intestinal mucosal biopsies, blood plasmas and urines collected at two time points (before and after 6-8 months of GFD) from CeD patients (n = 20) was carried out using proton NMR spectroscopy. The levels of arginine glutamate, and glutamine were significantly reduced in both intestinal mucosa and blood plasma of CeD patients after GFD compared to their baseline values. These amino acids play an important role in intestinal energy metabolism, and alleviating inflammation, thereby contributing to healing mechanisms of small intestinal mucosa, following GFD. A logistic regression statistical model based on the combination of the above three blood plasma metabolites demonstrated AUC of 0.980, Youden index 0.900 with a sensitivity and a specificity of 90 % and 100 % for monitoring treatment response in CeD patients after GFD. The study revealed a panel of non-invasive plasma biomarkers (arginine, glutamate and glutamine) which may serve as surrogates of mucosal healing and treatment response in CeD patients, however, the findings need to be validated in a large cohort of patients.

Keywords:  Arginine and glutamine; Celiac disease; Glutamate; Gluten-free diet; Metabolomics; NMR spectroscopy

DOI:  https://doi.org/10.1016/j.mri.2025.110421
Semin Cancer Biol. 2025 May 08. pii: S1044-579X(25)00063-X. [Epub ahead of print]113 9-24

Metabolic pathway analysis of tumors using stable isotopes.

Qiufen Bi, Junzhang Zhao, Jun Nie, Fang Huang.

  Metabolic reprogramming is pivotal in malignant transformation and cancer progression. Tumor metabolism is shaped by a complex interplay of both intrinsic and extrinsic factors that are not yet fully elucidated. It is of great value to unravel the complex metabolic activity of tumors in patients. Metabolic flux analysis (MFA) is a versatile technique for investigating tumor metabolism in vivo, it has increasingly been applied to the assessment of metabolic activity in cancer in the past decade. Stable-isotope tracing have shown that human tumors use diverse nutrients to fuel central metabolic pathways, such as the tricarboxylic acid cycle and macromolecule synthesis. Precisely how tumors use different fuels, and the contribution of alternative metabolic pathways in tumor progression, remain areas of intensive investigation. In this review, we systematically summarize the evidence from in vivo stable- isotope tracing in tumors and describe the catabolic and anabolic processes involved in altered tumor metabolism. We also discuss current challenges and future perspectives for MFA of human cancers, which may provide new approaches in diagnosis and treatment of cancer.

Keywords:  Cancer metabolism; Metabolic flux analysis; Stable-isotope tracing

DOI:  https://doi.org/10.1016/j.semcancer.2025.05.002
Cancers (Basel). 2025 Apr 27. pii: 1467. [Epub ahead of print]17(9):

Immunometabolism of Innate Immune Cells in Gastrointestinal Cancer.

Izabela Siemińska, Marzena Lenart.

  Cancer cells are often described as voracious consumers of nutrients, with glucose frequently cited as a key energy source; however, their metabolic plasticity allows them to adapt and utilize various substrates, including lipids and amino acids, to sustain growth and survival. However, the metabolic demands of immune cells within the tumor microenvironment (TME) are less commonly discussed despite their critical role in shaping the immune response. In this review, we explored the intricate interplay between immunometabolism and innate immunity cells in gastrointestinal cancers. We focused on how metabolic pathways, including glycolysis, fatty acid oxidation, and amino acid metabolism, drive the immunosuppressive functions of myeloid-derived suppressor cells (MDSCs) and tumor-associated neutrophils (TANs), tumor-associated macrophages (TAMs) and innate lymphocyte subsets such as NK cells. These cells contribute to a hostile immune landscape, supporting tumor growth and evasion from immune surveillance in a phenomenon of tumor-derived immunosuppression. Additionally, we investigated the influence of dietary interventions on the metabolic reprogramming of these immune cells, highlighting how nutrition can modulate the TME. Finally, we discussed emerging therapeutic strategies that target metabolic vulnerabilities in MDSCs, TANs, NK cells, and monocytes, offering a novel avenue for enhancing antitumor immunity. By dissecting these mechanisms, we aim to provide insights into how metabolic pathways can be harnessed to improve cancer treatment outcomes. This review underscores the importance of understanding immunometabolism not only as a driver of immune suppression but also as a potential therapeutic target in gastrointestinal cancer.

Keywords:  colorectal cancer; gastrointestinal cancer; immunometabolism; innate immune cells

DOI:  https://doi.org/10.3390/cancers17091467
Cancer Res. 2025 May 14.

MYLK-AS1 Enhances Glutamine Metabolism to Promote EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer.

Tianyu Qu, Lei Song, Jiali Xu, Xiyi Lu, Dandan Yin, Jiali Dai, Chen Zhang, Renhua Guo, Erbao Zhang.

Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) limits the efficacy of molecular targeted therapy in non-small cell lung cancer (NSCLC). Metabolic reprogramming is a hallmark of lung cancer that could contribute to TKI resistance. Through systematic screening and verification, we identified a role for the long noncoding RNA (lncRNA) MYLK-AS1 supporting acquired TKI resistance in lung cancer. Elevated expression of MYLK-AS1 correlated with TKI resistance in NSCLC patient samples and cell lines. c-Myc mediated transcriptional activation of MYLK-AS1, and m6A modification promoted post transcriptional upregulation. Mechanistically, MYLK-AS1 bound and directly drove phase separation of interleukin enhancer binding factor 3 (ILF3), thus interacting with the 3'UTR of glutamate dehydrogenase 1 (GLUD1) to post-transcriptionally promote its mRNA stability. MYLK-AS1-mediated GLUD1 upregulation accelerated mitochondrial glutamine catabolism, promoting TKI resistance. Inhibition of GLUD1 with the small-molecule inhibitor R162 in TKI resistant models suppressed cell proliferation in vitro and tumor growth in vivo. Moreover, knockdown of MYLK-AS1 also enhanced drug sensitivity in TKI resistant patient-derived xenograft models, suggesting its therapeutic potential. Collectively, these findings offer insights into the regulation of TKI resistance from the perspective of phase separation and metabolism and highlight targeting the MYLK-AS1/ILF3/GLUD1 axis as a potential strategy for improving the efficacy of EGFR TKIs in NSCLC.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3748
Am J Clin Oncol. 2025 May 15.

Metabolic Plasticity in Prostate Cancer: The Warburg Effect and Its Clinical Relevance.

Arielle Sabbah, Guila Delouya, Mikhael Laskine, Daniel Taussky.

   OBJECTIVES: This paper examines the life and research of Otto Warburg (1883 to 1970), who identified the so-called Warburg effect. Warburg personal life and scientific career were notable.
METHODS: This study summarizes the key aspects of his life, the Warburg effect, and its significance in prostate cancer.
RESULTS: Despite being classified as non-Aryan, Warburg continued his research as the director of the Kaiser Wilhelm Institute for Cell Physiology during World War II. He also cohabited openly with a male partner. The Warburg effect is a metabolic hallmark of cancer, where cells preferentially utilize glycolysis over oxidative phosphorylation, even in the presence of oxygen. This metabolic shift confers key advantages to tumor survival, including rapid ATP production, biosynthetic support for proliferation, and resistance to apoptosis. In prostate cancer, the metabolism undergoes a unique transformation. Normal prostate cells are characterized by citrate secretion; however, as malignancy develops, the cells adapt to oxidative metabolism. At the metastatic stage, the Warburg effect becomes more pronounced and is influenced by the tumor microenvironment and interactions with cancer-associated fibroblasts and bone marrow adipocytes. These metabolic changes have significant clinical implications. While FDG-PET scans serve as a diagnostic tool in many cancers, their utility in early-stage prostate cancer is limited owing to its delayed metabolic shift. Metabolic-targeted therapies, such as dichloroacetate (DCA) and glycolysis inhibitors, are emerging as promising strategies to enhance the efficacy of chemotherapy and radiotherapy.
CONCLUSIONS: Elucidating the role of metabolic reprogramming in prostate cancer could reveal new avenues for treatment, particularly for castration-resistant and metastatic diseases.

Keywords:  Warburg effect; glycolysis inhibitors; metabolic changes; metabolic-targeted therapies; prostate cancer

DOI:  https://doi.org/10.1097/COC.0000000000001215
ACS Catal. 2025 Mar 07. 15(5): 4359-4373

Activity Regulation of a Glutamine Amidotransferase Bienzyme Complex by Substrate-Induced Subunit Interface Expansion.

Franziska Jasmin Funke, Sandra Schlee, Isabel Bento, Gleb Bourenkov, Reinhard Sterner, Matthias Wilmanns.

  Glutamine amidotransferases are multienzyme machineries in which reactive ammonia is generated by a glutaminase and then transferred through a sequestered protein tunnel to a synthase active site for incorporation into diverse metabolites. To avoid wasteful metabolite consumption, there is a requirement for synchronized catalysis, but any generally applicable mechanistic insight is still lacking. As synthase activity depends on glutamine turnover, we investigated possible mechanisms controlling glutaminase catalysis using aminodeoxychorismate synthase involved in folate biosynthesis as a model. By analyzing this system in distinct states of catalysis, we found that incubation with glutamine leads to a subunit interface expansion by one-third of its original area. These changes completely enclose the glutaminase active site for sequestered catalysis and the subsequent transport of volatile ammonia to the synthase active site. In view of similar rearrangements in other glutamine amidotransferases, our observations may provide a general mechanism for the catalysis synchronization of this multienzyme family.

Keywords:  active site interface expansion; ammonia utilization in catalysis; enzyme product/substrate tunnel; multienzyme complex; nitrogen-containing metabolites; substrate/product sequestration

DOI:  https://doi.org/10.1021/acscatal.4c07438
Prog Biophys Mol Biol. 2025 May 13. pii: S0079-6107(25)00024-0. [Epub ahead of print]

Advances in the mechanisms of HIF-1α-enhanced tumor glycolysis and its relation to dedifferentiation.

Yu Zeng, Yonggang Tao, Guotu Du, Tianyu Huang, Shicheng Chen, Longmei Fan, Neng Zhang.

  Metabolic reprogramming, a hallmark of malignancy, enables tumor cells to adapt to the harsh and dynamic tumor microenvironment (TME) by altering metabolic pathways. Hypoxia, prevalent in solid tumors, activates hypoxia inducible factor 1α (HIF-1α). HIF-1α drives metabolic reprogramming, enhancing glycolysis primarily through the Warburg effect to reduce oxygen dependence and facilitate tumor cell growth/proliferation. The above process is associated with accelerated tumor cell dedifferentiation and enhanced stemness, generating cancer stem cells (CSCs) which possesses the potential for self-renewal and differentiation that can differentiate into a wide range of subtypes of tumor cells and fuel tumor heterogeneity, metastasis, and recurrence, complicating therapy. This review examines the HIF-1α-glycolysis-dedifferentiation crosstalk mechanisms, expecting that indirect inhibition of HIF-1α by targeting metabolic enzymes, metabolites, or their signaling pathways will offer an effective therapeutic strategy to improve the cancer treatment outcomes.

Keywords:  Aerobic glycolysis; Carcinoma; Dedifferentiation; HIF-1α

DOI:  https://doi.org/10.1016/j.pbiomolbio.2025.05.003
ESMO Open. 2025 May 12. pii: S2059-7029(25)00405-3. [Epub ahead of print]10(5): 104536

A phase I/II study of the safety and efficacy of telaglenastat (CB-839) in combination with nivolumab in patients with metastatic melanoma, renal cell carcinoma, and non-small-cell lung cancer.

M A Gouda, M H Voss, H Tawbi, M Gordon, S S Tykodi, E T Lam, U Vaishampayan, N M Tannir, J Chaves, P Nikolinakos, A Fan, R Lee, D McDermott, G I Shapiro, L Gandhi, S Bhatia, V Katragadda, F Meric-Bernstam.

   BACKGROUND: Telaglenastat (CB-839) is a glutaminase 1 inhibitor that targets the dysregulation in glutamine metabolism in cancer cells and the tumor microenvironment. Preclinical data suggested that the combination of telaglenastat with programmed cell death protein 1 (PD-1) or programmed cell death-ligand 1 (PD-L1) antibodies can lead to enhanced immune response against cancer.
PATIENTS AND METHODS: We designed a phase I/II trial to investigate the safety and efficacy of telaglenastat combined with nivolumab in patients with advanced solid tumors. Dose escalation was carried out using a 3 + 3 design with two dose levels for telaglenastat (600 mg and 800 mg twice daily). Nivolumab was given at a fixed dose of 240 mg by intravenous infusion on days 1 and 15 of a 28-day cycle in all patients. Expansion in phase II was planned using Simon's two-stage design in disease- and prior therapy-specific cohorts.
RESULTS: We included a total of 118 patients across different cohorts. The most frequently reported adverse events were fatigue (42.4%; n = 50), nausea (39%; n = 46), and photophobia (32.2%; n = 38). In the response-assessable analysis set (including 107 patients in dose expansion and recommended phase II dose of dose escalation), the overall response rate (ORR) was 8.4% (n = 9). The ORR was 24% in 25 patients with clear-cell renal cell carcinoma (ccRCC) who were checkpoint inhibitor-naïve, 5.9% in 17 patients with ccRCC after nivolumab, 0% in 9 patients with ccRCC after other prior anti-PD-1/PD-L1, 5.4% in 37 patients with melanoma after anti-PD-1/PD-L1, and 0% in 19 patients with non-small-cell lung cancer after anti-PD-1/PD-L1.
CONCLUSIONS: Telaglenastat in combination with nivolumab was generally well tolerated. The combination did not show a pattern of efficacy across different study cohorts.

Keywords:  CB-839; clinical trials; glutaminase inhibitor; nivolumab

DOI:  https://doi.org/10.1016/j.esmoop.2025.104536
Cancer Med. 2025 May;14(10): e70948

Advances in the Study of Metabolic Reprogramming in Gastric Cancer.

Yu Rong, Yuanyin Teng, Xiaoying Zhou.

   BACKGROUND: Gastric cancer is one of the most prevalent malignancies of the digestive system and is associated with a poor prognosis, particularly in advanced metastatic stages, where the 5-year survival rate is significantly low.
METHODS: Recent research has demonstrated that metabolic reprogramming-including alterations in glucose, lipid, and amino-acid metabolism-plays a critical role in both the development and progression of this disease. To gain deeper insights into these metabolic shifts, scientists have increasingly employed metabolomics, a non-invasive technique that detects and quantifies small molecules within cancerous tissues, thereby enhancing prognostic assessments.
AIM: Analyzing the metabolic profiles of gastric-cancer tissues can reveal significant changes in key metabolic pathways, which may open new avenues for targeted therapies and ultimately improve patient outcomes.
CONCLUSION: This article reviews recent advancements in the study of metabolic reprogramming in gastric cancer, aiming to identify potential therapeutic targets and offer new hope to patients.

Keywords:  gastric cancer; metabolic reprogramming; metabolomics; molecular targets

DOI:  https://doi.org/10.1002/cam4.70948
Life Sci. 2025 May 12. pii: S0024-3205(25)00343-1. [Epub ahead of print]374 123708

The role of glutamine and leucine supplementation in liver metabolic reprogramming during sepsis.

Yu-Chen Hou, Shang-Ming Tseng, Ting-Chun Kuo, Jin-Ming Wu, Kuen-Yuan Chen, Ming-Hsun Wu, Po-Jen Yang, Po-Chu Lee, Po-Da Chen, Sung-Ling Yeh, Ming-Tsan Lin.

   AIMS: Glutamine (Gln) and leucine (Leu) are amino acids known for modulating various biological functions. This study aimed to identify metabolism-related genes and their transcriptional pattern changes after Gln and/or Leu administration using next-generation sequencing technology in the liver during sepsis, a condition known to lead to liver metabolic reprogramming and damage.
MATERIALS AND METHODS: C57BL/6J mice were randomly assigned to a sham control group (C) and four septic groups subjected to cecal ligation and puncture (CLP). The septic groups were as follows: S group, sepsis control with saline injection after CLP; Gln group, injected with Gln after CLP; Leu group, injected with Leu after CLP; and GL group, injected with Gln plus Leu after CLP. All mice were sacrificed on day 4 after the operation, and liver samples were collected for further analysis.
KEY FINDINGS: Gln and/or Leu administration during sepsis significantly altered the hepatic transcriptome with different gene expression patterns. Notably, the G group had the highest number of gene changes among the amino acid-treated groups. Gln administration was associated with more pronounced downregulation of leukocyte inflammatory genes. Carbohydrate metabolic pathways were suppressed, but the oxidative phosphorylation pathway was enhanced by Gln administration, potentially improving metabolic reprogramming during sepsis.
SIGNIFICANCE: Gln and/or Leu treatment showed promise in alleviating sepsis-induced liver injury; however, only Gln administration alone demonstrated beneficial effects on hepatic macronutrient and energy metabolism during sepsis. These results highlight the potential therapeutic significance of specific amino acids on attenuating hepatic metabolic dysregulation and injury in septic insult.

Keywords:  Carbohydrate metabolism; Metabolic reprogramming; Next-generation sequencing technology; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.lfs.2025.123708
Front Immunol. 2025 ;16 1571431

Integrative single-cell RNA sequencing and bulk RNA sequencing reveals the characteristics of glutathione metabolism and protective role of GSTA4 gene in pancreatic cancer.

Xinya Jia, Qiang Zhang, Zhe Wang, Jianliang Cao, Anran Song, Chao Lan, Yuepeng Hu.

   Background: Recent studies have increasingly reported abnormal glutathione (GSH) metabolism within the tumor microenvironment across various solid tumors. However, the specific mechanisms underlying aberrant GSH metabolism in pancreatic cancer (PC) remain unclear. This study aims to investigate the prognostic significance of GSH metabolism-related genes in PC and to identify key molecular targets, thereby providing novel perspectives for targeted PC therapy.
Methods: The GSH metabolism gene set was retrieved from the KEGG database. Utilizing single-cell transcriptomic data from the GSE205049 dataset, this study analyzed the variation in GSH metabolic signaling intensity across distinct cell types within the tumor microenvironment of PC. Additionally, transcriptomic data from multiple repositories, including TCGA, ICGC, and GEO, comprising a total of 930 patients with PC, were integrated to construct a prognostic molecular classifier related to GSH metabolism. Furthermore, the role of the key gene GSTA4 in PC was experimentally validated through a series of in vitro assays.
Results: Significant differences in GSH metabolic signaling intensity were observed across various cell types in both normal pancreatic and PC tissues. A prognostic signature comprising six GSH metabolism-related genes (GSTA5, PGD, IDH2, GSTA4, GPX2, and GPX3) was established, wherein a high-risk score was associated with a poorer patient prognosis. Notably, GSTA4 expression was significantly reduced in PC tissues, and higher GSTA4 levels were linked to a favorable prognosis. In vitro functional analyses demonstrated that GSTA4 overexpression markedly inhibited PC cell proliferation and migration.
Conclusion: The GSH metabolism-associated prognostic signature developed in this study effectively identifies high-risk patients with PC. As a prognostic protective factor, GSTA4 exhibits downregulated expression in PC tissues and suppresses tumor proliferation and migration, highlighting its potential as a therapeutic target.

Keywords:  GSH metabolism; GSTA4 gene; bulk RNA sequencing; pancreatic cancer; single-cell RNA sequencing

DOI:  https://doi.org/10.3389/fimmu.2025.1571431
Redox Biol. 2025 May 06. pii: S2213-2317(25)00173-9. [Epub ahead of print]83 103660

Protein S-glutathionylation confers cellular resistance to ferroptosis induced by glutathione depletion.

Yi Ju, Yuting Zhang, Xiaolin Tian, Nanbin Zhu, Yufan Zheng, Yiming Qiao, Tao Yang, Baolin Niu, Xiaoyun Li, Liu Yu, Zhuolin Liu, Yixuan Wu, Yang Zhi, Yinuo Dong, Qingling Xu, Xiaoming Yang, Xuening Wang, Xiaokai Wang, Haiteng Deng, Yimin Mao, Xiaobo Li.

  Ferroptosis is one of the most critical biological consequences of glutathione depletion. Excessive oxidative stress, indicated by an elevated oxidized glutathione (GSSG)/reduced glutathione (GSH) ratio, is recognized as a key driver of ferroptosis. However, in glutathione depletion-induced ferroptosis, a marked decrease in total glutathione levels (including both GSH and GSSG) is frequently observed, yet its significance remains understudied. Protein S-glutathionylation (protein-SSG) levels are closely linked to the redox state and cellular glutathione pools including GSH and GSSG. To date, the role of protein-SSG during cell ferroptosis induced by glutathione depletion remains poorly understood. Here, we demonstrated that upregulation of CHAC1, a glutathione-degrading enzyme, acted as a key regulator of protein-SSG formation and exacerbated glutathione depletion-induced ferroptosis. This effect was observed in both in vitro and in vivo models, including erastin-induced ferroptosis across multiple cell lines and acetaminophen overdose-triggered ferroptosis in hepatocytes. Deficiency of CHAC1 resulted in increased glutathione pools, enhanced protein-SSG, improved liver function, and attenuation of hepatocyte ferroptosis upon acetaminophen challenge. These protective effects were reversed by CHAC1 overexpression. Using quantitative redox proteomics, we identified glutathione pool-sensitive S-glutathionylated proteins. As an important example, we discovered that ADP-ribosylation factor 6 (ARF6) was regulated by S-glutathionylation during glutathione depletion-induced ferroptosis. Our findings revealed that CHAC1 upregulation reduced the S-glutathionylation of ARF6, resulting in decreased ARF6 levels in lysosomes. This, in turn, enhanced the localization of the transferrin receptor (TFRC) on the cell membrane and increased transferrin uptake, ultimately compromising the protective role of ARF6 in ferroptosis induced by glutathione depletion. Targeting TFRC using GalNAc-siTfrc mitigated acetaminophen-induced liver injury in vivo. In conclusion, our study provide evidence that availability of glutathione pools affects protein S-glutathionylation and regulates protein functions to influence the process of ferroptosis, which opens an avenue to understanding the cell ferroptosis induced by glutathione depletion.

Keywords:  ADP-Ribosylation factor 6; CHAC1; Ferroptosis; Protein S-Glutathionylation; Transferrin

DOI:  https://doi.org/10.1016/j.redox.2025.103660
Front Pharmacol. 2025 ;16 1586655

The role of glutamate dehydrogenase in the ageing brain.

Tao Zhou, Haichuan Wang.

  The homeostasis of glutamate, the primary excitatory neurotransmitter in the brain and is crucial for normal brain function. The mitochondrial enzyme glutamate dehydrogenase (GDH) connects the multifunctional amino acid glutamate, which is intimately related to glutamate metabolism, to the Krebs cycle. As a result, GDH reglutes the synthesis and uptake of the chemical messenger glutamate in neuroendocrine cells, playing a crucial role in the metabolism of proteins and carbohydrates. Nonetheless, brain ageing and numerous neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, have been linked to GDH malfunction or dysregulation. In this review, we summarize the dynamics of GDH levels in the ageing brain and provide additional details about the role of GDH in the ageing brain. Understanding the metabolic mechanisms underlying glutamate homeostasis in the aging brain and how GDH regulates glutamate-dependent metabolic processes at synapses may lead to novel therapeutic approaches for neurodegenerative and psychiatric disorders, potentially slowing the aging process and promoting brain regeneration.

Keywords:  Alzheimer’s disease; Parkinson’s disease; ageing brain; glutamate dehydrogenase; glutamate metabolism

DOI:  https://doi.org/10.3389/fphar.2025.1586655