bims-glucam 2025-09-14 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–09–14
twenty-two papers selected by
Sreeparna Banerjee, Middle East Technical University

Metabolism, a Blossoming Target for Small-Molecule Anticancer Drugs.
L-5-[11C]-glutamine PET of breast cancer: Preclinical studies in mouse models.
Delivery-Graded Programmable Micelles Achieve Enhanced Tumor Starvation through Combined Glutamine Deprivation and Angiogenesis Inhibition.
The glutaminase activity of ASNS fuels glutamine metabolism in leukemia.
Targeting Wnt-driven metabolic adaptations in cancer: integrating glycolysis, glutaminolysis, IDO1-mediated immune evasion, and therapeutic delivery strategies.
18F-FGln PET/CT Imaging Shows High Uptake in Meningiomas Providing Insights for Diagnosis and Treatment.
Shen Ling Bai Zhu San promotes gut IgA+ plasma cells to alleviate chronic diarrhea in mice via increasing systematic glutamine.
Simultaneous in vivo detection of spectrally resolved glutamate, glutamine, and glutathione at 3 T with NAA-aspartyl editing and echo-time optimization.
Methods and Guidelines for Metabolism Studies: Applications to Cancer Research.
Glutamine Metabolism and Metabolic Profiling Using 7 T CRT-FID MRSI in Focal Epilepsy.
Fueling fibrosis: metabolic dysregulation in systemic sclerosis.
Therapeutic Potential of Glutaminase Inhibition Targeting Metabolic Adaptations in Resistant Melanomas to Targeted Therapy.
Short-term Physical Activity Reduces Metabolic-associated Steatohepatitis by Promoting the Degradation of Branched-chain Amino Acids in Skeletal Muscle.
TCA cycle-derived oncometabolites in cancer and the immune microenvironment.
Divergent metabolic rewiring shapes altered innate immunity.
Bacterial Glutamine Synthetases as a Novel Metabolic Selection Marker to Improve CHO Cell Culture Performance Through Selection Stringency Modulation.
Copper induces cystine/glutamate antiporter SLC7A11 through the activation of Nrf2 and Atox1 pathways.
GLS1-RNA Polymerase II Axis Mediates Glutamine-Dependent Hepatoprotective Effects on Alcoholic Liver Disease in High-Protein Diets.
Metabolites as regulators of autoimmune diseases.
Downregulation of miR-27a-3p Modulates TGF-β Signaling and Dysregulates Metabolism in Glioblastoma.
High-Resolution Mapping of Tumor and Peritumoral Glutamate and Glutamine in Gliomas Using 7-T MRSI.
Distribution of glutamate and glutamine in tumor microenvironments of brain metastasis: Insights from biochemical analysis and molecular imaging.

Molecules. 2025 Aug 22. pii: 3457. [Epub ahead of print]30(17):

Metabolism, a Blossoming Target for Small-Molecule Anticancer Drugs.

Michela Puxeddu, Romano Silvestri, Giuseppe La Regina.

  Reprogramming is recognized as a promising target in cancer therapy. It is well known that the altered metabolism in cancer cells, in particular malignancies, are characterized by increased aerobic glycolysis (Warburg effect) which promotes rapid proliferation. The effort to design compounds able to modulate these hallmarks of cancer are gaining increasing attention in drug discovery. In this context, the present review explores recent progress in the development of small molecule inhibitors of key metabolic pathways, such as glycolysis, glutamine metabolism and fatty acid synthesis. In particular, different mechanisms of action of these compounds are analyzed, which can target distinct enzymes, including LDH, HK2, PKM2, GLS and FASN. The findings underscore the relevance of metabolism-based strategies in developing next-generation anticancer agents with potential for improved efficacy and reduced systemic toxicity.

Keywords:  aerobic glycolysis; cancer; fatty acid synthesis; glutamine metabolism; metabolism

DOI:  https://doi.org/10.3390/molecules30173457
Nucl Med Biol. 2025 Aug 30. pii: S0969-8051(25)00101-5. [Epub ahead of print]150-151 109092

L-5-[11C]-glutamine PET of breast cancer: Preclinical studies in mouse models.

Christopher T Hensley, Prashanth Padakanti, Raheema Damani, Christina Dulal, Hoon Choi, Shihong Li, Jianbo Cao, Hsiaoju Lee, Austin Pantel, Elizabeth Li, David Mankoff, Rong Zhou.

   BACKGROUND: Glutamine is an important metabolic substrate in many aggressive tumors, with comparable importance to glucose metabolism. Utilizing human breast cancer mouse xenograft models, we studied the kinetics of the PET imaging agent, L-5-[11C]-glutamine ([11C]glutamine or [11C]GLN) a biochemical authentic substrate for glutamine metabolism, to further characterize the metabolism of glutamine and downstream labeled metabolites. Studies were performed with and without inhibition of the enzyme, glutaminase (GLS), the first step in glutamine catabolism that generates glutamate, and key target for therapy directed to glutamine-metabolizing cancers.
METHODS: The study used xenograft mouse models for two breast cancer cell lines, HCC1806, a highly glutaminolytic triple-negative cell line, and MCF-7, a hormone receptor positive line with only low levels of glutaminolysis. Mice were injected with [11C]glutamine and either underwent metabolite analysis or dynamic PET imaging. The contributions of individual metabolites to the total 11C-activity signal in blood and tumor tissue were measured at 10, 20, and 30 min via HPLC. We measured fractional activity in the form of [11C]glutamine versus labeled metabolites, focusing on L-5-[11C]-glutamate ([11C]glutamate or [11C]GLU), and any activity in the other metabolite small molecules labeled with 11C (11C-other or 11C-OTH). Additionally, the contribution of [11C]CO2 to total 11C-activity was measured. Together with image-based uptake curves, this generated estimated time activity curves for [11C]glutamine and downstream metabolites in both xenograft models treated with vehicle or GLS inhibitor (CB-839).
RESULTS: We found that, out to 30 min post-injection, the majority of radioactivity in highly glutaminolytic tumors (HCC1806) was in the form of [11C]glutamine and [11C]glutamate, with relatively low amounts of radioactivity in metabolites downstream of glutamate including [11C]CO2. In HCC1806 tumors, [11C]glutamate was retained in the large cellular glutamate pool leading to a majority fraction of total radioactivity in tumor tissue that is greater than the fraction within the blood, with this tumoral fractional pattern reversing with CB-839. This phenomenon leads to a total tumor time-activity curve that is only marginally different before and after CB-839. The radioactivity patterns of MCF-7 tumors after vehicle treatment were similar HCC1806 tumors after CB-839 treatment.
CONCLUSION: Our studies on [11C]glutamine in breast cancer models show significant retention of 11C-activity in the form of [11C]glutamate in tumors with high GLS activity that confounds non-invasive inference of GLS activity. This suggests limited utility for [11C]glutamine PET for inferring tumor GLS activity and its specific antagonism by drug inhibitors. Our analysis of labeled metabolites in mouse models does, however, yield insights that include the retention of glutamate generated by GLS-mediated catabolism in a large cellular pool and also provide data that is the basis for a compartmental model of glutamine metabolism that is the subject of a companion paper.

Keywords:  Cancer; Glutaminase; L-5-[(11)C]-glutamate; L-5-[(11)C]-glutamine; Metabolism

DOI:  https://doi.org/10.1016/j.nucmedbio.2025.109092
Research (Wash D C). 2025 ;5 0858

Delivery-Graded Programmable Micelles Achieve Enhanced Tumor Starvation through Combined Glutamine Deprivation and Angiogenesis Inhibition.

Xuan Wei, Jiamin Cheng, Meijuan Geng, Siyu Chen, Liyang Gong, Siyu Meng, Keying Chen, Ziyan Wang, Zhang Yuan, Kaiyong Cai, Liangliang Dai.

The inhibition of dependent glutamine metabolism is an effective treatment for triple-negative breast cancer (TNBC) starvation, but it is limited by compensatory glycolysis and inadequate delivery efficiency. Herein, we construct a pH-responsive size/charge-reprogrammed micelle with hierarchical delivery characteristics for TNBC suppression with glutamine depletion and vessel blockade. It consists of a positively charged prodrug micelle chemically grafted with the glutamine transport inhibitor V9302 as the inner core layer, the neovascular disruptor CA4P adsorbed in the middle layer, and a pH-responsive peelable polymer as the outer shell. The nanosystem PPD/PPQV@C could effectively reduce size and reverse charge in response to the tumor acidic microenvironment by removing the outer polymer PPD, as accompanying the release of CA4P. Furthermore, the remaining PPQV could responsively release V9302 in the cytoplasm of tumor cells, improving the bioavailability of cargoes and overcoming permeability barrier through precise hierarchical release strategy. Importantly, V9302 and CA4P localized in the tumor intracellular and extracellular matrix could effectively block TNBC-dependent glutamine metabolism and inhibit compensatory nutrient by blocking angiogenesis, achieving the desired tumor suppression with prolonged survival time. This work exhibits a smart nanoplatform for efficient TNBC treatment via dual blockade of the dependent glutamine metabolism and angiogenesis.

DOI: https://doi.org/10.34133/research.0858
Haematologica. 2025 Sep 11.

The glutaminase activity of ASNS fuels glutamine metabolism in leukemia.

Wai-Kin Chan, Lin Tan, Sara A Martinez, Di Du, Thomas D Horvath, Michael Pontikos, Leona A Rusling, Yulun Chiu, Bao Q Tran, Susan B Rempe, Sergei Sukharev, John N Weinstein, Philip L Lorenzi.

Not available.

DOI: https://doi.org/10.3324/haematol.2024.287099
Front Cell Dev Biol. 2025 ;13 1622218

Targeting Wnt-driven metabolic adaptations in cancer: integrating glycolysis, glutaminolysis, IDO1-mediated immune evasion, and therapeutic delivery strategies.

Eric Flores-Hernández, Grace Binder, Kuo-Ching Mei, Nydia Tejeda-Muñoz.

  The Wnt pathway is an evolutionarily conserved signaling cascade that regulates a wide range of fundamental cellular processes, including proliferation, differentiation, polarity, migration, metabolism, and survival. Due to its central regulatory roles, Wnt signaling is critically involved in the pathophysiology of numerous human diseases. Aberrant activation or insufficient inhibition of this pathway has been causally linked to cancer, degenerative disorders, metabolic syndromes, and developmental abnormalities. Wnt signaling drives cancer progression by reprogramming metabolism and promoting immune evasion. Wnt-driven tumors exhibit enhanced aerobic glycolysis (the Warburg effect), glutaminolysis, and macropinocytosis, which support rapid proliferation and help maintain redox homeostasis under nutrient-limited or nutrient-deprived conditions. These metabolic adaptations sustain tumor survival and contribute to immune suppression, as seen in the Wnt5a-indoleamine 2,3-dioxygenase 1 (IDO1) axis, which fosters regulatory T-cell expansion and an immunosuppressive microenvironment. The interplay among glycolysis, glutamine metabolism, and immune escape renders Wnt-driven cancers highly adaptable and resistant to conventional therapies. Targeting metabolic enzymes, such as pyruvate dehydrogenase kinase 1 (PDK1), lactate dehydrogenase A (LDHA), glutaminase (GLS), and monocarboxylate transporters (MCT-1), alongside immune checkpoint inhibitors or IDO1 blockade, presents a promising strategy for overcoming metabolic plasticity and immune evasion in Wnt-driven malignancies, thereby enhancing therapeutic efficacy and improving patient survival in otherwise refractory tumor types. Combining glycolysis and glutaminolysis inhibitors with T-cell activating therapies may disrupt tumor metabolic plasticity and restore anti-tumor immunity. Additionally, advanced drug delivery systems, including lipid nanoparticles (LNPs), polymeric nanocarriers, and exosome-based platforms, enhance the targeted accumulation of metabolic inhibitors and immunomodulatory agents while minimizing systemic toxicity. This review examines the metabolic and immune adaptations of Wnt-driven cancers, with a focus on glycolysis, glutaminolysis, and macropinocytosis. We highlight emerging therapeutic targets and nanomedicine-based delivery strategies to counteract metabolic adaptation and immune suppression. By integrating metabolic and immune-targeting with precision nano-delivery platforms, future treatment paradigms may improve outcomes for aggressive and therapy-resistant Wnt-driven cancers.

Keywords:  Wnt signaling; colorectal cancer; macropinocytosis; membrane trafficking; metabolic reprogramming; targeted cancer therapies

DOI:  https://doi.org/10.3389/fcell.2025.1622218
Clin Nucl Med. 2025 Sep 10.

18F-FGln PET/CT Imaging Shows High Uptake in Meningiomas Providing Insights for Diagnosis and Treatment.

Xiaoxia Xu, Zhi Yang.

  A 64-year-old woman with persistent headaches and vision disturbances underwent 18F-(2S,4R)-4-fluoroglutamine (18F-FGln) PET/CT due to MRI contraindications. Imaging revealed a sellar mass with high radiotracer uptake (SUVmax 7.17), later confirmed as a WHO grade I meningioma. This case highlights the potential of 18F-FGln PET/CT in detecting meningiomas, leveraging their glutamine metabolism. Given the tumor's metabolic profile, glutaminase inhibitors may offer novel therapeutic avenues. Further research is warranted to explore the mechanistic basis of 18F-FGln uptake in meningiomas and its implications for diagnosis and treatment.

Keywords:  ; PET/CT; glutamine metabolism; meningiomas

DOI:  https://doi.org/10.1097/RLU.0000000000006080
J Ethnopharmacol. 2025 Sep 05. pii: S0378-8741(25)01236-X. [Epub ahead of print] 120544

Shen Ling Bai Zhu San promotes gut IgA+ plasma cells to alleviate chronic diarrhea in mice via increasing systematic glutamine.

Rong Chen, Yulin Lin, Xinglin Gao, Haoxuan Zhao, Menghui Cao, Shuhong Chai, Mengjie Liu, Jianchi Lun, Yimu Ma, Weijie Lv, Wei Mao, Qian Qu, Shining Guo.

   ETHNOPHARMACOLOGICAL RELEVANCE: Shen Ling Bai Zhu San (SLBZS) is a classical Chinese herbal formula and has been used for treating chronic diarrhea (CD) for several centuries. However, there is a lack of robust evidence on how SLBZS regulates immune function to improve CD.
AIM OF THE STUDY: To reveal the spleen-invigorating and antidiarrheal effects of SLBZS in chronic diarrhea mice induced by spleen-deficiency, as well as to explore the underlying mechanism.
MATERIALS AND METHODS: Based on the modern living habits, the CD model was induced by multiple factors, and the antidiarrheal effects of SLBZS were evaluated by monitoring body weight, diarrhea scored, fecal water content, etc. Additionally, the flow cytometry and metabolomics were used to explore the changes of colonic B cells and related metabolites. Subsequently, the inhibitor of glutamine synthetase and antibiotic-treated mice were used separately to evaluate the roles of glutamine and gut microbiota in the treatment of CD with SLBZS.
RESULTS: High-dose SLBZS significantly alleviates CD and repairs the gut mucosal barrier. Moreover, SLBZS significantly increased the percentages of germinal center B cells, plasma cells (PC), IgA+ PC, IgA+ bacteria and the content of sIgA. Metabolomics results indicated that glutamine metabolism may be vital pathway for SLBZS treatment of CD, which has also been confirmed by supplementation of glutamine in CD mice and the used of inhibitor of glutamine synthetase. Lastly, we demonstrated that SLBZS promotes the differentiation of B cells to produce sIgA in a microbiota-dependent manner.
CONCLUSIONS: Our study proved that elevated glutamine plays a crucial role in the treatment of CD with SLBZS by promoting the differentiation of B cells to produce sIgA.

Keywords:  B cells; Shen Ling Bai Zhu San; alanylglutamine/glutamine; chronic diarrhea; gut microbiota

DOI:  https://doi.org/10.1016/j.jep.2025.120544
Magn Reson Med. 2025 Sep 08.

Simultaneous in vivo detection of spectrally resolved glutamate, glutamine, and glutathione at 3 T with NAA-aspartyl editing and echo-time optimization.

Li An, Sungtak Hong, Tara Turon, Adriana J Pavletic, Christopher S Johnson, Jun Shen.

   PURPOSE: To achieve spectrally resolved in vivo detection of glutamate, glutamine, and glutathione at 3 T.
METHODS: Difference editing of N-acetylaspartate CH2 protons (NAA-CH2) combined with a new echo-time (TE) optimization approach is introduced. Difference editing was used to detect NAA-CH2 independently of NAA-CH3, thereby eliminating systematic errors arising from constrained fitting of the entire NAA molecule. Numerical optimization of TE and TE1 minimized interference from highly dominant glutamate in glutamine detection in the ON/OFF sum spectrum. In vivo data were acquired from 6 healthy participants, including 2 who underwent oral administration of [U-13C]glucose.
RESULTS: The NAA-aspartyl-edited, cleaned-up in vivo spectrum showed distinct separation of glutamate, glutamine, and glutathione peaks at 3 T, facilitating spectral quantification and clinical applications. The post-13C proton MR-spectroscopy spectra clearly demonstrated the dynamic 13C-labeling of glutamate C4 following oral [U-13C]glucose intake.
CONCLUSION: This technique enables simultaneous spectral resolution of glutamate, glutamine, and glutathione peaks at 3 T using difference editing of NAA-CH2 and an optimized TE of 85 ms. Additionally, it demonstrates, for the first time, the feasibility of measuring 13C turnovers of spectrally resolved glutamate at 3 T with the high sensitivity and spatial resolution of proton MR spectroscopy.

Keywords:  13C; NAA‐CH2; glutamate; glutamine; glutathione

DOI:  https://doi.org/10.1002/mrm.70076
Int J Mol Sci. 2025 Aug 30. pii: 8466. [Epub ahead of print]26(17):

Methods and Guidelines for Metabolism Studies: Applications to Cancer Research.

Melvin Li, Sarah R Amend, Kenneth J Pienta.

  Metabolism is a tightly controlled, but plastic network of pathways that allow cells to grow and maintain homeostasis. As a normal cell transforms into a malignant cancer cell and proliferates to establish a tumor, it utilizes a variety of metabolic pathways that support growth, proliferation, and survival. Cancer cells alter metabolic pathways in different contexts, leading to complex metabolic heterogeneity within a tumor. There is an unmet need to characterize how cancer cells alter how they use resources from the environment to evolve, spread to other sites of the body, and survive current standard-of-care therapies. We review key techniques and methods that are currently used to study cancer metabolism and provide drawbacks and considerations in using one over another. The goal of this review is to provide a methods' guide to study different aspects of cell and tissue metabolism, how they can be applied to cancer, and discuss future perspectives on advancements in these areas.

Keywords:  13C-metabolic flux analysis; Seahorse metabolic flux analysis; cancer metabolism; fluorescent probes; genetically encoded fluorescent biosensors; isotope tracing; untargeted metabolomics

DOI:  https://doi.org/10.3390/ijms26178466
Eur J Neurol. 2025 Sep;32(9): e70343

Glutamine Metabolism and Metabolic Profiling Using 7 T CRT-FID MRSI in Focal Epilepsy.

Stefanie Chambers, Philipp Lazen, Matej Hotka, Haniye Shayeste, Matthias Tomschik, Jonathan Wais, Vitalij Zeiser, Lukas Hingerl, Bernhard Strasser, Lukas Haider, Tatjana Traub-Weidinger, Christoph Baumgartner, Johannes Koren, Florian Mayer, Martha Feucht, Christian Dorfer, Ekaterina Pataraia, Wolfgang Bogner, Siegfried Trattnig, Gregor Kasprian, Karl Rössler, Gilbert Hangel.

   BACKGROUND: Approximately one-third of people with epilepsy (PWE) remain drug-resistant. In these cases, surgical resection of the epileptogenic zone may significantly reduce or eliminate seizures. Surgery necessitates precise delineation of the epileptogenic zone (EZ) which proves especially challenging in the 20% of PWE that remain MRI-negative. The purpose of this study was to analyze the feasibility and robustness of ultra-high-field MRSI in identifying and characterizing pathologies in focal epilepsy. In addition, the relationship of glutamate and glutamine was evaluated in the EZ.
METHODS: Fifty-six people with focal epilepsy were prospectively measured using 7 T concentric ring trajectory direct acquisition of free-induction-decay MRSI, which generated whole-brain metabolic maps with an isotropic resolution of 3.4mm3. After exclusion criteria were applied, we assessed metabolite ratios in 15 lesional and 14 MRI-negative PWE.
RESULTS: In the lesional group, metabolic alterations in the suspected EZ were present in 86.7% of maps normalized to N-acetyl-aspartate, whereas this was reduced to 80% in creatine ratios. Metabolites with the highest consistency in the lesional group included myo-inositol and choline, showing increases in 92.3% of PWE. In MRI-negative patients, changes were heterogeneous, with a detection rate of 57.1%. We also observed a tendency toward an inverse relationship of glutamate to glutamine in the EZ, with increases of glutamine in PWE with lower seizure frequencies, contrasting glutamate increases in higher seizure frequencies.
CONCLUSION: Our preliminary analysis suggests that 7 T CRT-FID MRSI shows promise not only in identifying metabolic alterations in focal epilepsy but may also provide insights into disease pathomechanisms.

Keywords:  7 T; epilepsy; glutamine; spectroscopy; ultra‐high‐field MRSI

DOI:  https://doi.org/10.1111/ene.70343
Curr Opin Rheumatol. 2025 Sep 15.

Fueling fibrosis: metabolic dysregulation in systemic sclerosis.

Katja Lakota, Nika Boštic, Blaž Burja.

   PURPOSE OF REVIEW: This review examines how metabolic reprogramming drives fibrosis and immune dysregulation in systemic sclerosis (SSc), emphasizing the role of nutrient-sensing and energy pathways in disease progression.
RECENT FINDINGS: SSc is characterized by a shift from catabolic to anabolic metabolism, defined by reduced AMP-activated protein kinase (AMPK) and enhanced mechanistic target of rapamycin complex 1 (mTORC1) signaling. This promotes biosynthetic activity, with upregulated glycolysis supplying substrates for collagen production and supporting pro-inflammatory immune cell polarization. Remodeling of the tricarboxylic acid cycle yields key metabolites with extrametabolic roles. α-ketoglutarate (αKG) supports epigenetic regulation, collagen maturation, and AMPK activation, offering protective effects. In contrast, succinate and fumarate promote inflammation and fibrotic signaling. Despite increased anabolic activity, oxidative phosphorylation remains elevated in SSc fibroblasts, contributing to excess reactive oxygen species (ROS). Metabolomic analyses consistently show disrupted amino acid and lipid metabolism, including glutamine and tryptophan pathways, linked to immune activation and fibrogenesis. Single-cell transcriptomics reveal diverse fibroblast subtypes with distinct metabolic programs correlating with fibrosis severity.
SUMMARY: SSc is characterized by a metabolic reprogramming that favors anabolic, profibrotic, and proinflammatory states. These interconnected metabolic shifts illustrate how central carbon and nutrient pathways not only sustain energy demands but also actively regulate profibrotic signaling, offering new therapeutic targets for modulating fibrosis.

Keywords:  amino acids; anabolism; lipids; metabolism; systemic sclerosis

DOI:  https://doi.org/10.1097/BOR.0000000000001123
Int J Mol Sci. 2025 Aug 25. pii: 8241. [Epub ahead of print]26(17):

Therapeutic Potential of Glutaminase Inhibition Targeting Metabolic Adaptations in Resistant Melanomas to Targeted Therapy.

Laura Soumoy, Aline Genbauffe, Dorianne Sant'Angelo, Maude Everaert, Léa Mukeba-Harchies, Jean-Emmanuel Sarry, Anne-Emilie Declèves, Fabrice Journe.

  Targeted therapy with BRAFi has significantly improved outcomes for patients with BRAF-mutated metastatic melanoma. However, resistance mechanisms, particularly metabolic adaptations, such as increased glutaminolysis, present substantial clinical challenges. This study investigated the metabolic changes underlying BRAFi resistance in melanoma cells. Using pharmacological agents, including dabrafenib (BRAFi), pimasertib (MEKi), dasatinib (cKITi), and CB-839 (glutaminase inhibitor), we explored metabolic adaptations in melanoma cell lines harboring various mutations. Our methodologies included cell culture, qPCR, polysome profiling, animal studies in nude mice, and analyses of patient samples to evaluate the therapeutic potential of targeting glutaminolysis. Our findings confirmed that melanoma cells, with resistance to targeted therapies, exhibit metabolic adaptations, including enhanced glutaminolysis, increased mitochondrial content, and elevated antioxidative capacities. We evaluated the efficacy of CB-839 and demonstrated its ability to reduce the proliferation of resistant melanoma cells both in vitro and in vivo. Mechanistic studies revealed that CB-839 suppressed ATP production and TCA cycle intermediates in resistant cells while inducing oxidative stress in sensitive cells, thereby inhibiting their proliferation. High glutaminase expression in primary patient tumor samples was associated with poor prognosis. We identified a metabolic signature in tumors from patients responsive or unresponsive to BRAFi prior to treatment, which could serve as a predictive factor for BRAFi response. This study underscores the metabolic alterations driving resistance to BRAFi in melanoma cells and highlights the therapeutic potential of targeting glutaminolysis with CB-839. The identification of metabolic signatures in patient samples provides valuable insights for personalized treatment strategies, aiming to overcome resistance mechanisms and improve patient outcomes in melanoma management.

Keywords:  BRAF inhibitors; CB-839; glutaminase inhibition; melanoma resistance; metabolic adaptations; personalized therapy

DOI:  https://doi.org/10.3390/ijms26178241
J Clin Transl Hepatol. 2025 Jul 28. 13(7): 542-554

Short-term Physical Activity Reduces Metabolic-associated Steatohepatitis by Promoting the Degradation of Branched-chain Amino Acids in Skeletal Muscle.

Mingshu Gao, Jiaying Li, Yanan Zhang, Jiangtao Huang, Jiaqi Chen, Dawen Liao, Shengnan He, Qian Bi, Lele Ji, Yulu Du.

   Background and Aims: Metabolic-associated steatohepatitis (MASH) is an advanced and progressive liver disease that potentially causes cirrhosis and hepatocellular carcinoma. Exercise is a crucial and effective intervention for ameliorating metabolic dysfunction-associated steatotic liver disease. This study aimed to provide a comprehensive understanding of the underlying mechanisms of MASH, which benefit a broad spectrum of MASH patients, including those who have difficulty engaging in physical activity.
Methods: We established a mouse model of MASH and selectively knocked down L-type amino acid transporter 1 and alanine-serine-cysteine transporter 2. Mice were fed a high-fat high-cholesterol diet and subjected to either short- or long-term exercise regimens. We assessed the phosphorylation and activity of branched-chain alpha-keto acid dehydrogenase (BCKDH) as well as branched-chain amino acid (BCAA) content in skeletal muscle following exercise.
Results: Short-term exercise significantly reduced hepatic steatosis and inflammation without causing notable changes in body weight. It also enhanced BCKDH activity in skeletal muscle and decreased hepatic BCAA accumulation. Muscle-specific overexpression of BCKDH further promoted BCAA catabolism and significantly attenuated hepatic steatosis and inflammation in high-fat high-cholesterol-fed mice. In contrast, muscle-specific L-type amino acid transporter 1 knockdown, which suppresses BCAA uptake, markedly abolished these beneficial effects. Interestingly, BCKDH overexpression in muscle increased glutamine levels in both the blood and liver. Hepatic alanine-serine-cysteine transporter 2 knockdown, which inhibited glutamine uptake, lessened the protective effect of exercise on MASH. Further in vitro study revealed that glutamine derived from myocytes improved redox homeostasis and inhibited lipid accumulation in hepatocytes.
Conclusions: Short-term exercise enhances BCAA catabolism in skeletal muscle and promotes glutamine production, which circulates to the liver to improve redox balance and alleviate MASH.

Keywords:  Aerobic exercise; Amino acids; Branched-chain; Exercise; Glutamine; Liver-skeletal muscle crosstalk; Metabolic-associated steatohepatitis

DOI:  https://doi.org/10.14218/JCTH.2025.00072
J Biomed Sci. 2025 Sep 10. 32(1): 87

TCA cycle-derived oncometabolites in cancer and the immune microenvironment.

Shukla Sarkar, Chien-I Chang, Jussekia Jean, Meng-Ju Wu.

  Oncometabolites are aberrant metabolic byproducts that arise from mutations in enzymes of the tricarboxylic acid (TCA) cycle or related metabolic pathways and play central roles in tumor progression and immune evasion. Among these, 2-hydroxyglutarate (2-HG), succinate, and fumarate are the most well-characterized, acting as competitive inhibitors of α-ketoglutarate-dependent dioxygenases to alter DNA and histone methylation, cellular differentiation, and hypoxia signaling. More recently, itaconate, an immunometabolite predominantly produced by activated macrophages, has been recognized for its dual roles in modulating inflammation and tumor immunity. These metabolites influence cancer development through multiple mechanisms, including epigenetic reprogramming, redox imbalance, and post-translational protein modifications. Importantly, their effects are not limited to cancer cells but extend to various components of the tumor microenvironment, such as T cells, macrophages, dendritic cells, and endothelial cells, reshaping immune responses and contributing to immune suppression. In this review, we highlight the emerging insights into the roles of TCA cycle-associated oncometabolites in cancer biology and immune regulation. We discuss how these metabolites impact both tumor-intrinsic processes and intercellular signaling within the tumor microenvironment. Finally, we examine therapeutic strategies targeting oncometabolite pathways, including mutant IDH inhibitors, α-ketoglutarate mimetics, and immunometabolic interventions, with the goal of restoring immune surveillance and improving cancer treatment outcomes.

Keywords:  2-hydroxyglutarate; Epigenetic regulation; Fumarate; Itaconate; Metabolic reprogramming; Oncometabolites; Succinate; TCA cycle; Tumor immunity; α-ketoglutarate

DOI:  https://doi.org/10.1186/s12929-025-01186-y
Cell Immunol. 2025 Sep 06. pii: S0008-8749(25)00111-X. [Epub ahead of print]417 105025

Divergent metabolic rewiring shapes altered innate immunity.

Mohua Liu, Xiao Wang, Xiaoya Qu, Yao Wang, Xihui Shen, Lei Xu.

  Both trained immunity (TRIM) and endotoxin tolerance (ET) initiate similar metabolic reprogramming characterized by enhanced glycolysis following an initial stimulus. However, TRIM exhibited heightened immune activation upon restimulation, whereas ET showed suppressed innate immune response. This divergence is attributed to distinct metabolic intermediates accumulated after the initial stimulation. In TRIM, metabolites like fumarate and glutamine derivatives accumulate, reinforcing pro-inflammatory epigenetic modifications. Conversely, ET is characterized by increased itaconate and lactate levels, promoting anti-inflammatory epigenetic changes and metabolic paralysis. This review highlights metabolic intermediates as key regulators of innate immune fate decisions, presenting avenues for targeted immune modulation.

Keywords:  Endotoxin tolerance (ET); Fumarate; Itaconate; Mevalonate pathway; Trained immunity (TRIM)

DOI:  https://doi.org/10.1016/j.cellimm.2025.105025
Biotechnol J. 2025 Sep;20(9): e70119

Bacterial Glutamine Synthetases as a Novel Metabolic Selection Marker to Improve CHO Cell Culture Performance Through Selection Stringency Modulation.

Daniel Heinzelmann, Nicholas Michelarakis, Franziska Reuss, Benjamin Lindner, Anne R Karow-Zwick, Joschka Bauer, Benjamin Renner, Simon Fischer, Patrick Schulz, Moritz Schmidt.

  The use of metabolic selection markers has advanced stable cell line generation, increasing productivity while simultaneously eliminating the need for antibiotic reagents. This study explores the potential of bacterially derived glutamine synthetases (GS) as a novel generation of metabolic selection markers to further enhance CHO cell culture performance. GS-I proteins were extracted from the genomes of enterobacterial and actinomycetes species. Three of these enzymes demonstrated functionality when stably transfected into GS-deficient CHO cells, leading to a 3- to 4-fold increase in antibody titer compared to endogenous GS from Cricetulus griseus. This study indicates that the functionality of bacterial GS enzymes in mammalian cells is determined by solvent accessibility and the geometry of the catalytic binding pocket. Dysfunctional variants showed a less accessible bifunnel. Bacterial GS were evaluated for their bioprocess performance leading to superior stable pool and clone performance. Transcriptome analysis further revealed that regulatory cellular mechanisms were decoupled in a cross-species set-up, reinforcing the suitability of repurposing bacterial enzymes as selection markers in mammalian cell lines. By modulating the selection stringency, an increase in expression performance was achieved without impairing the bioprocess behavior or long-term cell line stability.

Keywords:  Chinese hamster ovary cells; cell culture performance; cell line stability; glutamine synthetase; homology modelling; metabolic selection marker; molecular simulation

DOI:  https://doi.org/10.1002/biot.70119
Free Radic Res. 2025 Sep 12. 1-15

Copper induces cystine/glutamate antiporter SLC7A11 through the activation of Nrf2 and Atox1 pathways.

Tetsuro Kamiya, Ryoka Teruya, Haruka Tahara, Yuki Inoue, Aoi Ikeda, Sayaka Hosowari, Tomo Arioka, Tomohiro Otsuka, Hirokazu Hara.

  Amino acid metabolism plays a crucial role in tumor biology. The sodium-independent cystine/glutamate exchange system, known as system Xc-, is significantly activated in cancer cells and plays a role in tumor progression. Copper (Cu), an essential micronutrient, plays a crucial role in physiological processes; however, its accumulation in tumors has been associated with tumor progression. Nonetheless, the relationship between system Xc--mediated amino acid metabolism and Cu remains inadequately understood. In this study, CuCl2 treatment resulted in the significant induction of SLC7A11, a light chain subunit of system Xc-, and glutamate receptor mGluR1 expression in human triple-negative MDA-MB-231 cells. Conversely, FeCl2 treatment induced the expression of SLC7A11 but not mGluR1, indicating that Cu specifically activated SLC7A11-mediated amino acid metabolism. The investigation focused on the role of Nrf2, a redox-sensitive transcription factor, in the induction of SLC7A11 under conditions of oxidative stress induced by CuCl2 treatment. Upon treatment with CuCl2, the nuclear translocation of Nrf2 was observed, and knockdown of Nrf2 significantly suppressed the induction of SLC7A11. Given that the Cu chaperone, antioxidant-1 (Atox1), functions as a Cu-dependent transcription factor, the role of Atox1 in the expression of SLC7A11 was further investigated. Like the effects of Nrf2 knockdown, Atox1 was found to play a pivotal role in the Cu-mediated induction of SLC7A11. Our findings indicate that intratumoral Cu influences the expression of SLC7A11 and may play a role in tumor progression.

Keywords:  Copper, SLC7A11, mGluR1, Nrf2, Atox1

DOI:  https://doi.org/10.1080/10715762.2025.2560847
Adv Sci (Weinh). 2025 Sep 11. e02738

GLS1-RNA Polymerase II Axis Mediates Glutamine-Dependent Hepatoprotective Effects on Alcoholic Liver Disease in High-Protein Diets.

Wenbiao Wu, Haowen Jiang, Yichang Liu, Chang Peng, Hanlin Wang, Wenhua Yang, Zan Lyu, Yan Sun, Huan Ma, Hongyu Gu, Weijuan Kan, Liya Jing, Tiancheng Dong, Chunmei Xia, Saifei Lei, Rui Wu, Jinlong Li, Jia Li.

  The RNA polymerase II (RNA pol II) complex is essential for gene transcription throughout life, and numerous cofactors have been identified as critical for diverse transcriptional processes. Herein, it is discovered that the RNA pol II complex is modulated by glutaminase 1 (GLS1), which affects lipid metabolism. In alcoholic fatty liver disease (AFLD), RNA pol II activation is observed, whereas RNA pol II inhibition reverse hepatic steatosis. Furthermore, high-protein diets are recognized for their adjuvant effect on patients with AFLD; glutamine is indispensable for its protective effects against hepatic steatosis, which is dependent on RNA pol II. Mechanistically, GLS1 acts as a chaperone that affects the RNA pol II complex in the nucleus by interacting with its subunits, ROLR2H and POLR2E. In vivo studies have shown that hepatic overexpression of GLS1 ameliorates alcohol-induced fatty liver, whereas deficiency worsens this condition. Moreover, the overexpression of POLR2E or POLR2H, but not the truncated variants, abolishes the protective effects of GLS1 against alcohol-induced fatty liver. Thus, the study clarifies GLS1 as a cofactor involved in assembling the RNA pol II complex, regulating hepatic steatosis, and provides foundational insights for future therapeutic approaches in AFLD.

Keywords:  GLS1; RNA polymerase II; alcoholic fatty liver disease; hepatic lipogenesis; high‐protein diets

DOI:  https://doi.org/10.1002/advs.202502738
Front Immunol. 2025 ;16 1637436

Metabolites as regulators of autoimmune diseases.

Maria Tada, Michihito Kono.

  Immune cell metabolism is essential for regulating immune responses, including activation, differentiation, and function. Through glycolysis and oxidative phosphorylation (OXPHOS), metabolism supplies energy and key intermediates for cell growth and proliferation. Importantly, some metabolites generated during these processes act as signaling molecules that influence immune activity. Autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) involve multiple immune cell types, and recent research in immunometabolism has revealed that disrupted metabolic pathways in these cells contribute to disease progression. Effector T cells, for instance, undergo metabolic reprogramming, particularly increased glycolysis, to meet the demands of proliferation and function during autoimmune responses. Targeting metabolic enzymes has shown therapeutic potential. In addition, metabolites themselves, termed immunometabolites, can directly modulate immune responses. These include both intracellularly generated and secreted molecules. Itaconate is a key immunometabolite and is derived from the TCA cycle by aconitate decarboxylase 1 (ACOD1) in activated macrophages. It inhibits the NLRP3 inflammasome and pro-inflammatory cytokines, such as IL-1β and IL-6. Beyond macrophages, itaconate alters metabolism and epigenetics in T cells by reducing 2-hydroxyglutarate and the S-adenosyl-L-methionine (SAM)/S-adenosyl-L-homocysteine (SAH) ratio, thereby suppressing Th17 differentiation and enhancing Foxp3 expression in Tregs. Itaconate ameliorates disease in experimental autoimmune encephalomyelitis, RA, SLE, and others. It also exhibits antimicrobial effects by blocking bacterial isocitrate lyase and viral replication. Despite increasing interest, reviews focusing specifically on immunometabolites remain limited. This review highlights emerging insights into metabolites involved in glycolysis, the TCA cycle, glutaminolysis, one-carbon metabolism, and lipid metabolism that influence autoimmune pathophysiology.

Keywords:  cellular metabolism; glutaminolysis; glycolysis; itaconate; metabolite

DOI:  https://doi.org/10.3389/fimmu.2025.1637436
Int J Mol Sci. 2025 Sep 08. pii: 8729. [Epub ahead of print]26(17):

Downregulation of miR-27a-3p Modulates TGF-β Signaling and Dysregulates Metabolism in Glioblastoma.

Augusto Ferreira Weber, Juliete Nathali Scholl, Camila Kehl Dias, Vinícius Pierdoná Lima, Tamires de Bona, Renata Marschner, Arieli Cruz de Sousa, Fábio Klamt, Fabrício Figueiró.

  Several microRNAs (miRNAs) are key influencers of tumor microenvironment (TME) cell plasticity, regulating the progression of various tumor types such as glioblastoma (GBM). Differential expressions of miR-27a-3p and miR-155-5p in GBM cells and biopsies have already been described as markers of tumor subtype and progression. We aimed to evaluate the cellular and molecular impacts of inhibiting these two overexpressed miRNAs in GBM cell lines. A172 cells were transfected with miR-27a-3p and miR-155-5p inhibitors, and the effects on cellular processes and the expression of malignancy-related genes were analyzed by flow cytometry and qPCR, respectively. Thus, several cellular characteristics in A172 cells were modulated; however, only the inhibition of miR-27a-3p resulted in apoptosis, reduced glucose uptake, and a decrease in mitochondrial membrane potential. Both inhibitors modulated metabolic and immunological targets, negatively regulating genes in the glycolysis pathway and modulating other metabolic pathways involving glutamine and fatty acids, for example. Additionally, it modulates the TGF-β pathway, which can influence the GBM microenvironment due to its immunosuppressive role in advanced tumors. miR-27a-3p appears to be a pivotal factor in the functional duality of TGF-β and its interaction with HIF1A in the hypoxic tumor environment, modulating SMAD partners or TGF-β pathway inhibitors. Here, we demonstrate the importance of inhibiting overexpressed miRNAs, particularly miR-27a-3p, in modulating key pathways for tumor cell survival. The results of this work provide new insights into potential targets for immune-metabolic interactions in the TME and their implications for tumorigenesis, shedding light on new therapeutic approaches for GBM.

Keywords:  TGF-β signaling; glioblastoma; metabolism reprogramming; miR-155-5p; miR-27a-3p

DOI:  https://doi.org/10.3390/ijms26178729
Radiol Imaging Cancer. 2025 Sep;7(5): e240494

High-Resolution Mapping of Tumor and Peritumoral Glutamate and Glutamine in Gliomas Using 7-T MRSI.

Gilbert Hangel, Philipp Lazen, Cornelius Cadrien, Stefanie Chambers, Julia Furtner, Lukas Hingerl, Bernhard Strasser, Barbara Kiesel, Mario Mischkulnig, Matthias Preusser, Thomas Roetzer-Pejrimovsky, Adelheid Wöhrer, Wolfgang Bogner, Karl Rössler, Siegfried Trattnig, Georg Widhalm.

  Purpose To evaluate glutamate (Glu) and glutamine (Gln) concentrations in patients with glioma using 7-T MR spectroscopic imaging, identify significant differences in metabolic ratios between tumor and peritumoral regions, and assess associations of Glu and Gln with tumor-associated epilepsy and other tumor characteristics. Materials and Methods This retrospective study included data from patients with gliomas who underwent 7-T MR spectroscopic imaging in a single university hospital between September 2018 and April 2021. Median values for nine metabolic ratios were calculated within the visible tumor and peritumoral shell, and Dice similarity coefficients were used to assess the spatial overlap of elevated metabolic regions between these compartments. Statistical significance between regions of interest and between glioma attributes (eg, isocitrate dehydrogenase status) was assessed. Results Thirty-six patients (median age, 52 years [IQR, 23 years]; 22 male, 14 female) were included in the study. The Glu to total creatine (Glu/tCr) median was significantly higher in the peritumoral volume of interest (median, 1.13) compared with the tumor (median, 0.92; P = .00015) and normal-appearing white matter (NAWM; median, 0.87; P < .00011), while the Gln/tCr median was highest in the tumor (median, 0.77; peritumoral: median, 0.44; P < .00011; NAWM: median, 0.33; P < .00011). Glu to total choline was higher in the peritumoral region as well (median, 3.44; tumoral: median, 2.23; P < .00011; NAWM: median, 2.06; P < .00011). Peritumoral Dice similarity coefficients for Glu/tCr and Gln/tCr hotspots were comparable (0.51 to 0.53). Specific metabolic ratios were significantly different between isocitrate dehydrogenase mutant and wild-type gliomas (eg, tumoral Glu/total N-acetylaspartate [tNAA], P = .0054), oligodendroglioma and astrocytoma (eg, tumoral Gln/tNAA, P = .0033), and oligodendroglioma and glioblastoma (eg, tumoral Glu/tNAA, P = .0034). Conclusion The 7-T MR spectroscopic imaging revealed increased Glu and Gln metabolic ratios within the peritumoral region compared with NAWM of patients with glioma distinct from intratumoral changes. Keywords: Glioma, 7 T, MR Spectroscopic Imaging, MRSI, Infiltration, Iisocitrate Dehydrogenase, IDH Supplemental material is available for this article. © The Author(s) 2025. Published by the Radiological Society of North America under a CC BY 4.0 license.

Keywords:  7 T; Glioma; IDH; Iisocitrate Dehydrogenase; Infiltration; MR Spectroscopic Imaging; MRSI

DOI:  https://doi.org/10.1148/rycan.240494
iScience. 2025 Sep 19. 28(9): 113371

Distribution of glutamate and glutamine in tumor microenvironments of brain metastasis: Insights from biochemical analysis and molecular imaging.

Jun Tang, Yutong Zhao, Liangpeng Chen, Yangyang Liu, Hexin Xie, Zehui Wu, Lu Zhang, Di Fan, Xiaoxia Xu, Lin Ai, Qian Liu, Hua Zhu, Deling Li.

  Cancer neuroscience has implicated peritumoral neurons in facilitating breast-to-brain metastasis (BrBM) progression via the N-methyl-D-aspartate receptor (NMDAR), a glutamate (Glu) receptor. The Glu-glutamine (Gln) cycle converts Glu into Gln, forming the combined Glx pool. This study investigated the spatial distribution of phosphorylated GluN2B (pGluN2B), an NMDAR subunit, and Glx in BrBM. Ex vivo analysis revealed elevated pGluN2B expression in BrBM, particularly in tumor cores, while Glx levels were paradoxically reduced. In mouse models, glutamine-based positron emission tomography (Gln-PET) imaging revealed higher tracer uptake in BrBM than that in paired breast tumors, with uptake values correlated positively with Glx concentration and pGluN2B expression. Strong Gln-PET uptake in BrBM noninvasively indicated elevated Glx metabolism in a BrBM patient, confirmed by ex vivo staining. This study highlighted the regional distribution of NMDAR and Glx, underscoring their potential as diagnostic biomarkers for BrBM. Glutamine-based molecular imaging can noninvasively visualize the tumor microenvironment relevant to cancer neuroscience.

Keywords:  Molecular biology; Pathology; Radiation biology

DOI:  https://doi.org/10.1016/j.isci.2025.113371