bims-glucam 2025-09-28 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–09–28
twenty-two papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting hepatocyte-specific SLC2A8 blocks hepatic steatosis and dissociates TCA cycle flux inhibition from glutamine anaplerosis.
Modulating Glutamine Metabolism Reprograms Pro-Inflammatory Differentiation in Macrophages.
Glutaminase Expression in Canine Large-Cell Alimentary Lymphoma Cells and Effects of Glutaminase Inhibition by CB-839.
The role of glutamine metabolism and ASCT2/SLC1A5 transporter on insulin resistance and endoplasmic reticulum stress in 3T3-L1 adipocytes.
Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis.
Molecular subtypes based on the expression of glutamine metabolism-related genes predict prognosis, tumor microenvironment, and drug therapy response of colon adenocarcinoma.
Targeting ROS-metabolism dual pathways to trigger PANoptosis by cobalt-vanadium oxides biomimetic nanocakes for tumor immunotherapy.
Glutamine synthetase shields triple-negative breast cancer cells from ferroptosis in metastasis triggered by glutamine deprivation.
STK11 coordinates IL-4 signaling with metabolic reprogramming to control M2 macrophage polarization and antitumor immunity.
Breaking the vicious cycle: Multifunctional nanomaterials targeting Tumor metabolic reprogramming to overcome T cell exhaustion and bone repair failure in bone tumors.
UDP-glucose ceramide glucosyltransferase promotes radioresistance via membrane reorganization to maintain redox balance in glioblastoma.
HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer.
Structure and enzymology of glutaminase mutants that disrupt glutamine-glutamate homeostasis and cause neurological disease.
FAK modulates glioblastoma stem cell energetics via regulation of glycolysis and glutamine oxidation.
MicroRNA Landscape in Hepatocellular Carcinoma: Metabolic Re-Wiring, Predictive and Diagnostic Biomarkers, and Emerging Therapeutic Targets.
Rates of Mitochondrial Metabolism of Glucose, Amino Acids, and Fatty Acids by the HEI-OC1 Inner Ear Cell Line.
Monitoring of Allograft Adaptation After Kidney Transplantation in Pediatric Patients by Targeted Plasma Metabolomics.
Metabolomic biomarkers associated with trismus and dysphagia, radiation therapy, tumour stage and location in patients with head and neck cancer.
Liver-specific glucagon dysfunction promotes PP-cell hyperplasia and formation of glucagon and PP double-positive cells.
CDK12 regulates cellular metabolism to promote glioblastoma growth.
Near-infrared spectroscopy of blood plasma amino acids with chemometrics towards breast cancer discrimination.
Intravenous Arginine Stimulates Glucagon Secretion More Than Equimolar Alanine, Leucine, Glutamine, and Proline in Humans.

Hepatol Commun. 2025 Oct 01. pii: e0810. [Epub ahead of print]9(10):

Targeting hepatocyte-specific SLC2A8 blocks hepatic steatosis and dissociates TCA cycle flux inhibition from glutamine anaplerosis.

Joshua A Adams, Yiming Zhang, Jiameng Sun, Andrew Tilston-Lunel, Cassandra B Higgins, Monique Heitmeier, Sam Ballentine, Eric Tycksen, Roland E Dolle, Paul W Hruz, Brian J DeBosch.

   BACKGROUND: Excess TCA cycle and glutamine anaplerosis are hallmarks of metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Blocking glutamine metabolism attenuates metabolic dysfunction-associated steatohepatitis. However, inhibiting TCA cycle flux by blocking plasma membrane carbohydrate transport is limited by the ubiquitous tissue distribution, function, and homology among the SLC2A family of facilitative carbohydrate transporters, and the potential for carbohydrate blockade to invoke or exacerbate glutamine anaplerosis. Here, we quantify alterations in hepatocyte carbon flux, define the broader metabolic consequences of hepatocyte-specific GLUT8/SLC2A8 inhibition, and delineate the antisteatotic efficacy of a novel small-molecule GLUT8-selective inhibitor.
METHODS: We generated mice with floxed SLC2A8 alleles and expressed hepatocyte-specific Cre by breeding these mice with albumin-Cre transgenic mice, or by administering AAV8 encoding hepatocyte-specific iCre. We performed stable-isotope glucose, fructose, and glutamine metabolic labeling in isolated GLUT8WT and GLUT8LKO hepatocytes and performed metabolic phenotyping in lean and diet-induced obese GLUT8WT and GLUT8LKO mice. Finally, we performed high-throughput screening to identify a GLUT8-selective inhibitor, which we characterized using in vitro models of triglyceride accumulation.
RESULTS: Hepatocyte-specific SLC2A8 deletion reduced diet-induced hepatic and peripheral fat accumulation and increased thermogenesis during ZT12-24 (eg, the dark phase). It also disrupted TCA cycle flux without inducing compensatory glutamine utilization. High-throughput screening identified a small-molecule, GLUT8-selective inhibitor, P20, which blocked hepatocyte TG accumulation and inflammation in in vitro steatotic and inflammatory models.
CONCLUSIONS: Deleting the hepatocyte carbohydrate transporter GLUT8 suppresses TCA cycle flux without inducing compensatory glutamine anaplerosis. The net effect of this is liver protection against multiple forms of dietary insult. Given that selective pharmacological GLUT8 inhibition is feasible, GLUT8 may be a viable target to abate metabolic dysfunction-associated steatohepatitis and other complications of obesity.

Keywords:  GLUT8; TCA cycle; caloric restriction; energy metabolism; fasting; fructose; glucose transporter; glutamine anaplerosis; metabolic dysfunction–associated steatohepatitis; metabolic dysfunction–associated steatotic liver disease

DOI:  https://doi.org/10.1097/HC9.0000000000000810
bioRxiv. 2025 Sep 18. pii: 2025.09.16.675216. [Epub ahead of print]

Modulating Glutamine Metabolism Reprograms Pro-Inflammatory Differentiation in Macrophages.

Sumeng Qi, Jiawei Fan, Dao-Sian Wu, Sudipto Ganguly, Ie-Ming Shih, Tian-Li Wang.

Previous in vivo studies demonstrated that JHU083/DON, a glutamine analog drug, potently reprograms M1/M2 macrophages. To determine whether these effects are direct or indirect, we utilized an in vitro murine bone marrow-derived macrophage (BMDM) model, which recapitulates macrophage differentiation and polarization processes, to examine the impact of DON on the M1 macrophages. DON was applied during M1 differentiation or to fully polarized M1 macrophages, revealing that glutamine inhibition initially suppressed M1 activity but later enhanced it, resulting in sustained pro-inflammatory activation. Multi-omics analyses (bulk RNA-seq and LC-MS), time-course assays, and glutamine depletion experiments consistently suggested that prolonged glutamine inhibition elevates glutamine levels, which sustain pro-inflammatory gene transcription. In contrast, M2 and tumor-associated macrophages (TAM), which are immunosuppressive, were more susceptible to DON, leading to functional suppression. Collectively, our findings uncover stage-specific mechanisms by which glutamine inhibition modulates M1 polarization, offering a mechanistic rationale for therapeutic strategies that sustain pro-inflammatory, anti-tumor macrophage activity while concurrently suppressing immunosuppressive myeloid subsets in cancer.

DOI: https://doi.org/10.1101/2025.09.16.675216
Vet Med Sci. 2025 Sep;11(5): e70601

Glutaminase Expression in Canine Large-Cell Alimentary Lymphoma Cells and Effects of Glutaminase Inhibition by CB-839.

Kosei Sakai, Masaki Hirao, Satoshi Kameshima, Yasuhiko Okamura, Takuya Mizuno, Shunsuke Shimamura.

  Glutamine metabolism plays a crucial role in tumour progression, making glutaminase a promising therapeutic target in various human cancers. However, its role in canine large-cell alimentary lymphoma (AL) remains unclear. This study investigated glutaminase expression and the effects of a glutaminase inhibitor (CB-839) on canine large-cell AL cell lines. Western blotting analysed glutaminase expression in three canine large-cell AL cell lines (CLC, Ema and Nody-1) and peripheral blood mononuclear cells (PBMCs) isolated from eight clinically healthy dogs. Cell viability was determined in each cell line after treatment with varying concentrations (0-10 µM) of CB-839. Flow cytometry was used to analyse the cell cycle and assess annexin assays in each cell line following treatment with 1 µM of CB-839 or a vehicle control. Additionally, metabolome analysis was performed in Nody-1 cells after treatment with 1 µM of CB-839 or a vehicle control. Glutaminase expression was significantly higher in cell lines than in PBMCs. CB-839 suppressed cell proliferation in a dose-dependent manner, with CLC and Nody-1 cells exhibiting greater susceptibility than Ema cells. Flow cytometric analysis revealed that CB-839 induced G0/G1 phase arrest and apoptosis in susceptible cell lines. Metabolomic analysis revealed that CB-839 led to glutamine accumulation and depletion of key tricarboxylic acid cycle intermediates in Nody-1 cells. These findings indicate that glutamine metabolism is upregulated in canine large-cell AL and plays a crucial role in tumour cell growth and survival. Inhibiting glutaminase could serve as a promising therapeutic strategy for this disease.

Keywords:  CB‐839; alimentary lymphoma; dog; glutaminase; glutamine; tumour metabolism

DOI:  https://doi.org/10.1002/vms3.70601
Cytotechnology. 2025 Oct;77(5): 177

The role of glutamine metabolism and ASCT2/SLC1A5 transporter on insulin resistance and endoplasmic reticulum stress in 3T3-L1 adipocytes.

Gulizar Aydogdu, Benan Pelin Sermikli, Sumer Aras, Erkan Yilmaz.

  Obesity is one of the major health issues of recent times. It is known that obesity increases endoplasmic reticulum (ER) stress, contributing to the development of insulin resistance in type-2 diabetes. This study investigates the relationship of glutamine metabolism with insulin resistance and ER stress under obese conditions. Using differentiated 3T3-L1 adipocytes, we demonstrate that increased glutamine supplementation enhances insulin sensitivity and reduces ER stress. Enhanced glutamine treatment also upregulated key amino acid transporters, Alanine-Serine-Cysteine Transporter 2 (ASCT2), L-type Amino Acid Transporter 1 (LAT1), and Cystine/Glutamate Antiporter (xCT), activating the mammalian target of rapamycin (mTOR) pathway. To investigate the specific role of ASCT2, its expression was reduced in 3T3-L1 fibroblasts via sh-ASCT2 transfection prior to adipogenic differentiation. Interestingly, the levels of other selected glutamine-glutamate transporters, LAT1 and xCT, were also decreased. Knockdown of ASCT2 via shRNA significantly impaired adipocyte differentiation. The significant reduction of intracellular lipid accumulation leads to decreased ER stress and insulin resistance in sh-ASCT2 adipocytes. Metabolomic analysis results revealed that intracellular glutamine and malate levels increased during fat cell differentiation. The glutamine levels decreased in sh-ASCT2 adipocytes, while malate levels remained unchanged. In conclusion, glutamine may enhance insulin sensitivity by modulating ER stress and influencing transporter expression. ASCT2 might play a role in adipocyte differentiation, and evidence indicates that ASCT2 inhibition could be associated with reduced adipogenesis and improved insulin signaling, suggesting its potential relevance as a therapeutic target in obesity-related insulin resistance. Further studies are needed to clarify the context-dependent mechanisms by which glutamine and ASCT2 regulate metabolic stress adaptation.

Keywords:  ASCT2; Endoplasmic reticulum stress; Glutamine transporter; Insulin resistance; Obesity

DOI:  https://doi.org/10.1007/s10616-025-00844-1
Nat Metab. 2025 Sep;7(9): 1924-1938

Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis.

Saloua Benhmammouch, Coraline Borowczyk, Clara Pierrot-Blanchet, Thibault Barouillet, Florent Murcy, Sébastien Dussaud, Marina Blanc, Camille Blériot, Tiit Örd, Lama Habbouche, Nathalie Vaillant, Yohan Gerber, Clément Cochain, Emmanuel L Gautier, Florent Ginhoux, Edward B Thorp, Erik A L Biessen, Judith C Sluimer, Susanna Bodoy, Manuel Palacin, Béatrice Bailly-Maitre, Minna U Kaikkonen, Laurent Yvan-Charvet.

Atherosclerosis is a life-threatening condition characterized by chronic inflammation of the arterial wall. Atherosclerotic plaque macrophages are key players at the site of disease, where metabolic reprogramming dictates the progression of pathogenesis. Here we show that reduced macrophage glutaminase activity is related to glutaminase (GLS)-1 and not GLS2 expression. While glutamine synthetase serves as a metabolic rheostat controlling nutrient flux into cells in vitro, macrophage restorative functions in the context of atherosclerosis relies more heavily on glutamine influx. Enhanced glutamine flux is largely mediated by the SLC7A7 exchanger in macrophages: Slc7a7-silenced macrophages have reduced glutamine influx and GLS1-dependent glutaminolysis, impeding downstream signalling involved in macrophage restorative functions. In vivo, macrophage-specific deletion of Slc7a7 accelerates atherosclerosis in mice with more complex necrotic core composition. Finally, cell-intrinsic regulation of glutaminolysis drives macrophage metabolic and transcriptional rewiring in atherosclerosis by diverting exogenous Gln flux to balance remodelling and restorative functions. Thus, we uncover a role of SLC7A7-dependent glutamine uptake upstream of glutaminolysis in atherosclerotic plaque development and stability.

DOI: https://doi.org/10.1038/s42255-025-01354-2
Arab J Gastroenterol. 2025 Sep 20. pii: S1687-1979(25)00112-1. [Epub ahead of print]

Molecular subtypes based on the expression of glutamine metabolism-related genes predict prognosis, tumor microenvironment, and drug therapy response of colon adenocarcinoma.

Lijian Yu, Xia Lin.

   BACKGROUND AND STUDY AIMS: Glutamine metabolism (GM) plays an instrumental role in the occurrence and progression of tumors. However, the characteristics of glutamine metabolism-related genes (GMRGs) in colon adenocarcinoma (COAD) have not been elucidated. This project aims to dig out the role of GMRGs in COAD molecular subtypes, prognosis, and tumor microenvironment (TME) to proffer a scientific foundation for the evaluation of COAD prognosis and mechanism research.
MATERIAL AND METHODS: Disease data of COAD (including clinical information and gene expression data) and GMRG data were collected from The Cancer Genome Atlas (TCGA)-COAD. GMRGs in COAD were obtained through differential analysis, cluster analysis, protein-protein interaction (PPI) network analysis, and regression analysis for setting up a prognostic model. Disease information was collected from GSE29621 to validate the model. Differences in immunotherapy response and drug sensitivity among high-Riskscore (HR) and low-Riskscore (LR) groups were evaluated.
RESULTS: 45 GMRGs associated with COAD survival rate were identified through univariate analysis. Cluster and survival analyses revealed that these genes could cluster the COAD population into two clusters with great survival differences. A risk model with 10 feature genes was established through regression analysis. Prediction of immunotherapy sensitivity uncovered that the LR group was more sensitive to immunotherapy.
CONCLUSION: In summary, this project set up a reliable prognostic risk model with GMRGs, which can proffer a feasible basis for the study of prognosis and related mechanisms in COAD.

Keywords:  Colon adenocarcinoma; Glutamine metabolism; Molecular subtypes; Prognosis; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.ajg.2025.08.006
Biomaterials. 2025 Sep 17. pii: S0142-9612(25)00645-3. [Epub ahead of print]326 123726

Targeting ROS-metabolism dual pathways to trigger PANoptosis by cobalt-vanadium oxides biomimetic nanocakes for tumor immunotherapy.

Silin Du, Guangyu Ma, Xiang Li, Minghao Chao, Liying Fan, Zhiqiang Zhao, Rongze Tang, Junjie Li, Chaonan Jing, Yufan Liu, Dehong Yu, Zhao Liu, Fenglei Gao.

  To overcome the resistance of tumor cells to death through a single pathway, PANoptosis, a novel synergistic mode of cell death, can simultaneously activates pyroptosis, apoptosis, and necroptosis. Most current strategies for inducing PANoptosis focused on amplifying reactive oxygen species (ROS) through exogenous stimuli, while the regulatory role of tumor cell metabolic characteristic in this process has long been overlooked. We propose a ROS-Metabolism dual axis synergistic induction of PANoptosis, simultaneously enhancing antitumor immune responses, and construct a novel bionic nanoplatform named CVOVM. This platform consists of CoVOx nanocakes and the glutamine transporter inhibitor V-9302, with 4T1 cell membranes as camouflage. In tumors, CVOVM initiates a series of catalytic reactions: CoVOx promotes numerous ROS generation, while V-9302 disrupts glutamine metabolism, depleting glutathione (GSH) and nicotinamide adenine dinucleotide (NAD+), thereby triggering the assembly of PANoptosome primarily composed of NLRP3 and NLRC5, which initiates pyroptosis, apoptosis, and necroptosis. The occurrence of PANoptosis promotes immunogenic cell death (ICD) to remodel tumor immunosuppressive microenvironment, and enhances immunotherapy and inhibits lung metastasis. Overall, we present a previously unreported mechanis to achieve the synergistic induction of PANoptosis through ROS amplification and metabolic inhibition, enhancing antitumor immunity, and potentially providing new opportunities and possibilities for combination cancer therapy.

Keywords:  Cobalt; Glutamine metabolism; Immunotherapy; PANoptosis; Vanadium

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123726
Breast Cancer Res. 2025 Sep 26. 27(1): 165

Glutamine synthetase shields triple-negative breast cancer cells from ferroptosis in metastasis triggered by glutamine deprivation.

Zhaoting Yang, Xinyu Lian, Yuan Luo, Qiao Ye, Guangjin Guo, Guoquan Liu.

   BACKGROUND: Epithelial-mesenchymal transition (EMT) in cancer cell metastasis involves complicated metabolic plasticity to survive the highly challenging environment, such as oxidative stress, after subsequent circulation in the bloodstream. Glutamine synthetase (GS) is an enzyme that converts glutamate and ammonia to glutamine (Gln) during Gln deprivation stress. This study revealed for the first time that GS plays an important role in protecting triple-negative breast cancer (TNBC) cells from ferroptosis during Gln deprivation-induced EMT, namely ferroptosis-resistant EMT (FR-EMT).
METHODS: To better understand this finding, we focused on the mechanism of GS-mediated FR-EMT in TNBC through transcriptomic analysis and murine metastasis modeling.
RESULTS: This study specifically investigated the effects of GS on lipid peroxidation and iron metabolism, the two major metabolic disorders in ferroptosis. An abnormal increase in monounsaturated fatty acids (MUFAs) mediated by mechanistic target of rapamycin complex 1 (mTORC1) decreased the ferroptosis sensitivity under Gln deprivation. Additionally, aberrant iron metabolism via lipocalin 2 (LCN2) and transferrin receptor (TFRC) affected the sensitivity to ferroptosis. Moreover, this study confirmed that GS protects TNBC cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood in the lung metastasis mouse model.
CONCLUSION: This investigation provides insights into the role of ferroptosis in metastasis and demonstrates that GS may be a viable target for preventing metastases in TNBC.

Keywords:  Epithelial-mesenchymal transition; Ferroptosis; Glutamine; Glutamine synthetase; Triple-negative breast cancer

DOI:  https://doi.org/10.1186/s13058-025-02115-5
Sci Adv. 2025 Sep 26. 11(39): eadx5495

STK11 coordinates IL-4 signaling with metabolic reprogramming to control M2 macrophage polarization and antitumor immunity.

Jing Yang, Naresh Singh, Chengxian Xu, Dehui Kong, Samantha Sharma, Sheng Liu, Joseph Lechner, Ankhbayar Lkhagva, Haiyan Tan, Zhiping Wu, Martin J Richer, Yong Zang, Xiumei Huang, Reuben Kapur, Jun Wan, Anthony A High, Xinna Zhang, Xusheng Wang, Xiongbin Lu, Kai Yang.

Macrophages integrate microenvironmental cues to orchestrate complex transcriptional and metabolic programs that drive functional polarization. Here, we demonstrate that STK11 links interleukin-4 (IL-4) signaling with metabolic reprogramming to restrain alternatively activated (M2) macrophage polarization. Through integrative transcriptomic and metabolomic analyses, we identified STK11 as a key transcriptional and metabolic regulator during M2 polarization. STK11 deficiency enhanced the expression of M2-associated markers and promoted glutamine metabolism in IL-4-stimulated macrophages. Mechanistically, STK11 deficiency led to increased FOXO1 activation, thereby promoting M2 polarization. Pharmacological inhibition of FOXO1 or glutamine metabolism effectively reversed the enhanced M2 polarization. In an orthotopic model of pancreatic ductal adenocarcinoma, myeloid-specific deletion of STK11 resulted in increased accumulation of M2-like tumor-associated macrophages, impaired antitumor immunity, and accelerated tumor progression. These findings uncover a previously unrecognized role for STK11 in modulating M2 macrophage polarization, offering mechanistic insights that may inform the development of immunometabolic therapies for pancreatic cancer.

DOI: https://doi.org/10.1126/sciadv.adx5495
Mater Today Bio. 2025 Oct;34 102258

Breaking the vicious cycle: Multifunctional nanomaterials targeting Tumor metabolic reprogramming to overcome T cell exhaustion and bone repair failure in bone tumors.

Shijin Guo, Ziyi Yan, Yuling Huang, Xueneng Hu, Huaiyuan Zhang, Yu Wang, Tinglin Zhang, Huifen Qiang, Minghao Xue, Jie Gao, Zuochong Yu.

  Bone tumors establish a self-perpetuating vicious cycle wherein metabolic reprogramming (e.g., aerobic glycolysis, glutamine addiction) drives both T cell exhaustion and osteolytic damage. Tumor-derived lactate and nutrient depletion suppress T cell function while promoting osteoclast activation and inhibiting osteoblast differentiation. Reciprocally, bone damage releases immunosuppressive factors (e.g., TGF-β, and calcium) that further exacerbate T cell exhaustion, creating a pathological feedback loop. This review proposes the "Metabolic-Immune-Bone Network" (MIBN) as a framework for understanding this interplay. Crucially, multifunctional nanomaterials offer a promising strategy to disrupt this cycle. By precisely targeting metabolic pathways, they simultaneously suppress tumor growth and alleviate microenvironmental immunosuppression/acidosis. Their multifunctional design enables co-delivery of metabolic inhibitors, immune modulators, and osteogenic agents, thereby restoring T cell cytotoxicity and promoting bone regeneration. This dual "anti-tumor and osseous-preserving" functionality addresses the limitations of conventional therapies, shifting the paradigm from lesion-focused treatment toward holistic rehabilitation. This aligns with the "3R" strategy-Remodel, Repair, and Remove-highlighting microenvironment modulation, bone regeneration, and immune-mediated tumor clearance. Future advances in stimulus-responsive and metabolically targeted nanomaterials hold significant potential for breaking the MIBN-driven vicious cycle in bone oncology.

Keywords:  Aerobic glycolysis; Bone Tumor microenvironment; Bone damage; Glutamine metabolism; Metabolic reprogramming; Nanomaterials; T cell exhaustion

DOI:  https://doi.org/10.1016/j.mtbio.2025.102258
Br J Cancer. 2025 Sep 22.

UDP-glucose ceramide glucosyltransferase promotes radioresistance via membrane reorganization to maintain redox balance in glioblastoma.

Haksoo Lee, Dahye Kim, Byeongsoo Kim, DongJoo Joung, Jaewan Jeon, Tae-Oh Kim, HyeSook Youn, BuHyun Youn.

BACKGROUND: Glioblastoma (GBM) is an aggressive brain tumor characterized by a poor prognosis and resistance to radiotherapy. Although multiple mechanisms of radioresistance have been proposed, the contribution of membrane-driven metabolic adaptations to radioresistance remains poorly understood.
METHODS: The role of UDP-glucose ceramide glucosyltransferase (UGCG) was investigated using radioresistant GBM cell lines and in vivo xenograft models. After inhibiting UGCG function through genetic or pharmacological (miglustat) approaches, we assessed the effects on lipid raft integrity, localization of the ASCT2 transporter, glutamine uptake, oxidative stress, and radiosensitivity.
RESULTS: UGCG was upregulated in radioresistant GBM cells and promoted lipid raft stabilization. This facilitated the membrane recruitment of the glutamine transporter ASCT2 (SLC1A5), thereby sustaining redox homeostasis under radiation stress. Genetic or pharmacological inhibition of UGCG disrupted lipid raft integrity, impaired ASCT2 localization, reduced glutamine uptake, and increased oxidative stress, leading to enhanced radiosensitivity. In GBM xenograft models, UGCG inhibition combined with radiotherapy significantly suppressed tumor growth and extended survival.
CONCLUSIONS: These findings reveal a previously underexplored, membrane-centric mechanism of radioresistance in which UGCG orchestrates lipid raft remodeling to facilitate glutamine-dependent redox balance. This highlights UGCG as a potential therapeutic target to enhance the efficacy of radiotherapy in GBM.

DOI: https://doi.org/10.1038/s41416-025-03191-2
Cell Metab. 2025 Sep 23. pii: S1550-4131(25)00382-1. [Epub ahead of print]

HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer.

Yi Xiao, Ying Xu, Han Wang, Fan Yang, Xiao-Hong Ding, Tong Fu, Li Chen, Xi Jin, Ya-Xin Zhao, Ying Wang, Fenfang Chen, Zhi-Ming Shao, Yi-Zhou Jiang.

  Immunotherapy demonstrates limited efficacy in triple-negative breast cancer (TNBC), influenced by intricate metabolic interactions within the tumor microenvironment. Here, we developed a single-cell RNA sequencing (scRNA-seq) immunotherapy cohort (N = 27) and a spatial transcriptomics cohort (N = 88) to elucidate metabolic crosstalk associated with therapeutic efficacy in TNBC. We illustrated that heme binding protein 2 (HEBP2)high tumor cells (featured by active glutathione metabolism) and CCL3+ macrophages (characterized by oxidative metabolism) indicated immunotherapy efficacy and were quantitatively and spatially negatively correlated. HEBP2-mediated glutamine face-off between these cell types induced this phenomenon. Mechanistically, HEBP2 disrupted FOXA1 cytoplasmic phase separation, promoting its nuclear translocation to upregulate glutathione S-transferase P1 (GSTP1) expression and glutamine consumption in tumor cells. This metabolic shift induced ferroptosis of CCL3+ macrophages, impairing the antitumor immunity. The utilization of a GSTP1 inhibitor sensitized TNBC to immunotherapy. Collectively, we delineate a tumor-macrophage metabolic checkpoint governed by the HEBP2/GSTP1 axis and pioneer single-cell-level immunometabolism as a paradigm for evaluating immunotherapeutic vulnerabilities.

Keywords:  immunometabolic crosstalk; immunotherapy; precision immunotherapy; single-cell metabolism; triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.cmet.2025.08.009
bioRxiv. 2025 Sep 17. pii: 2025.09.14.674662. [Epub ahead of print]

Structure and enzymology of glutaminase mutants that disrupt glutamine-glutamate homeostasis and cause neurological disease.

Cléa S Crane, Thora K McIssac, Shawn K Milano, Richard A Cerione, Scott M Ulrich.

The glutaminase (GLS) isoforms KGA and GAC are expressed in neurons where they hydrolyze glutamine to produce the excitatory neurotransmitter glutamate. Two de novo gain-of-function mutants of GLS, S482C and H461L, were recently identified in patients with developmental delay, epilepsy, and infantile cataract. These patients exhibited high glutamate and low glutamine concentrations in the brain, suggesting that the GLS mutants have abnormal enzymology. Here, we examined the enzymatic properties of these GLS mutants and found that they exhibit a total (S482C) or partial (H461L) loss of glutamate product inhibition, lifting this restriction on glutamate accumulation. The mutant enzymes also no longer require the anionic activator phosphate to stimulate enzymatic activity or induce filament formation. Structural analysis of the S482C GAC mutant shows the mutation shifts the key catalytic residue Y466 into the catalytically competent position and disrupts a key hydrogen bond between it and the glutamate product, explaining how the S482C mutant has enzymatic activity in the absence of phosphate and is insensitive to glutamate product inhibition. These results shed new light on the mechanism of phosphate activation and glutamate product inhibition of GLS and show that loss of these enzymatic properties disrupts glutamate homeostasis in the brain and causes neurological disease.

DOI: https://doi.org/10.1101/2025.09.14.674662
Dis Model Mech. 2025 Sep 22. pii: dmm.052634. [Epub ahead of print]

FAK modulates glioblastoma stem cell energetics via regulation of glycolysis and glutamine oxidation.

Roza H A Masalmeh, John C Dawson, Virginia Alvarez Garcia, Morwenna T Muir, Roderick N Carter, Giles Hardingham, Cameron Davies, Rosina Graham, Alex von Kriegsheim, Jair Marques, Chinmayi Pednekar, Steven M Pollard, Neil O Carragher, Valerie G Brunton, Margaret C Frame.

  Glycolysis and the TCA cycle are reprogrammed in cancer cells to meet bioenergetic and biosynthetic demands, including by engagement with the extracellular matrix (ECM). However, the mechanisms by which the ECM engagement reprograms core energy metabolism is still un known. We show that the canonical cell-ECM adhesion protein FAK, and specifically its kinase activity, is driving cellular energetics. Using a stem cell model of glioblastoma, we show that FAK gene deletion simultaneously inhibits glycolysis and glutamine oxidation, increases mitochondrial fragmentation, elevates phosphorylation of the mitochondrial protein MTFR1L at S235 and triggers a mesenchymal-to-epithelial transition. These metabolic and structural changes arise through altered acto-myosin contractility as shown by phospho-myosin light chain (p-MLC S19). This can be reversed by Rho-kinase (ROCK) inhibitors revealing mechanotransduction pathway control of both mitochondrial dynamics and glutamine oxidation. FAK-dependent metabolic programming is associated with regulation of cell migration, invasive capacity and tumour growth in vivo. Our work describes a previously unrecognised FAK-ROCK axis that couples mechanical cues to the rewiring of energy metabolism, linking cell shape, mitochondrial function, and malignant behaviour.

Keywords:  Adhesion proteins; Extracellular matrix; Glutamine oxidation; Glycolysis; Mechanical forces; Mitochondria

DOI:  https://doi.org/10.1242/dmm.052634
Biomedicines. 2025 Sep 11. pii: 2243. [Epub ahead of print]13(9):

MicroRNA Landscape in Hepatocellular Carcinoma: Metabolic Re-Wiring, Predictive and Diagnostic Biomarkers, and Emerging Therapeutic Targets.

Dimitris Liapopoulos, Panagiotis Sarantis, Theodora Biniari, Thaleia-Eleftheria Bousou, Eleni-Myrto Trifylli, Ioanna A Anastasiou, Stefania Kokkali, Dimitra Korakaki, Spyridon Pantzios, Evangelos Koustas, Ioannis Elefsiniotis, Michalis V Karamouzis.

  Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, in part due to late diagnosis and limited prognostic tools. In recent years, microRNAs, small, non-coding regulators of gene expression, have emerged as key modulators of tumor metabolism, microenvironmental crosstalk, and therapeutic response in HCC. This narrative review synthesizes evidence published from January 2000 through April 2025, focusing on four interrelated themes: (1) miRNA-driven metabolic rewiring; (2) circulating and exosomal miRNAs as diagnostic and (3) predictive biomarkers; (4) miRNA-based therapeutic strategies. We conducted a targeted PubMed search using terms related to HCC, miRNA biology, biomarkers, metabolism, and therapy, supplemented by manual reference mining. Preclinical and clinical studies reveal that loss of tumor-suppressor miRNAs and gain of oncomiRs orchestrate glycolysis, lipid and glutamine metabolism, and stromal-immune remodeling. Circulating miRNA signatures, including single- and multimarker panels, demonstrate diagnostic AUCs up to 0.99 for early-stage HCC and distinguish HCC from cirrhosis more accurately than alpha-fetoprotein. Predictively, miRNAs such as miR-21 and miR-486-3p correlate with sorafenib resistance, while tissue and exosomal miRNAs forecast recurrence and survival after curative therapy. Therapeutic manipulation, restoring tumor-suppressor miRNAs via mimics or AAV vectors and inhibiting oncomiRs with antagomirs or LNA oligonucleotides, yields potent anti-tumor effects in models, affecting cell cycle, apoptosis, angiogenesis, and immune activation. Despite technical and delivery challenges, early-phase trials validate target engagement and inform safety optimization. In this review, we highlight opportunities to integrate miRNA biomarkers into surveillance algorithms and combine miRNA therapeutics with existing modalities, charting a roadmap toward precision-guided management of HCC.

Keywords:  diagnostic biomarkers; hepatocellular carcinoma; metabolic rewiring; miRNA-based therapeutics; microRNA; predictive biomarkers

DOI:  https://doi.org/10.3390/biomedicines13092243
Biology (Basel). 2025 Aug 24. pii: 1118. [Epub ahead of print]14(9):

Rates of Mitochondrial Metabolism of Glucose, Amino Acids, and Fatty Acids by the HEI-OC1 Inner Ear Cell Line.

Kento Koda, Teru Kamogashira, Ken Hayashi, Chisato Fujimoto, Shinichi Iwasaki, Tatsuya Yamasoba, Kenji Kondo.

   BACKGROUND: Mitochondrial substrate switching plays an important role in aging. The substrate metabolic rate is closely related to mitochondrial activity, as mitochondria are the primary site for substrate oxidation and ATP production. Different substrates (glucose, amino acids, and fatty acids) enter the mitochondria through distinct pathways and are metabolized at different rates, depending on the energy demand and cellular conditions. However, it remains unclear how the mitochondrial metabolic rate of these substrates affects auditory cellular function. This study aimed to characterize the substrate-dependent mitochondrial respiratory responses of cochlear cells under varying energy supply conditions and metabolic stress, focusing on glucose, amino acids, and fatty acids as representative energy sources.
METHODS: The oxygen consumption rate (OCR) was measured after substrate addition using an Agilent Seahorse XF24 Flux Analyzer In-House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, and the maximum OCR (MOCR) was determined as part of the mitochondrial stress test. Statistical analyses were performed using analysis of variance (ANOVA).
RESULTS: The OCR increased significantly after glutamine (L-Gln) or palmitate addition. The MOCR after L-Gln addition was significantly higher than that after glutamic acid, glycine, and phenylalanine addition. The MOCR after pyruvate addition was significantly higher than that after glucose addition. However, there was no significant increase in the MOCR after fatty acid addition.
CONCLUSIONS: Glucose is essential for basal metabolism but cannot rapidly meet sudden energy demands. Pyruvate and L-Gln serve as effective substrates for short-term, high-intensity energy demands. Fatty acids increase OCR through mitochondrial uncoupling effects, though their role may be limited in inner ear cells. These findings provide a foundation for exploring metabolic interventions to support cochlear function and hearing health.

Keywords:  HEI-OC1; age-related hearing loss; glucose; mitochondrial metabolic rate; oxygen consumption rate

DOI:  https://doi.org/10.3390/biology14091118
Int J Mol Sci. 2025 Sep 20. pii: 9190. [Epub ahead of print]26(18):

Monitoring of Allograft Adaptation After Kidney Transplantation in Pediatric Patients by Targeted Plasma Metabolomics.

Jelena Klawitter, Bruce E Kirkpatrick, Ryan Shillingburg, Jost Klawitter, Garrett Wheeler, Touraj Shokati, Melissa A Cadnapaphornchai, Jeffrey L Galinkin, Joshua M Thurman, Uwe Christians.

  End-stage kidney disease is preferably treated by kidney transplantation. The function of the allograft often determines kidney-controlled processes and requires long-term monitoring. Kidneys are organs with a very high metabolic rate, and, thus, a metabolomics approach is suitable to observe systemic metabolic changes that are related to graft adaptation. To understand these ongoing changes in post-transplant pediatric patients, we applied a targeted liquid chromatography/tandem mass spectrometry-based metabolomics approach. Time-dependent changes of 140 metabolites in plasma samples prospectively collected from 23 pediatric kidney graft recipients receiving tacrolimus-based immunosuppression were monitored over the first 4 years after transplantation and compared to levels prior to transplantation. Furthermore, by comparing the pre-transplant metabolite levels to those measured in healthy children, we were able to obtain insights into the pathways associated with kidney failure. Arginine biosynthesis, alanine, aspartate, glutamine, and glutamate metabolism, taurine and tryptophan metabolism were the most affected pathways that separate the pediatric patients with and without kidney failure. Accumulation of uremic toxins such as various tryptophan/kynurenine and tryptophan/indole metabolism pathway intermediates, and betaine and methionine cycle metabolites was evident in patients with restricted kidney function. Furthermore, reduced nicotinamide production, insufficient hydroxylation of phenylalanine to tyrosine, lowered cysteine, arginine, glutamine, taurine, and overall amino acid utilization, as well as diminished levels of protective antioxidants such as glutathione and vitamins B6 and C, were all the result of progressive kidney failure leading to transplantation. Importantly, following kidney transplantation and recovery of kidney function, the levels of most of the previously described metabolites normalized toward the levels observed in healthy participants. The here identified metabolic patterns could be used as markers to monitor the progression of pediatric chronic kidney disease patients towards kidney failure, and assuming their direct association with kidney function, they could serve as markers of successful graft adaptation.

Keywords:  kidney failure; kidney transplant; metabolomics; pediatric patients; tacrolimus

DOI:  https://doi.org/10.3390/ijms26189190
Acta Otolaryngol. 2025 Sep 26. 1-14

Metabolomic biomarkers associated with trismus and dysphagia, radiation therapy, tumour stage and location in patients with head and neck cancer.

Åsa Torinsson Naluai, Lisa Tuomi, Therese Karlsson, Caterina Finizia, Dragana Skiljic.

   BACKGROUND: Trismus, difficulty opening the jaw, and dysphagia, difficulty swallowing, are complications in head and neck cancer (HNC). Metabolic imbalances, including alterations in amino acids, lipids, and inflammatory markers, potentially influence these conditions.
AIM/OBJECTIVE: The aim of this study was to investigate associations of metabolic and inflammatory metabolites in HNC patients, focusing on trismus and dysphagia.
MATERIAL AND METHODS: Nuclear Magnetic Resonance (NMR) spectroscopy, and Bruker IVDr Lipoprotein Subclass analysis was used to analyse metabolites in plasma from 302 patients before, during and after treatment for HNC.
RESULTS: Sixteen lipoprotein subclasses (LDL 1-6, HDL 1-4 VLDL 1-6) as well as creatinine, creatine, glutamine, alanine, glycine, GlycA, GlycB, and a combined lipoprotein-derived NMR signal named Supramolecular Phospholipid Composite (SPC), were analysed. An increase in several lipoprotein sub fractions and elevated inflammatory biomarkers (GlycA and GlycB) were associated with Maximal Interincisal Opening (MIO) before treatment. The M.D. Anderson Dysphagia Inventory (MDADI) before treatment was associated with elevated GlycA and GlycB. The results also showed significant correlations between metabolites and BMI, sex, age, radiation therapy as well as tumour stage and location.
CONCLUSION AND SIGNIFICANCE: Metabolic and inflammatory markers highlight the metabolic heterogeneity in HNC and provide potential targets for future therapeutic strategies.

Keywords:  Head and neck cancer; biomarkers; dysphagia; metabolomics; trismus

DOI:  https://doi.org/10.1080/00016489.2025.2561911
PLoS One. 2025 ;20(9): e0329094

Liver-specific glucagon dysfunction promotes PP-cell hyperplasia and formation of glucagon and PP double-positive cells.

Yuko Nakagawa, Takuro Horii, Ayako Fukunaka, Takashi Sato, Zhehao Zhang, Masaki Kobayashi, Tadahiro Kitamura, Yoshitaka Hayashi, Takashi Nishimura, Izuho Hatada, Yoshio Fujitani.

Understanding the mechanisms that regulate cell identity acquisition and cell proliferation is crucial, not only for elucidating cellular functions but also for clarifying the pathogenesis of various diseases, including neoplasms. Pancreatic endocrine cells typically express a single hormone, and their numbers are tightly regulated. Contrary to this general principle, in this study, we found that proglucagon-deficient mice exhibit a significant increase in the number of glucagon (GCG) and pancreatic polypeptide (PP) double-positive cells (GCG+ PP+ cells), together with the hyperplasia of both PP and α cells. Similarly, glucagon receptor-deficient mice displayed PP-cell hyperplasia and an increased number of GCG+ PP+ cells, with PP-cell replication implicated in this process. mTOR signaling was activated in GCG+ PP+ cells, suggesting its involvement in endocrine differentiation. Furthermore, impaired hepatic GCG signaling led to elevated plasma amino acid levels, which in turn promoted pancreatic endocrine cell proliferation and disrupted the maintenance of cellular identity in mice. Moreover, we found that increased glutamine levels promote GCG+ PP+ cell formation via mTOR signaling, revealing a novel regulatory mechanism underlying pancreatic endocrine cell plasticity. These findings provide new insights into endocrine cell regulation, and may contribute to a better understanding of pancreatic neuroendocrine tumor development, as well as the identification of novel therapeutic strategies.

DOI: https://doi.org/10.1371/journal.pone.0329094
JCI Insight. 2025 Sep 25. pii: e190780. [Epub ahead of print]

CDK12 regulates cellular metabolism to promote glioblastoma growth.

Jeong-Yeon Mun, Chang Shu, Qiuqiang Gao, Zhe Zhu, Hasan O Akman, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin.

  Glioblastoma IDH-wildtype is the most common and aggressive primary brain tumor in adults, with poor prognosis despite current therapies. To identify new therapeutic vulnerabilities, we investigated the role of CDK12, a transcription-associated cyclin-dependent kinase, in glioblastoma. Genetic or pharmacologic inactivation of CDK12 impaired tumor growth in patientderived xenograft (PDX) models and enhanced the efficacy of temozolomide. Metabolic profiling using extracellular flux analysis and stable isotope tracing with U-¹³C-glucose and U-¹³Cglutamine showed that CDK12 inhibition disrupted mitochondrial respiration, resulting in energy depletion and apoptotic cell death characterized by caspase activation and Noxa induction. Mechanistically, we identified a direct interaction between CDK12 and GSK3β. CDK12 inhibition activated GSK3β, leading to downregulation of PPARD, a transcriptional regulator of oxidative metabolism. This CDK12-GSK3β-PPARD axis was required for glioblastoma cell proliferation and metabolic homeostasis. In vivo, CDK12 inhibition significantly extended survival without overt toxicity and induced complete tumor regression in a subset of animals. Strikingly, combined CDK12 inhibition and temozolomide treatment led to complete tumor eradication in all animals tested. These findings establish CDK12 as a key regulator of glioblastoma metabolism and survival, and provide strong preclinical rationale for its therapeutic targeting in combination with standard-of-care treatments.

Keywords:  Apoptosis; Brain cancer; Metabolism; Oncogenes; Oncology

DOI:  https://doi.org/10.1172/jci.insight.190780
Transl Oncol. 2025 Sep 23. pii: S1936-5233(25)00273-6. [Epub ahead of print]62 102542

Near-infrared spectroscopy of blood plasma amino acids with chemometrics towards breast cancer discrimination.

Liying Zhu, Haizhi Li, Wen Qian, Chengcheng Li, Changyudong Huang, Yiqiong Zhang, Yunfeng Duan, Shuang Wang, Yongjie Xu, Jingzhi Zhang, Mi Liu, Xing Li, Shuyun Zhao, Wei Pan.

  Breast cancer (BC) is the most prevalent cancer type in women worldwide. BC cells need more amino acids to meet the demands of rapid proliferation. The present study focused on the role of near-infrared (NIR) spectroscopy in analyzing blood plasma samples of patients with BC to differentiate them from healthy controls. The possibility of quantitative detection of 20 amino acids in BC plasma by NIR spectroscopy was investigated. A total of 180 samples (from 80 patients with BC, 30 patients with benign breast disease and 70 healthy controls) were analyzed. Canonical correlation analysis was used to analyze the relationship between clinical biochemical parameters and the amino acid metabolic profile of patients with BC. In the study, plasma glutamine, histidine, threonine, proline and phenylalanine content of patients with BC was higher than that in plasma from healthy controls (P<0.05) based on NIR spectroscopy. There was an overall correlation (r=0.935) between three clinical parameters (age, albumin and total triglyceride) and four amino acids (glutamic acid, tyrosine, valine and lysine) in patients with BC. In this study, a quantitative and qualitative model was constructed, and this was used to detect plasma amino acids of patients with BC using NIR spectroscopy with good performance. It fully demonstrated the potential and advantages of NIR spectroscopy combined with chemometrics in BC research, which can provide a novel research strategy and technical platform for the study of plasma amino acid metabolism of BC and provide basic experimental for the clinical diagnosis and treatment of BC.

Keywords:  Amino acids; Breast cancer; Canonical correlation analysis; Chemometrics; NIR spectroscopy

DOI:  https://doi.org/10.1016/j.tranon.2025.102542
J Endocr Soc. 2025 Oct;9(10): bvaf139

Intravenous Arginine Stimulates Glucagon Secretion More Than Equimolar Alanine, Leucine, Glutamine, and Proline in Humans.

Malte Palm Suppli, Astrid Høgedal, Jonatan Ising Bagger, Magnus Frederik Gluud Grøndahl, Julie Lyng Forman, Samuel Addison Jack Trammell, Ana Vranešević, Trisha Jean Grevengoed, Hendrik Vilstrup, Mikkel Bring Christensen, Nicolai Jacob Wewer Albrechtsen, Asger Bach Lund, Jens Juul Holst, Filip Krag Knop.

   Context: Amino acids are known to stimulate glucagon secretion, and most amino acids can elicit a glucagon response after IV administration. Recent studies have identified a feedback loop between the liver and pancreatic α cells, regulated by glucagon and circulating amino acids, termed the liver-α cell axis.
Objective: We compared the glucagonotropic effects of amino acids suggested to drive the liver-α cell axis in humans.
Methods: We recruited 12 healthy male participants for a double-blind, randomized study. Each participant received equimolar bolus injections of alanine, arginine, leucine, glutamine, proline, and saline (placebo) after an overnight fast on separate days.
Results: Arginine significantly increased glucagon plasma concentrations compared to placebo, evaluated by the incremental area under the curve after 30 minutes ([mean ± SD] 133 ± 71 vs 34 ± 34 pmol/L × min) and the maximum concentration of glucagon after injection (44 ± 18 vs 15 ± 4 pmol/L) (P < .01 for both). Alanine injection resulted in a minor increase in the peak concentration of glucagon, while glutamine showed a nonsignificant trend toward increased glucagon secretion. Insulin secretion was significantly increased by injections of arginine, alanine, and glutamine, with leucine showing a nonsignificant trend.
Conclusion: In the given experimental setting, arginine was identified as the most efficient stimulator of glucagon secretion. Arginine, alanine, and glutamine stimulated insulin secretion, with arginine eliciting the largest response. Our results indicate that arginine could be involved in regulating the liver-α cell axis in humans.

Keywords:  amino acids; arginine; hepatic steatosis; liver α cell axis; metabolic dysfunction-associated steatotic liver disease

DOI:  https://doi.org/10.1210/jendso/bvaf139