bims-glucam 2026-08-09 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–08–09
nine papers selected by
Sreeparna Banerjee, Middle East Technical University

Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor.
METTL7A Downregulation Drives SLC1A5-Mediated Glutamine Competition to Promote Tumor Proliferation and Suppress CD8+ T Cell Immunity in Gastric Cancer.
D-2HG Inhibits Glutamine Synthetase Activity and Induces Senescence in IDH-Mutant Gliomas.
Glutamate-glutamine axis in pancreatic β-cells: mechanistic insights and therapeutic prospects in diabetes and its complications.
Glutamine-restricted diets restore sensitivity to KRASG12D inhibitor through the reversal of ANXA1 mediated metabolic reprogramming.
Clinical study on the screening of biomarkers for Crohn's disease based on blood metabolomics.
Mechanical stress, metabolic reprogramming and stromal remodeling: an emerging paradigm in the bladder cancer mechano-micro-environment.
GLDC, PYCR3, and PID1: Potential biomarkers and therapeutic targets for comorbid breast cancer and depression.
Metabolic Control of Alveolar Epithelial Regeneration: Implications for Lung Repair and Pulmonary Fibrosis.

RSC Chem Biol. 2026 Jul 13.

Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor.

Jack M Scully, Michael J Sun, Siddharth Das, Nataly J Arias, Edmund D Kapelczak, Tiffany D Robinson, Katie G Vineall, Teagan S Dean, Tara TeSlaa, Ajit S Divakaruni, Danielle L Schmitt.

Glutamine is the most abundant amino acid in serum, used as a key nutrient by cells for protein synthesis, energy production, carbon and nitrogen metabolism, and cellular redox balance. The use of glutamine in the cell is highly compartmentalized, but the dynamics of glutamine metabolism across organelles and individual cells are not fully understood. To illuminate subcellular glutamine dynamics, we developed a green fluorescent protein-based intracellular glutamine optical reporter, iGlo. We find iGlo is sensitive and specific for glutamine and can be used to measure glutamine uptake, production, and consumption with high spatiotemporal resolution in multiple cell types. Furthermore, multiplexed imaging of iGlo with a lactate biosensor in single cells reveals the temporal crosstalk between glucose and glutamine metabolism to maintain energy homeostasis. Thus, iGlo enables the sensitive and precise study of compartmentalized glutamine dynamics and represents a new and enhanced tool for studying the spatiotemporal dynamics and regulation of metabolism.

DOI: https://doi.org/10.1039/d6cb00164e
Adv Sci (Weinh). 2026 Aug 03. e76963

METTL7A Downregulation Drives SLC1A5-Mediated Glutamine Competition to Promote Tumor Proliferation and Suppress CD8+ T Cell Immunity in Gastric Cancer.

Mingjun Sun, Shuwei Dang, Dazhi Zhou, Lixian Ding, Xun Sun, Wei Suo, Jirui Niu, Qingzhu Yang, Zhicheng Zhang, Yanyan Sun, Jinxing Li, Zhongsheng Chen, Tao Ban, Yingji Wang, Tianzhu Li, Ming Liu, Guodong Li.

  Tumor metabolic dysregulation is a critical determinant of tumor progression and response to immunotherapy. Aberrant glutamine metabolism is a hallmark of gastric cancer (GC). However, beyond fueling GC cell anabolism, its role in remodeling the immunosuppressive tumor microenvironment remains poorly understood. Here, we show that GC cells overexpress solute carrier family 1 member 5 (SLC1A5) to drive glutamine accumulation, which not only promotes their own proliferation but also reduces glutamine availability to CD8+ T cells, thereby suppressing antitumor immunity. These dual effects cooperatively drive GC progression. Mechanistically, loss of methyltransferase-like protein 7A (METTL7A) stabilizes SLC1A5 mRNA by reducing its m6A modification. Concurrently, METTL7A deficiency increased N-glycosyltransferase β-1,4-galactosyltransferase 5 (B4GALT5) expression. B4GALT5 stabilizes SLC1A5 via N-glycosylation at the N212 site, which blocks K48-linked polyubiquitination and proteasomal degradation. We identify the natural flavonoid luteolin as an agent that upregulates METTL7A expression, which subsequently downregulates SLC1A5 expression and inhibits GC progression. Furthermore, luteolin significantly enhances the efficacy of anti-PD-1 therapy in GC. Collectively, our findings reveal that SLC1A5-mediated glutamine competition drives both tumor cell proliferation and immune evasion in GC, and suggest that targeting the METTL7A/SLC1A5 axis may represent a promising therapeutic strategy.

Keywords:  CD8+ T cells; METTL7A; SLC1A5; glutamine competition

DOI:  https://doi.org/10.1002/advs.76963
Aging Dis. 2025 Aug 04. 17(5): 2636-2653

D-2HG Inhibits Glutamine Synthetase Activity and Induces Senescence in IDH-Mutant Gliomas.

Yuanlin Zhao, Jiankuan Shi, Yuan Yuan, Ying Yang, Xing Gao, Risheng Yang, Yuying Wang, Lijun Zhang, Jing Li, Peizhen Hu, Yingmei Wang, Chao Sun, Ruili Han, Yuqiao Xu, Zengshan Li, Zhe Wang, Yu Gu, Jing Ye.

IDH1/2 mutations are prevalent genetic alterations in gliomas that facilitate metabolic reprogramming and epigenetic modifications, which are essential for glioma progression. However, their exact contributions to tumorigenesis remain to be fully elucidated. Cellular senescence is a known precursor to tumorigenesis, and multiple oncogenes can initiate this senescence program. Our study demonstrated that the IDH1 mutation inhibits the proliferation of astrocytes and glioma cells, inducing cellular senescence through mechanisms involving DNA damage and increased production of reactive oxygen species (ROS). Notably, these effects were mitigated by the addition of exogenous glutamine. Within cells, glutamine synthetase (GS) serves as the sole enzyme responsible for glutamine synthesis. We found that D-2-hydroxyglutarate (D-2HG), an oncometabolite generated by mutant IDH enzymes, directly inhibits GS activity by binding to the glutamate site, substantially reducing endogenous glutamine production and exacerbating senescence in IDH1-mutant glioma cells. Additionally, in human glioma samples, a greater prevalence of GS-positive astrocytes was detected in IDH-mutant gliomas, likely providing adequate glutamine to sustain growth and mitigate senescence in these cells. Our findings suggest that D-2HG promotes senescence in IDH1-mutant glioma cells by inhibiting GS activity and that disrupting glutamine transport between astrocytes and glioma cells may constitute a promising therapeutic strategy for targeting IDH-mutant gliomas.

DOI: https://doi.org/10.14336/AD.2025.0554
J Diabetes Metab Disord. 2026 Dec;25(2): 218

Glutamate-glutamine axis in pancreatic β-cells: mechanistic insights and therapeutic prospects in diabetes and its complications.

Ahmed Olatunde, Hawwa'u Bala Disina, Abdulazeez Ridwanullah Eyitayo, Abdulrauf Muhammad Jahun, Musbaudeen Taye Tiamiyu, Raihanatu Muhammad Baba, Philemon Mshelia, Titilayo O Johnson.

  Glutamate and glutamine, two closely related amino acids, play vital roles in cellular metabolism, neurotransmission, immune regulation, and, in maintaining pancreatic β‑cell structure and function. The former serves as the primary excitatory neurotransmitter and is essential for energy metabolism, protein synthesis, and insulin secretion. Its counterpart, glutamine, the amide derivative of glutamate, supports mitochondrial activity, nucleotide biosynthesis, and serves as an alternative metabolic fuel during physiological stress. Dysregulation of glutamate and glutamine pathways has been increasingly associated with the pathogenesis of both type 1 and 2 diabetes. In type 1 diabetes, disruptions in the glutamate‑glutamine cycle contribute to pancreatic β‑cell dysfunction and autoimmune‑mediated destruction. In type 2 diabetes, altered glutamate metabolism promotes insulin resistance and pancreatic β‑cell apoptosis, largely through mechanisms involving oxidative stress and inflammation. The glutamate‑glutamine cycle within pancreatic β‑cells is essential for insulin production and cellular homeostasis. Impairment of this cycle may play a key role in the development of diabetic complications, including neuropathy, nephropathy, and retinopathy. Emerging evidence suggests that targeting glutamate and glutamine metabolism offers promising therapeutic strategies for diabetes and its associated complications. Potential interventions include modulation of specific receptors, regulation of key metabolic enzymes, and amino acid supplementation, each aimed at restoring the metabolic balance of these amino acids, enhancing insulin sensitivity, and reducing tissue damage. This review underscores the critical importance of understanding glutamate and glutamine dynamics in the pancreas, with the goal of identifying innovative approaches for the treatment and prevention of diabetes and its complications.
Graphical abstract:

Keywords:  Amino acids; Diabetes complications; Diabetes management; Insulin resistance; Pancreatic β-cell

DOI:  https://doi.org/10.1007/s40200-026-02017-z
Cell Rep Med. 2026 Aug 06. pii: S2666-3791(26)00393-9. [Epub ahead of print] 102976

Glutamine-restricted diets restore sensitivity to KRASG12D inhibitor through the reversal of ANXA1 mediated metabolic reprogramming.

Jiatong Li, Ao Gu, Ziheng Jia, Mengyao Li, Jinlu Zuo, Ziyi Wang, Xuechuan Li, Jiayi Feng, Tong Xue, Shuyang Zhai, Zhuying Yue, Yang An, Siyuan Kang, Zhiqing Yuan, Shimei Qiu, Yadong Xue, Liguo Liu, Nannan Tang, Yingbin Liu.

  Approximately 90% of patients with pancreatic cancer harbor KRAS mutations, predominantly the KRASG12D subtype. HRS-4642, a non-covalent inhibitor targeting KRASG12D, demonstrates potent antitumor efficacy but may ultimately lead to resistance. This study investigates the mechanisms underlying KRASG12D inhibitor resistance and evaluates strategies to enhance treatment sensitivity. Our findings indicate that a glutamine-restricted diet not only reverses KRASG12D inhibitor resistance in pancreatic ductal adenocarcinoma (PDAC) but also achieves remission with prolonging survival. Mechanistically, KRASG12D inhibitor resistance markedly upregulates ANXA1 expression, which, in turn, promotes its binding to the glutamine-related enzyme GOT1 and stabilizes its expression. Additionally, we find that ANXA1 upregulation facilitates mitochondrial localization of GLS1, thereby altering glutamine metabolism. These findings highlight ANXA1-mediated glutamine metabolism as a key driver of KRASG12D inhibitor resistance and support glutamine-restricted diets as a potential therapeutic strategy for KRASG12D mutant PDAC.

Keywords:  ANXA1; KRAS-G12D inhibitors; PDAC; drug resistance; glutamine

DOI:  https://doi.org/10.1016/j.xcrm.2026.102976
Front Gastroenterol (Lausanne). 2026 ;5 1867424

Clinical study on the screening of biomarkers for Crohn's disease based on blood metabolomics.

Tongyuan Lin, Xianhong Hu, Kaifei Yuan, SiYuan Li, Ping Lin, Wei Wang, Li Cui, YuanYuan Wang, Ping Liu, Yong Yang.

   Background: Crohn's disease (CD) is a chronic inflammatory condition that affects the gastrointestinal tract. Currently, the diagnosis of CD is predominantly dependent on endoscopic procedures and histopathological tissue analysis. Endoscopy is an invasive procedure, patient compliance is poor, and the results are subject to the operator's subjective judgment. Infliximab (IFX) and ustekinumab (UST) are two new biologics used for the treatment of CD, which are effective in reducing inflammatory markers. However, the correlation between blood metabolites and inflammatory markers has rarely been studied in the biologic agents employed in the management of CD, and their effects on metabolic processes remain inadequately understood. This study aimed to elucidate the effects of IFX and UST on the blood metabolites in patients with CD, investigate the correlations between metabolic variations and clinical indicators, and examine the relationship between the identified biomarkers and clinical efficacy.
Methods: A total of 81 patients with CD who were receiving biologic therapy enrolled at week 16 between January 2022 and December 2023 (45 receiving IFX and 36 receiving UST) and 45 healthy controls were included. Metabolite profiling was performed using high-performance liquid chromatography-tandem mass spectrometry, followed by multivariate statistical and pathway enrichment analyses to identify differential metabolites and their correlations with clinical indicators.
Result: Despite achieving clinical remission, both the IFX and UST groups exhibited significantly elevated C-reactive protein levels and erythrocyte sedimentation rate values compared with the control group (p < 0.05). IFX primarily influenced amino acid metabolism, including pathways involving arginine and glutamine, and glycolysis and the tricarboxylic acid cycle. UST impacted glutathione and purine metabolism. Pearson's correlation analysis demonstrated that l-arginine, l-glutamine, and l-lysine were significantly negatively correlated with C-reactive protein. In the UST group, glutathione, adenosine, and hypoxanthine were primarily significantly negatively correlated with C-reactive protein and absolute lymphocyte count (p < 0.05).
Conclusion: We identified two sets of diagnostic biomarkers: the biomarkers for the IFX group were l-arginine, l-glutamine, and l-lysine, while those for the UST group were glutathione and adenosine.

Keywords:  Crohn’s disease; high-performance liquid chromatography–tandem mass spectrometry; infliximab; metabolomics; ustekinumab

DOI:  https://doi.org/10.3389/fgstr.2026.1867424
Front Genet. 2026 ;17 1896399

Mechanical stress, metabolic reprogramming and stromal remodeling: an emerging paradigm in the bladder cancer mechano-micro-environment.

Xiaofei Dong, Zixuan Chen, Yi Chen, Zheng Xiao, Jingjing Zhang, Yingcun Li, Haifang Du.

  Recently managing bladder cancer (BLCA) has been hampered by two stubborn challenges, one is high recurrence rate in non-muscle-invasive tumors (NMIBC), the other is muscle-invasive disease (MIBC) showed limited responsiveness to immune checkpoint inhibitors (ICIs). Tumor micro-environment (TME) is characterized exclusively, while the physical and mechanical forces that actively remodel tumors have been largely overlooked. The bladder, a mechanically dynamic organ that undergoes continuous cycles of filling and voiding, provides an exceptionally instructive model for dissecting tumor biology driven by mechanical stress. In this review, we systematically delineates how mechanical stresses in BLCA, including extracellular matrix (ECM) stiffening, solid stress, fluid shear stress, and cyclic stretch-drive metabolic reprogramming, resulting in enhanced glycolysis, glutamine metabolic remodeling, and lactate accumulation. These metabolic alterations subsequently promote fibroblast activation, collagen deposition, and lysyl oxidase (LOX)-mediated matrix crosslinking via epigenetic mechanisms such as histone lactylation. Building upon these mechanisms, we propose a therapeutic rationale that jointly targets mechanotransduction, aberrant metabolism, and the immunosuppressive micro-environment, and we further discuss the distinctive translational advantages of intravesical instillation for locoregional combinatorial delivery. This review aims to provide a novel conceptual framework for overcoming intravesical chemoresistance and ICI resistance in BLCA.

Keywords:  Bladder cancer; mechanical stress; mechanotransduction; metabolic reprogramming; stromal remodeling

DOI:  https://doi.org/10.3389/fgene.2026.1896399
J Affect Disord. 2026 Aug 05. pii: S0165-0327(26)01205-X. [Epub ahead of print] 122352

GLDC, PYCR3, and PID1: Potential biomarkers and therapeutic targets for comorbid breast cancer and depression.

Zehui Xu, Xiaofei Li, Jiayu Sheng, Ke Jiang.

   BACKGROUND: Triple-negative breast cancer (TNBC) and major depressive disorder (MDD) frequently co-occur, yet the shared biological mechanisms underlying this comorbidity remain poorly understood. Increasing evidence suggests that metabolic dysregulation may represent a critical link between tumor progression and depressive phenotypes.
METHODS: An integrative strategy combining metabolomics, bioinformatic analyses, and experimental validation was employed. Untargeted metabolomic profiling of brain and tumor tissues was performed in a well-established TNBC-MDD mouse model induced by 4 T1 tumor-bearing. Differentially expressed genes (DEGs) were identified from datasets of MDD (GEO) and TNBC (TCGA), followed by intersection analysis focusing on glutamine metabolism- and tricarboxylic acid (TCA) cycle-related genes. Key genes were validated by qRT-PCR and WB in both brain and tumor tissues, while candidate therapeutic agents were predicted using a drug-gene interaction network.
RESULTS: Metabolomic analysis revealed significant depletion of glutamine-related metabolites and adenosine in the TNBC-MDD comorbidity model. Transcriptomic bioinformatic analyses identified 21 DEGs shared by TNBC and MDD. Among these DEGs, those associated with core metabolic pathways were highlighted: GLDC and PYCR3 were consistently upregulated, whereas PID1 exhibited downregulation. qRT-PCR and WB validation confirmed aberrant expression of GLDC, PYCR3, and PID1 in both brain and tumor tissues. Drug prediction analysis identified several candidate compounds, including valproic acid, with potential dual therapeutic relevance for TNBC and MDD.
CONCLUSION: GLDC, PYCR3, and PID1 were identified as key metabolic regulators underlying the co-occurrence of TNBC and MDD. Their coordinated dysregulation may drive glutamine and TCA cycle reprogramming, which links peripheral malignancy to central mood dysfunction, providing a foundation for integrated therapeutic strategies.

Keywords:  GLDC; Glutamine-glutamate depletion; Major depressive disorder; PID1; PYCR3; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.jad.2026.122352
Am J Respir Cell Mol Biol. 2026 Aug 03. pii: aanag155. [Epub ahead of print]

Metabolic Control of Alveolar Epithelial Regeneration: Implications for Lung Repair and Pulmonary Fibrosis.

Morgan A Pantuck, Ying Tian.

  Alveolar type 2 (AT2) cells are the resident progenitors of the distal lung. They maintain tissue homeostasis and regenerate the alveolar surface after injury through coordinated self-renewal and differentiation into alveolar type 1 (AT1) cells. When this differentiation program fails, AT2 cells accumulate in aberrant intermediate states, now recognized as the epithelial "transitional state" or alveolar differentiating intermediate (ADI), a defining feature of idiopathic pulmonary fibrosis (IPF) and other fibrotic lung diseases. Although the signaling pathways and transcription factors governing AT2 cell fate have been extensively characterized, the metabolic requirements for successful AT2-to-AT1 differentiation remain poorly understood. Emerging evidence indicates that AT2 cells undergo dynamic metabolic reprogramming during repair, with fatty acid oxidation, glucose metabolism, and glutamine catabolism each playing temporally distinct and mechanistically integrated roles. In IPF, AT2 cells exhibit profound mitochondrial structural abnormalities that compromise oxidative metabolism and likely underlie, at least in part, the broader pattern of metabolic dysregulation observed in diseased epithelium. This mitochondrial dysfunction, together with Warburg-like glycolytic reprogramming and impaired fatty acid oxidation, may function not only as a consequence of epithelial injury but also as a driver of differentiation failure. This review synthesizes current evidence, evaluates causal relationships among metabolic pathways, integrates metabolism with established signaling networks, and proposes a translational framework for metabolism-directed restoration of alveolar repair capacity in fibrotic lung disease.

Keywords:  alveolar differentiating intermediate; alveolar epithelial cells; cell differentiation; lung repair; metabolism; pulmonary fibrosis

DOI:  https://doi.org/10.1093/ajrcmb/aanag155