bims-glucam 2026-08-30 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–08–30
nineteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Plumbagin Is a PKM2 Activator That Modulates Glutamine Metabolism and Dependency in Leukemia.
Excess glutamine rewires endothelial cell metabolism.
Unraveling the role of glutamine metabolism in cancer: from cell death mechanisms to tumor microenvironment modulation.
Decoding the metabolic‑immune crosstalk: The role of glutamine and ammonium reprogramming in prostate cancer immune evasion (Review).
Glutamine alleviates lead-induced neuroinflammation via αKG-JMJD3-H3K27me3 pathway: Population, animal, and in vitro evidence.
Editorial: Rising stars in tuberculosis.
Context-dependent roles of UCP2 in cancer: functional heterogeneity, molecular mechanisms and translational perspectives.
Evaluation of Curcumin as a Supplement to Improve Mitotane Effects on Adrenocortical Carcinoma.
Metabolic switch: lymphocytes and the onset of T-cell-mediated autoimmunity.
d-Sorbose Promotes Regulatory T-Cell Differentiation and Ameliorates Autoimmune and Allergic Diseases via Hexosamine Biosynthetic Pathway Inhibition.
Six hours of hypoxia at 4500 m does not affect psychobiological parameters, regardless of glutamine supplementation: A randomized, double-masked, placebo-controlled clinical trial.
ACC1 inhibition enhances BCG-induced trained immunity by reprogramming Acetyl-CoA metabolism.
Reprogramming immunometabolism: linking nutrient sensing, cell death, and therapeutic innovation.
Glucose and Glutamine Deprivation Promotes Breast Cancer Lung Metastasis via BRD4-Dependent Enhancer Activation.
Reprogramming the immunosuppressive microenvironment in glioblastoma: the microglia-MDSC-Treg axis and translational therapeutic strategies.
Guanosine Attenuates Astrocyte-Associated Glutamatergic Dysregulation and Improves Survival in Acute Liver Failure-Induced Hepatic Encephalopathy.
Benzene Metabolite-Targeted Gene ATF7IP2 Drives Glutamate Metabolic Reprogramming to Promote Acute Myeloid Leukemia Initiation.
SEFA: Semantic Embedding-Based Feature Augmentation of Biomedical Language-Model Embeddings Improves Interpretable Metabolomic Prediction of Lung Cancer.
Proton minibeam radiation therapy induces distinct metabolic and synaptic remodelling in rats with orthotopic glioblastoma.

Metabolites. 2026 Aug 16. pii: 577. [Epub ahead of print]16(8):

Plumbagin Is a PKM2 Activator That Modulates Glutamine Metabolism and Dependency in Leukemia.

Nikolina Vrdoljak, Mark D Minden, Paul A Spagnuolo.

   BACKGROUND: AML cells can be defined by impairments in glycolytic metabolism, resulting in increased glucose uptake coupled with reduced glycolytic flux. Consequently, cells rely on alternative pathways such as glutamine metabolism to fuel mitochondrial respiration through anapleurosis. AML cells express upregulated levels of glutamine transporters and catabolic enzymes such as solute carrier family 1 member 5 (SLC1A5) and glutaminase 1 (GLS-1), respectively, to support metabolic needs; impairment of glutamine metabolism induces proliferative arrest. Our previous work identified plumbagin (PLB) as a selective activator of pyruvate kinase isoform M2 (PKM2), resulting in increased PKM2 tetrameric protein, impaired PKM2 nuclear translocation and suppressed c-Myc expression.
OBJECTIVE: Therefore, we aimed to investigate whether PLB-mediated PKM2 activation influences glutamine metabolism as a downstream effect of c-Myc suppression in AML.
METHODS/RESULTS: AML cell lines treated with PLB were cultured in the presence or absence of glutamine and were compared to cell models with genetically suppressed PKM2 to assess for differences in growth. Spectrophotometric analysis revealed that PLB treatment reduces intracellular glutamine uptake, and immunoblotting indicated suppression of GLS-1 expression, ultimately leading to reduced AML cell proliferation and viability. Supplementation with glutamine partially restored cell growth, indicating that PKM2 modulation is associated with impaired glutamine uptake and utilization.
CONCLUSION: Overall, this study explores the downstream implications of PLB-induced alterations in the c-Myc/PKM2 axis, expanding the understanding of PKM2's function beyond glycolysis. The findings presented confirm that PKM2 activation leads to indirect consequences on glutamine metabolism in AML, providing further insight into the mechanisms of PLB-mediated AML cell death.

Keywords:  acute myeloid leukemia (AML); glutaminase-1 (GLS-1); glutamine metabolism; metabolic reprogramming; metabolism; nutraceutical; pyruvate kinase M2 (PKM2)

DOI:  https://doi.org/10.3390/metabo16080577
Metabolomics. 2026 Aug 22. pii: 143. [Epub ahead of print]22(5):

Excess glutamine rewires endothelial cell metabolism.

Marzyeh Kheradmand, Xinyao Zhou, Funke Okunrinboye, Ganesh Sriram, Alisa Morss Clyne.

INTRODUCTION: Glutamine, the most abundant amino acid in the body, is a key metabolic substrate for endothelial cells. Glutamine supplementation protects against cardiovascular disease in animal models and in humans; however, glutamine in vitro has inconsistent effects on endothelial function. Furthermore, little is known about how altered metabolite concentrations, for example excess glucose in hyperglycemia or excess glutamine in cell culture media, affect endothelial cell metabolism.
OBJECTIVES: The objective of this study was to determine how physiological and supplemented glutamine affect endothelial metabolism in normal and high glucose conditions.
METHODS: Primary human coronary artery endothelial cells were cultured in varied glutamine concentrations and in normal and high glucose. Glutamine uptake and glutamate secretion were measured using a YSI bioanalyzer; oxidative respiration was assessed using a Seahorse Metabolic Analyzer; and glutamine carbon incorporation into the TCA cycle, amino acids, antioxidants, and other pathways was evaluated via liquid chromatography-mass spectrometry.
RESULTS: As extracellular glutamine increased, endothelial cells took up more glutamine, but glutamate secretion saturated above 2 mM glutamine. Excess glutamine was primarily stored intracellularly, although increasing extracellular glutamine concentration did increase oxidative respiration and TCA cycle isotope enrichment. We also observed increased glutamine incorporation into glutathione, UDP-GlcNAc, and amino acids. When total metabolite abundance was examined, intracellular succinate, unsaturated fatty acids, and one-carbon metabolism-related metabolites decreased with increasing glutamine.
CONCLUSION: These findings demonstrate that excess extracellular glutamine reprograms endothelial metabolism, suggesting that glutamine supplementation should be used with caution in cardiovascular therapies and endothelial cell culture.

DOI: https://doi.org/10.1007/s11306-026-02515-4
Exp Hematol Oncol. 2026 Aug 25. pii: 80. [Epub ahead of print]15(1):

Unraveling the role of glutamine metabolism in cancer: from cell death mechanisms to tumor microenvironment modulation.

Xintong Peng, Shuang Liu, Yongguang Tao.

  Glutamine, the most abundant amino acid in human serum, serves not only as a key nutrient for maintaining normal cellular biological functions but also as an essential metabolic substrate for the proliferation and survival of tumor cells. Tumor cells exhibit a pronounced characteristic of "glutamine addiction" through metabolic reprogramming. This trait endows tumor cells with the dual capacity to exhibit both adaptability and vulnerability when confronted with regulated cell death (RCD) under metabolic stress, thereby opening up potential avenues for cancer therapy. This paper systematically reviews the biological functions of glutamine metabolism, delves into its relationships with various types of regulated cell death, elucidates its role in immune microenvironment, and summarizes the current application progress of anti-tumor drugs targeting glutamine metabolism.

Keywords:  Glutamine metabolism; Glutamine metabolism-targeted drugs; Regulated cell death; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40164-026-00812-1
Oncol Rep. 2026 Oct;pii: 180. [Epub ahead of print]56(4):

Decoding the metabolic‑immune crosstalk: The role of glutamine and ammonium reprogramming in prostate cancer immune evasion (Review).

Peilong Wang, Xiaoran Li, Teng Ma, Jun Mi.

  Prostate cancer progression is typically driven by metabolic reprogramming and immune evasion, yet the interface between these processes remains incompletely understood. Dysregulated glutamine metabolism extends beyond bioenergetic support to actively shape antitumor immunity through nutrient competition and ammonium accumulation within the tumor microenvironment. Ammonium, traditionally viewed as a toxic waste product, is a critical immunosuppressive metabolite that impairs T cell function and promotes macrophage M2 polarization. The present review aimed to summarize the bidirectional crosstalk between tumor metabolism and immune cells, with emphasis on how metabolic alterations drive therapeutic resistance. While the majority of evidence supporting this axis derives from preclinical models, the present review highlights the glutamine‑ammonium axis as a promising but largely untapped therapeutic target requiring translation into clinical investigation, including combination strategies with immunotherapy.

Keywords:  ammonium; glutamine metabolism; immune evasion; immunometabolism; metabolic reprogramming; prostate cancer; therapeutic target; tumor microenvironment

DOI:  https://doi.org/10.3892/or.2026.9186
Ecotoxicol Environ Saf. 2026 Aug 27. pii: S0147-6513(26)01051-1. [Epub ahead of print]323 120721

Glutamine alleviates lead-induced neuroinflammation via αKG-JMJD3-H3K27me3 pathway: Population, animal, and in vitro evidence.

Meitao Tan, Kaiju Chen, Gang Zheng, Tao Wang, Anfei Liu, Yunting Li, Lifan Li, Ying Li, Bin Wang, Xingmei Zhang, Fei Zou, Xiaojing Meng.

  Lead (Pb) exposure is linked to neuroinflammation and cognitive decline, yet the role of glutamine metabolism in this process remains unclear. In a cross-sectional study of 150 residents, we demonstrated that prolonged Pb exposure is associated with reduced Montreal Cognitive Assessment (MoCA) scores and decreased serum glutamine levels. In vivo, C57BL/6 J mice (n = 8/group) were exposed to Pb (100 mg/L in drinking water) and concurrently treated with glutamine (250 mg/kg, every other day) via gavage. Pb exposure results in learning and memory deficits, hippocampal microglial activation, and inflammatory pathological damage. Furthermore, Pb exposure disrupted hippocampal glutamine metabolism, significantly reducing glutamine, glutamate, and α-ketoglutarate (αKG) levels in a dose-dependent manner. In vitro mechanistic experiments utilizing the immortalized murine microglial cell line (BV2) (n = 3 independent replicates/group) exposed to 10 μM Pb acetate confirmed these dose-dependent metabolic disruptions. Crucially, Glutamine supplementation (250 mg/kg in vivo; 2 mM in vitro against 10 μM Pb) alleviated these impairments across both models. Pharmacological investigations suggest that the glutamine metabolite αKG enhances the expression of Jumonji domain-containing 3 (JMJD3) in microglia, which correlates with the inhibition of Pb-induced upregulation of H3K27me3 and facilitates the shift from a pro-inflammatory (M1) to an anti-inflammatory (M2) microglial phenotype. In summary, our integrated findings suggest the involvement of a novel metabolic-epigenetic axis in Pb-induced neuroinflammation and suggest glutamine metabolism as a potential target for intervention.

Keywords:  Glutamine; Microglia; Neuroinflammation; Pb; αKG-JMJD3-H3K27me3

DOI:  https://doi.org/10.1016/j.ecoenv.2026.120721
Front Tuberc. 2025 ;3 1635563

Editorial: Rising stars in tuberculosis.

Harald G Wiker, Elsa Anes, Philippe Clevenbergh, Seyed Ehtesham Hasnain, Sven Hoffner, Alissa C Rothchild, Vishwanath Venketaraman.



Keywords:  Mycobacterium tuberculosis; antigenic variation; bacterial fitness; glutamine metabolism; mucosal immmunity; multi-drug resistance (MDR); transcriptional regulatory network (TRN); tuberculosis

DOI:  https://doi.org/10.3389/ftubr.2025.1635563
Front Oncol. 2026 ;16 1906646

Context-dependent roles of UCP2 in cancer: functional heterogeneity, molecular mechanisms and translational perspectives.

Wangde Jin, Xinglin Jin.

  Uncoupling protein 2 (UCP2), a member of the solute carrier family 25 (SLC25) of mitochondrial carriers, is situated in the inner mitochondrial membrane and has conventionally been associated with proton leak, mitochondrial membrane potential, and control of reactive oxygen species (ROS). Recent research has expanded this perspective by establishing connections between UCP2 and C4 metabolite transport, glutamine utilization, tricarboxylic acid (TCA) cycle anaplerosis, and metabolic restructuring of the tumor immune microenvironment. Thus, the significance of UCP2 in cancer surpasses the traditional role of an energy-dissipating protein. Present data suggest that UCP2 exhibits context-specific roles across various cancer types. In certain contexts, it facilitates tumor adaptation by preserving redox balance, supporting glutamine metabolism, and enhancing metabolic flexibility under therapeutic pressure. Conversely, in different cancer types or immune-cell environments, UCP2 expression correlates with unique prognostic trends, treatment outcomes, or immune infiltration characteristics. This review outlines UCP2 biology with a focus on context specificity, highlighting its expression patterns across different cancers, metabolic alterations, redox regulation, intercellular signaling, and the tumor immune milieu. Furthermore, we explore the translational implications of UCP2 as both a biomarker and a therapeutic target. In essence, UCP2 should be regarded as a metabolic vulnerability that necessitates classification based on cancer type, mutational profile, metabolic requirements, and immune status, rather than as a universal target for broad-spectrum cancer inhibition.

Keywords:  UCP2; functional heterogeneity; mitochondrial metabolism; redox homeostasis; translational medicine; tumor immune microenvironment; tumor metabolic reprogramming

DOI:  https://doi.org/10.3389/fonc.2026.1906646
Cells. 2026 Aug 20. pii: 1498. [Epub ahead of print]15(16):

Evaluation of Curcumin as a Supplement to Improve Mitotane Effects on Adrenocortical Carcinoma.

Marta Claudia Nocito, Alice Amico, Tarig Hamad, Alessandro Cormace, Constanze Hantel, Catia Morelli, Diego Sisci, Marilena Lanzino, Vincenzo Pezzi, Ivan Casaburi, Rosa Sirianni.

  For many types of cancer, pre-clinical studies have shown that dietary interventions and supplements can be effective in reducing the toxicity and increasing the efficacy of chemotherapeutics. In this context, the polyphenol curcumin is an attractive molecule. We have previously demonstrated that curcumin inhibits adrenocortical carcinoma (ACC) cell growth, has an impact on ACC cell metabolism, decreasing cholesterol availability and promoting glucose and glutamine metabolism. In this study, we evidenced that curcumin downregulates the transcription factors SF-1 and SREBPs and their targets, while inducing a ROS-dependent, HIF1α- and NRF2-mediated metabolic rewiring. NRF2 sustained an adaptive antioxidant mechanism dependent on glutamine, cysteine, and glycine uptake to support glutathione synthesis and avoid lipid peroxidation. Furthermore, the combination of curcumin with mitotane demonstrated synergistic effects in inhibiting ACC cell viability and reducing steroidogenic gene expression. These synergistic effects were observed with sub-therapeutic doses of mitotane, which are reached by patients who fail to attain the therapeutic plasma concentrations of the drug. Crucially, in vivo, curcumin administration to tumor-free mice significantly upregulated NRF2 expression and preserved liver tissue integrity. These results warrant further preclinical evaluation of the proposed combination therapy, particularly for those patients who fail to achieve or maintain mitotane plasma concentrations in the therapeutic range.

Keywords:  NRF2; SF-1; adrenocortical carcinoma; antioxidant mechanism; cell metabolism; curcumin; mitotane; steroidogenic enzymes

DOI:  https://doi.org/10.3390/cells15161498
Cell Mol Immunol. 2026 Aug 24.

Metabolic switch: lymphocytes and the onset of T-cell-mediated autoimmunity.

Andisheh Mosaffa Jahromi, Fatemeh Mirzaei, Sara Mirzazadeh, Seppo Meri, Dieter Kabelitz, Kurosh Kalantar.

  T cell-mediated autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), and type 1 diabetes (T1D), are being increasingly recognized as disorders driven not only by immune dysregulation but also by profound metabolic reprogramming in lymphocytes. Emerging evidence from the field of immunometabolism reveals that altering the balance between oxidative phosphorylation (OXPHOS) and aerobic glycolysis, along with enhancing fatty acid synthesis and dysregulated glutamine metabolism, critically shapes lymphocyte activation, differentiation, and pathogenicity. Here, we review the metabolic pathways that regulate T cells and B cells. We discuss how changes in glucose, lipid, and mitochondrial metabolism influence immune responses that lead to chronic inflammation and autoimmunity in MS, RA, and T1D. Interestingly, similar immunometabolic changes, such as increased glycolysis, mitochondrial dysfunction, and mTOR signaling, have been identified in another autoimmune disorder, systemic lupus erythematosus (SLE). Connecting metabolic dysregulation to immune tolerance failure, this review highlights immunometabolism as a key mechanism in autoimmunity. Immunometabolic pathways represent a new avenue for precision immunotherapy, although challenges persist in targeting cells specifically without systemic toxicity. Understanding these metabolic adaptations and epigenetic-metabolic crosstalk will be essential for translating these insights into next-generation therapies.

Keywords:  Autoimmunity; B cells; Immunometabolism; T cells

DOI:  https://doi.org/10.1038/s41423-026-01460-5
FASEB J. 2026 Sep 15. 40(17): e72252

d-Sorbose Promotes Regulatory T-Cell Differentiation and Ameliorates Autoimmune and Allergic Diseases via Hexosamine Biosynthetic Pathway Inhibition.

Fumiaki Sato, Masato Hoshi, Hiroyuki Yokoi, Sayaka Yoshida, Ryosuke Takenaka, Nao Shimoga, Nanaka Morita, Chieko Tashita, Kyoka Yamazaki, Yuka Kishimoto, Hiroyuki Tezuka, Hiroyasu Ito, Kuniaki Saito.

  Monosaccharides are fundamental biomolecules involved in various biological processes. Rare sugars, naturally scarce monosaccharide derivatives, exhibit unique physiological effects independent of standard energy metabolism. Among them, d-sorbose, the C-3 epimer of d-fructose, has poorly understood biological functions. This study investigated the immunometabolic effects of d-sorbose, focusing on regulatory T-cell (Treg) differentiation and immune modulation. Ex vivo assays using splenic naïve CD4+ T cells revealed that d-sorbose significantly increased Foxp3+ Treg frequencies to levels comparable to d-mannose, without inducing the CD8+ T cell reduction observed with d-mannose. In vivo, continuous d-sorbose administration ameliorated ovalbumin-induced airway inflammation and prevented autoimmune diabetes in non-obese diabetic mice by selectively increasing interleukin-10-producing Tregs in regional lymph nodes and inflamed tissues. Histological analyses revealed reduced inflammatory cell infiltration and preserved tissue architecture in d-sorbose-treated groups. Metabolomic profiling indicated that d-sorbose suppressed glycolysis, the pentose phosphate pathway, and the hexosamine biosynthetic pathway (HBP), as evidenced by decreased UDP-GlcNAc levels, while elevating the tricarboxylic acid cycle intermediate malate. Pharmacological inhibition of glutamine-fructose-6-phosphate aminotransferase, combined with glutamine restriction and GlcNAc rescue assays, demonstrated that d-sorbose promotes Treg differentiation through coordinated metabolic reprogramming of glucose partitioning and glutamine catabolism rather than passive HBP inhibition. Notably, d-sorbose treatment did not alter T-cell survival and demonstrated a favorable safety profile during long-term administration. These findings identify d-sorbose as a novel immunoregulatory sugar that promotes functional Treg differentiation by orchestrating intracellular glucose and glutamine metabolism, highlighting its potential as a dietary or therapeutic agent for controlling inflammatory and autoimmune diseases.

Keywords:  OVA‐induced asthma model; d‐sorbose; hexosamine biosynthetic pathway; non‐obese diabetes (NOD) model; rare sugar; regulatory T cell

DOI:  https://doi.org/10.1096/fj.202601110R
Nutr Health. 2026 Aug 25. 2601060261480418

Six hours of hypoxia at 4500 m does not affect psychobiological parameters, regardless of glutamine supplementation: A randomized, double-masked, placebo-controlled clinical trial.

Wanessa Yg Souza, Valdir A Lemos, Marcus Vl Dos Santos Quaresma, Jean C Silvestre, Camila G Marques, Ronaldo V Thomatieli-Santos.

  Background: Hypoxia represents a challenge to human physiology and has been associated with the worsening of various brain functions. Glutamine mediates the synthesis of neurotransmitters such as glutamate and GABA. Aim: This study evaluated the effects of glutamine supplementation on mood and cognition in people under hypoxic conditions. Methods: It was a randomized, double-blind, placebo-controlled study in men aged 20 to 30 years. Participants were allocated into four groups: Normoxia placebo (NP), Normoxia glutamine (NG), Hypoxia placebo (HP), and Hypoxia glutamine (HG). The glutamine-supplemented groups received 20 g of glutamine daily for 6 days, followed by a 6-h hypoxia simulation at 13.5% O2 in a normobaric chamber (the normoxic groups remained in the chamber with the device off). Pre- and post-hypoxia assessments encompassed physiological parameters (peripheral oxygen saturation, C-reactive protein, glutamine, heart rate, blood pressure) and psychobiological factors (mood profile, anxiety, memory, psychomotor performance). Summary: There is a significant decrease in peripheral oxygen saturation (F(26, 3) = 17.1; p < 0.001; η2G = 0.527) and an increase in heart rate (F(26, 3) = 6.05; p = 0.003; η2G = 0.167) due to hypoxia. However, psychobiological parameters remained unchanged by both hypoxia exposure and glutamine supplementation. In summary, prior glutamine supplementation did not produce statistically significant psychobiological effects under the present experimental conditions. However, subtle effects cannot be excluded due to sample size limitations.

Keywords:  Glutamine; high altitude; inflammation; mood and reaction time

DOI:  https://doi.org/10.1177/02601060261480418
Mol Ther. 2026 Aug 25. pii: S1525-0016(26)00714-8. [Epub ahead of print]

ACC1 inhibition enhances BCG-induced trained immunity by reprogramming Acetyl-CoA metabolism.

Ilayda Baydemir, Fabian Nikolka, Özlem Bulut, Anaísa V Ferreira, Gizem Kilic, Büsra Geckin, Robbin Kramer, Jorge Cuenca-Escalona, Evelien Floor, Marisol Báez-Magaña, Vasiliki Matzaraki, Jeroen Deckers, Tom Anbergen, Yuri van Elsas, Thijs Beldman, Simone Jcfm Moorlag, L Charlotte J de Bree, Victoria Spanou, Theano Andriopoulou, Yang Li, Evangelia Karagianni, Boris Novakovic, Yahya Sohrabi, Leo A B Joosten, Karsten Hiller, Jorge Domínguez-Andrés.

Trained immunity enhances long-term innate immune responsiveness through metabolic and epigenetic rewiring. Using BCG as a model, we demonstrate that inhibition of acetyl-CoA carboxylase 1 (ACC1) enhances BCG-induced trained immunity by increasing intracellular acetyl-CoA (ACoA) availability. This shift redirects ACoA from lipid biosynthesis towards enhanced tricarboxylic acid (TCA) cycle flux and histone acetylation, reinforcing metabolic and epigenetic programs that sustain trained immunity. ACC1 inhibitors amplify cytokine production, mitochondrial respiration, and glutamine metabolism in monocytes, with heightened histone H3K27 acetylation and reduced H3K9 methylation at pro-inflammatory loci. In vivo, ACC1 inhibition amplified BCG-driven myelopoiesis, increasing granulocyte-macrophage progenitors and systemic cytokine responses. Notably, genetic variation in ACoA metabolism genes influenced trained immunity responses in BCG-vaccinated individuals. These findings highlight ACC1 as a metabolic checkpoint linking cellular metabolism to innate immune memory. Targeting ACoA metabolism may represent a promising strategy to optimize vaccine efficacy and enhance broad-spectrum protection against infections.

DOI: https://doi.org/10.1016/j.ymthe.2026.08.033
Immunol Res. 2026 Aug 25. pii: 94. [Epub ahead of print]74(1):

Reprogramming immunometabolism: linking nutrient sensing, cell death, and therapeutic innovation.

Priya Sharma.

  Development of Immunometabolism as a central paradigm in the modern immunology has revolutionized the understanding of metabolism from being a passive supplier of energy to an important determinant of immune cell fate and function. Immune cells are activated, differentiated, survive and undergo programmed cell death through the activity of distinct metabolic programs, including those involving glycolysis, oxidative phosphorylation (OXPHOS), nutrient sensing through Mechanistic Target of Rapamycin (mTOR), AMP-Activated Protein Kinase (AMPK), and HIF‑1α. Rapid proliferation and production of cytokines by effector T cells and pro-inflammatory macrophages is mediated by glycolysis, while persistence and tolerance by memory T cells and reparative macrophages is mediated by oxidative metabolism. Metabolic input and output are also coupled with immune specialization and cell death mechanisms, such as apoptosis, Pyroptosis and ferroptosis, via mitochondrial bioenergetics and production of Reactive Oxygen Species (ROS). Altered immunometabolism is linked to a variety of pathologies: competition for nutrients in tumor physiology leads to T cell exhaustion; an unchecked glycolytic pathway maintains a state of autoimmune inflammation; pathogens exploit host metabolism to escape immunological control; and metabolic diseases, such as obesity and diabetes, foster chronic low‑grade inflammation. Therapies such as rapamycin, metformin, glycolysis and glutamine inhibitors, and metabolic adjuvants in vaccines underscore the translational potential of targeting metabolic checkpoints. But there are still debates on the specificity of the metabolic intervention, the balance between the effector and regulation responses, and the restrictions of the existing experimental models. New strategies, such as single-cell metabolomics and precision medicine, are expected to bring in more sophisticated ways for fine-tuning immune metabolism. Immunometabolism is thus a paradigm shift, with metabolism now being at the heart of immune regulation, and providing new opportunities for critical evaluation and translational innovation in cancer, autoimmunity, infections and metabolic disease.

Keywords:  Cancer immunotherapy; Glycolysis; Immune cell death; Immunometabolism; Metabolic reprogramming; Nutrient sensing

DOI:  https://doi.org/10.1007/s12026-026-09831-w
Adv Sci (Weinh). 2026 Aug 29. e77493

Glucose and Glutamine Deprivation Promotes Breast Cancer Lung Metastasis via BRD4-Dependent Enhancer Activation.

Poshan Yugal Bhattarai, Arathy Vasukutty, Yujin Na, Sung-Chul Lim, Hong Seok Choi.

  Nutrient deprivation in the tumor microenvironment drives metastatic progression. However, its role in breast cancer metastasis and underlying epigenetic mechanisms remain unclear. We identify an enhancer-driven transcriptional program that promotes breast cancer metastasis under nutrient deprivation. Transient glucose-glutamine deprivation in MCF7 and MDA-MB-231 cells induces the expression of genes involved in migration, invasion, and metastasis. Chromatin immunoprecipitation sequencing shows distinct enhancer activation, marked by increased histone H3 lysine 27 and bromodomain-containing protein 4 (BRD4) recruitment. Targeted enhancer acetylation using dCas9-p300 increases cognate gene expression. Motif and CUT&RUN analyses indicate the enrichment and direct binding of ATF3 and c-JUN at enhancers-essential for their activation. Transient transcriptome sequencing shows an increase in endothelin 1 (EDN1) enhancer RNA (eRNA) transcription to facilitate enhancer activation, which is reduced by treatment with eRNA-targeting antisense oligonucleotides (ASOs). In an orthotopic mouse model, BRD4 inhibition using JQ1 or MZ1 suppresses 4T1 cell metastasis. EDN1 enhancer acetylation with dCas9-p300 increases MCF7 tumor growth, which is reduced by BRD4 inhibition or ASO treatment. BRD4 and EDN1 expression is commonly upregulated in human breast metastasis. These findings define nutrient stress-responsive enhancers as epigenetic drivers of metastatic adaptation and highlight their therapeutic potential in breast cancer.

Keywords:  BRD4; EDN1; breast cancer metastasis; enhancer; enhancer RNA; nutrient deprivation

DOI:  https://doi.org/10.1002/advs.77493
Front Oncol. 2026 ;16 1782775

Reprogramming the immunosuppressive microenvironment in glioblastoma: the microglia-MDSC-Treg axis and translational therapeutic strategies.

Hasan Ali Aydın, Emrah Keskin, Murat Kalaycı.

  Glioblastoma (GBM) remains one of the most lethal primary brain tumors despite maximal surgical resection, radiotherapy, and temozolomide. Immune checkpoint inhibitors have failed to demonstrate durable benefit in three large phase III trials (CheckMate 143, 498, and 548), underscoring profound, multilayered immune resistance. This narrative review synthesizes the immunosuppressive GBM microenvironment, situating the microglia-myeloid-derived suppressor cell (MDSC)-regulatory T cell (Treg) axis within the broader immune landscape, including dendritic cells, natural killer cells, exhausted CD8+ T cells, neutrophils, and B cells. We distinguish ontogenetically distinct resident microglia from bone marrow-derived macrophages, separate monocytic (M-MDSC) from polymorphonuclear (PMN-MDSC) subsets, and examine how radiotherapy reshapes immunity. We extend the immunometabolic discussion beyond indoleamine 2,3-dioxygenase (IDO) to the adenosine (CD39/CD73/A2A), arginine, hypoxia, lactate, and glutamine pathways, and critically analyze why checkpoint blockade has failed. We summarize emerging strategies, including CSF1R, CCR2, CXCR2, CD47-SIRPα, STING, CD40, TGF-β, and IL-1β targeting, together with candidate biomarkers such as circulating MDSCs, CSF1, IL-1β, multiplex immunofluorescence, spatial transcriptomics, and single-cell RNA sequencing, for rational patient selection. We frame these mechanisms as a single, self-reinforcing circuit integrating myeloid-driven immune regulation, metabolic reprogramming, and treatment-induced immune remodeling. We argue that future progress depends on biomarker-driven combinations that reprogram the myeloid compartment, relieve metabolic suppression, and actively inflame the tumor, integrated with radiotherapy and tailored to molecular context (IDH and MGMT status).

Keywords:  cancer immunotherapy; glioblastoma; immunometabolism; microglia; myeloid immunity; myeloid-derived suppressor cells; regulatory T cells; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2026.1782775
Metabolites. 2026 Aug 18. pii: 587. [Epub ahead of print]16(8):

Guanosine Attenuates Astrocyte-Associated Glutamatergic Dysregulation and Improves Survival in Acute Liver Failure-Induced Hepatic Encephalopathy.

Pedro Arend Guazzelli, Felipe Dos Santos Fachim, Anderson Santos Travassos, Yasmine Nonose, Andréia Silva da Rocha, Francieli Rohden, Fernanda Urruth Fontella, Adriano Martimbianco de Assis, Diogo Onofre Souza.

  Background/Objectives: Acute liver failure (ALF) rapidly induces hepatic encephalopathy (HE), a severe neurological syndrome associated with astrocytic dysfunction and glutamatergic dysregulation. Guanosine (GUO), an endogenous guanine-based nucleoside, has neuroprotective properties, but its effects on astrocyte-associated glutamate regulation in ALF-induced HE remain incompletely understood. This study tested whether GUO attenuates neurological deterioration and glutamatergic dysfunction in an experimental model of ALF-induced HE. Methods: Male Wistar rats underwent 92% subtotal hepatectomy and received intraperitoneal GUO (7.5 mg/kg) or saline at prespecified time points after surgery. Neurological severity and survival were monitored for 72 h. Astrocytic morphology was assessed by GFAP immunofluorescence. Cerebrospinal fluid (CSF) albumin, glutamate, and glutamine levels, cortical Na+-dependent glutamate uptake, GLAST immunocontent, and the 67 kDa GLT-1 monomer immunocontent were evaluated. Results: Subtotal hepatectomy induced progressive neurological impairment, high mortality, GFAP-associated astrocytic remodeling, increased CSF albumin, glutamate, and glutamine levels, and reduced cortical glutamate uptake. GUO attenuated neurological deterioration and increased 72 h survival from 10.5% to 39.0% (log-rank p = 0.03). GUO also reduced CSF albumin, glutamate, and glutamine concentrations and improved cortical Na+-dependent glutamate uptake without altering GLAST or GLT-1 monomer immunocontent. Conclusions: GUO attenuated astrocyte-associated glutamatergic dysregulation and improved survival in ALF-induced HE. These findings support further mechanistic and translational investigation of GUO as an experimental modulator of astrocyte-associated glutamate handling in ALF-induced HE.

Keywords:  acute liver failure; astrocytes; cerebrospinal fluid biomarkers; glutamate uptake; guanosine; hepatic encephalopathy; neuroprotection

DOI:  https://doi.org/10.3390/metabo16080587
Toxicol Lett. 2026 Aug 22. pii: S0378-4274(26)01368-8. [Epub ahead of print] 113185

Benzene Metabolite-Targeted Gene ATF7IP2 Drives Glutamate Metabolic Reprogramming to Promote Acute Myeloid Leukemia Initiation.

Shucong Zheng.

   BACKGROUND: Benzene exposure is a recognized environmental risk factor for acute myeloid leukemia (AML). This study aimed to identify key drivers of benzene-associated AML and elucidate its pathogenic mechanisms.
METHODS: Candidate genes were screened by integrating two-sample Mendelian randomization (MR), transcriptomics, and single-cell sequencing data. Their biological functions were validated using functional experiments and metabolomics, and the efficacy of targeted interventions was assessed using in vivo and in vitro models.
RESULTS: Integrated analysis identified 138 genes associated with AML, among which ATF7IP2 was a reliable prognostic biomarker and independent risk factor. Benzene significantly upregulated ATF7IP2 expression in a dose-dependent manner. Mechanistically, ATF7IP2 is a key regulator of glutamate metabolism; knockdown of ATF7IP2 reduces intracellular glutamate/glutamine levels, thereby impairing cell viability and inducing cell cycle arrest, while exogenous glutamate can prevent these effects. scRNA-seq and trajectory analysis showed that in a benzene-associated microenvironment, ATF7IP2 drives the malignant differentiation of hematopoietic stem cells (HSCs) into a leukemia precursor stem cell (pre-LSC) subset. The peptidomimetic inhibitor TCMCB07, targeting this axis, inhibited leukemia cell proliferation, delayed disease progression, and prolonged mouse survival.
CONCLUSION: Our results indicate that ATF7IP2 is a key transcriptional metabolic hub that mediates benzene-induced AML by reprogramming glutamate metabolism and driving the conversion of HSCs to pre-LSCs.

Keywords:  ATF7IP2; Acute myeloid leukemia; Benzene exposure; Glutamate metabolism; Mendelian randomization; Pre-leukemic stem cells

DOI:  https://doi.org/10.1016/j.toxlet.2026.113185
Biomedicines. 2026 Aug 18. pii: 1856. [Epub ahead of print]14(8):

SEFA: Semantic Embedding-Based Feature Augmentation of Biomedical Language-Model Embeddings Improves Interpretable Metabolomic Prediction of Lung Cancer.

Jiawen Wu, Jean-François Haince, Rashid A Bux, Guoyu Huang, Paramjit S Tappia, Bram Ramjiawan, Maria Vaida.

  Background/Objectives: Feature engineering remains a major challenge in metabolomics-based prediction, particularly when rich biochemical knowledge is available but underutilized. Conventional metabolomics models rely primarily on measured variables and statistically driven feature selection, overlooking the molecular and pathway context encoded in curated metabolite knowledge bases. We propose SEFA (Semantic Embedding-based Feature Augmentation), a model-agnostic framework that integrates metabolite-level textual knowledge from the Human Metabolome Database (HMDB) into structured metabolomics modeling for lung-cancer prediction. Methods: SEFA encodes HMDB metabolite descriptions as 768-dimensional MedBERT vectors and projects measured metabolite concentrations into this semantic space via concentration-weighted aggregation, producing a 928-dimensional candidate feature matrix that concatenates 11 clinical variables, 149 metabolite concentrations, and 768 semantic projection features. Sparse L1-guided feature selection reduced this representation to 24 features (2.6% of candidates) within a leakage-free cross-validation pipeline. Six classifiers were evaluated on a lung-cancer plasma metabolomics cohort of 800 participants (586 cases, 214 controls) with a stratified 80:20 split, and a controlled ablation study compared the augmented representation with a 24-metabolite-only baseline. Pathway-enrichment analysis of the metabolite sets associated with the retained embedding dimensions was performed using MetaboAnalyst 5.0. Results: Logistic regression on the 24-feature SEFA representation achieved a test ROC-AUC of 0.969, a precision-recall AUC of 0.987, and an accuracy of 94.4%, competitive with less interpretable approaches. Under the same 24-feature budget, embedding augmentation improved test ROC-AUC by 0.008, precision-recall AUC by 0.004, and accuracy by 3.1 percentage points over the metabolite-only baseline. Five retained embedding dimensions mapped onto coherent metabolic themes-sphingolipids and acylcarnitines, carnitine and glutamine metabolism, one-carbon and nitrogen handling, purine catabolism, and oxidative stress markers-and their associated metabolite sets were enriched for arginine and proline metabolism and glycine, serine, and threonine metabolism, pathways with established roles in lung-cancer biology. Conclusions: SEFA demonstrates that semantic embeddings derived from biomedical language models can convert curated metabolite annotations into patient-level features that supply complementary predictive signal while preserving biological interpretability through pathway-level analysis. The present evidence is limited to a single region-specific cohort; external, cross-platform, and cross-disease evaluation is required before broader generalization or clinical application.

Keywords:  HMDB; biomedical language models; feature augmentation; interpretable machine learning; lung cancer; metabolomics; pathway enrichment; semantic embeddings

DOI:  https://doi.org/10.3390/biomedicines14081856
Int J Radiat Oncol Biol Phys. 2026 Aug 26. pii: S0360-3016(26)04235-5. [Epub ahead of print]

Proton minibeam radiation therapy induces distinct metabolic and synaptic remodelling in rats with orthotopic glioblastoma.

Loris Roncali, Miriam Riquelme-Perez, Ramon Handerson Gomes Teles, Jacob Torrejon, Julie Espenon, Cristèle Gilbert, Lorea Iturri, Alfredo Fernandez-Rodriguez, Anthony Bonfrate, Bérangère Lombard, Damarys Loew, Véronique Marsaud, Marjorie Juchaux, Olivier Ayrault, Yolanda Prezado.

   PURPOSE: Glioblastoma (GB) is an aggressive primary brain tumour with limited therapeutic options. Although radiotherapy (RT) remains a cornerstone of treatment, its efficacy is constrained by collateral damage to healthy brain tissue. Proton minibeam radiotherapy (pMBRT), a spatially fractionated modality, has shown promise in preclinical models and early clinical applications by mitigating normal tissue toxicity while enhancing tumour control. Notably, previous studies in rats have reported long-term neuroprotective effects following brain irradiation, as well as the emergence of long-term survivors accompanied by immune memory in GB-bearing models. To investigate the underlying radiobiological mechanisms of pMBRT, we performed an untargeted proteomics profiling comparing pMBRT with conventional proton therapy (CPT) in an orthotopic rat model of GB.
METHODS AND MATERIALS: Male Fischer rats were orthotopically injected with 50,000 RG2 cells into the right caudate nucleus. After validation of tumour uptake at day 13 by bioluminescence, rats received pMBRT or CPT treatment at day 14. Seven days after irradiation, brains were harvested to perform proteomics analysis and immunofluorescence staining.
RESULTS: Both modalities attenuated proliferative signalling in tumours after seven days; however, pMBRT was associated with distinct metabolic modulation in tumours, notably upregulation of vanin-1 and attenuated glutamine synthetase induction, changes that may reflect increased tumour radiosensitivity. These alterations were further validated via immunofluorescence on brain cryosections. In normal brain, pMBRT was associated with preservation of synaptic-related protein expression and modulation of nitrogen metabolism, including altered glutamate dehydrogenase levels.
CONCLUSIONS: Collectively, these findings highlight the dual capacity of pMBRT to sensitise tumours to radiation while preserving healthy brain tissue, supporting its translational potential for GB treatment.

Keywords:  Glioblastoma; normal tissue sparing; proteomics; proton minibeam radiotherapy; spatially fractionated radiotherapy

DOI:  https://doi.org/10.1016/j.ijrobp.2026.08.047