bims-glucam 2026-06-14 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–06–14
23 papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine-Linked Cellular Stress Responses in Viral Infection: Mechanisms, Crosstalk, and Future Perspectives.
Glutamate and glutamine metabolism in neurodegenerative diseases.
Multi-omics analysis identifies gut microbiota-glutamine axis contributing to the pathogenesis of reflux esophagitis.
Engineered probiotic for hepatic encephalopathy.
Synergistic dual targeting of mTOR and GLS1 overcomes glutamine-driven resistance in triple-negative breast cancer.
Beyond Glycolysis: Targeting Non-Glycolytic Metabolic Pathways in Brain Tumors for Therapeutic Innovation: A Narrative Review.
Inhibition of 5'-tiRNAGly restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer.
Mitochondrial Metabolic Reprogramming in Colorectal Cancer-Associated Fibroblasts: An Up-to-Date Review.
Metabolomic Profiling of LPS-Induced Systemic Inflammation in Mice: Tryptophan as a Biomarker for Nutritional and Inflammatory Status.
Dietary fat alters goblet cell function and microbial bile acid metabolism to promote intestinal lipid absorption in mice.
Design, Synthesis, and Evaluation of Bibenzyl Analogues against Hepatocellular Carcinoma by Targeting Pyruvate Carboxylase.
Targeted Metabolic Therapy in Cancer: A Comprehensive Metabolic Treatment Strategy.
The Glutamate-Glutamine Axis in Pediatric Septic Shock: Immunometabolic Mechanisms, Biomarker Potential, and Clinical Implications.
HHLA2 as an emerging immune checkpoint in lung cancer: linking EGFR signaling, macrophage polarization, and CD8+ T-cell metabolic suppression.
Hypoxia-induced PLOD3 activates the NEDD4/GOT2 axis to exacerbate renal cell carcinoma progression.
Metabolomics analysis identifies differential metabolites and potential diagnostic biomarkers among pediatric sepsis subtypes.
Benchtop NMR as a clinical tool for acute respiratory illness: metabolic signatures associated with disease severity.
Integrated metabolomics of tumor and plasma reveals local and systemic metabolic responses to T-DM1 therapy.
From energy metabolic homeostasis to immune remodeling: the role and therapeutic potential of STING signaling in the tumor microenvironment.
Letter to the editor: Higher anterior cingulate glutamatergic metabolites in schizophrenia with past alcohol use disorders.
VSIG4 suppresses antitumor T cell immunity via the SLC3A2-dependent metabolic-ionic checkpoint.
SUCNR1 coordinates metabolic flux, mitochondrial function, and nutrient-dependent adaptation in hepatocytes.
Luteolin ameliorates cigarette smoke-induced chronic obstructive pulmonary disease by modulating gut and lung microbiota and amino acid metabolism in C57Bl/6 mice.

Int J Mol Sci. 2026 May 23. pii: 4717. [Epub ahead of print]27(11):

Glutamine-Linked Cellular Stress Responses in Viral Infection: Mechanisms, Crosstalk, and Future Perspectives.

Ngan Thi Kim Pham, Quang Duy Trinh, Hiroshi Ushijima, Shihoko Komine-Aizawa, Kazuaki Yoshimune.

  Glutamine is the most abundant amino acid in human plasma and tissues and plays essential roles in cellular metabolism, biosynthesis, and redox homeostasis. Beyond these canonical functions, glutamine availability and utilization have emerged as key regulators of multiple cellular stress responses, including the integrated stress response, endoplasmic reticulum stress, metabolic checkpoint signaling, and autophagy. During viral infection, host glutamine metabolism is frequently reprogrammed to meet the energetic and biosynthetic demands of viral replication, thereby inducing or reshaping glutamine-linked stress pathways. Increasing evidence indicates that these stress responses are not merely secondary consequences of infection but actively influence key stages of the viral life cycle, including viral entry, genome replication, protein synthesis, and host antiviral responses. In this review, we summarize current advances in understanding how glutamine metabolism regulates cellular stress responses in the context of both viral and non-viral infections, and how these pathways, in turn, modulate viral pathogenesis and host defense. We discuss the context-dependent roles of glutamine-linked stress signaling in either promoting viral replication or restricting infection, depending on viral species, host cell type, and metabolic conditions. Finally, we highlight emerging concepts and unresolved questions, including the potential of targeting glutamine metabolism and associated stress pathways as host-directed antiviral strategies. A deeper understanding of the interplay between glutamine metabolism, cellular stress responses, and viral infection may provide new insights into disease mechanisms and inform the development of novel therapeutic approaches.

Keywords:  ER stress; autophagy; cellular stress response; glutamine metabolism; integrated stress response (ISR); metabolic stress; oxidative stress; viral entry; viral replication; virus–host interactions

DOI:  https://doi.org/10.3390/ijms27114717
Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00008-5. [Epub ahead of print]186 1-24

Glutamate and glutamine metabolism in neurodegenerative diseases.

Kesharthini Karthikeyan, Gowshika Velmurugan, Riddhi Upadhyay, Murugan Sevanan, Subashchandrabose Chinnathambi.

  Glutamate is known as the most important excitatory neurotransmitter in brain. Glutamate and glutamine recycling is very essential to maintain the nitrogen metabolism. Despite of its major functions, its dysregulation is a basic pathology which is common to neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic lateral sclerosis (ALS). Amyloid-β and Tau in AD disrupt glutamate uptake and the glutamate-glutamine cycle, accelerating synaptic failure, whereas loss of astrocytic EAAT2 in ALS generates unrelenting excitotoxicity and motor neuron demise. Toxic α-synuclein aggregation in PD exacerbates dopamine-glutamate imbalance through destabilizing corticostriatal transmission. This review explores on the key mechanisms by which glutamate impairment leads to the pathogenies of neurogenerative disorders and also about current medications like amantadine, memantine, and riluzole which are glutamate antagonists, are shown to partially alleviative but cannot halt the advancement of the disease. One of the potential targets for disease-modifying treatments could be the receptor modulation, astrocytic function, and elimination of excess glutamate.

Keywords:  EAAT2 dysfunction; Excitotoxicity; Glutamate dysregulation; Glutamine; VGLUT

DOI:  https://doi.org/10.1016/bs.irn.2026.01.008
Front Microbiol. 2026 ;17 1805181

Multi-omics analysis identifies gut microbiota-glutamine axis contributing to the pathogenesis of reflux esophagitis.

Yu Wu, Qi Gao, Huichao Yang, Yu Wang, Lin Lang, Bin Liu, Xiaolin Jiang, Di Li, Ximo Wang, Jing Xun, Qi Zhang.

   Background: Reflux esophagitis (RE), a common gastroesophageal reflux disease characterized by esophageal mucosal inflammation, is closely associated with gut microbiota dysbiosis and metabolic abnormalities. The glutamine-glutamate metabolic pathway regulates inflammation and mucosal barrier function, but its role in RE and association with gut microbiota remain unclear. This study aimed to characterize gut microbiota and serum metabolites in RE patients via integrated multi-omics (focusing on the gut microbiota-glutamine axis), and verify the activation status of this pathway in RE inflammatory models and the anti-inflammatory effect of its targeted inhibition.
Methods: RE patients and healthy controls (HCs) were enrolled. Fecal metagenomic sequencing and serum untargeted metabolomics (LC-MS/MS) were performed to identify differential gut microbiota and serum metabolites between the two groups, followed by Pearson correlation analysis to explore their associations. In vitro experiments were conducted on human esophageal epithelial cells (HEECs) divided into four groups: normal, inflammatory, glutamine-supplemented, and inflammatory + glutamine + glutaminase inhibitor (BPTES) groups. qPCR was used to detect the mRNA expression of glutamine-glutamate pathway molecules (GLS, c-Myc, SLC1A5), mucosal barrier markers (ZO-1, Occludin), and pro-inflammatory cytokines (IL-8, IL-6, IL-1β, TNF-α). Intracellular concentrations of glutamine, glutamate, and α-ketoglutarate were measured, and the anti-inflammatory effect of BPTES was verified.
Results: RE patients showed significant differences in gut microbiota diversity and composition compared with HCs, with Bacteroidota, Pseudomonadota, Escherichia coli, and Klebsiella pneumoniae as dominant taxa. Serum metabolomics revealed elevated glutamine and glutamate in RE patients, which were identified as key differential metabolites related to RE pathogenesis. Pearson analysis revealed that alterations in serum metabolite profiles of RE patients were significantly correlated with changes in gut bacterial abundance. Notably, glutamate-glutamate (Glu-Glu) metabolism exhibited negative correlations with multiple bacterial genera (Acrocarpospora, Limnobacter, Pseudobacter, Shewanella, and Tropicimonas). In vitro, inflammatory HEECs exhibited increased intracellular glutamine, glutamate, and α-ketoglutarate, upregulated glutamine-glutamate pathway molecules and pro-inflammatory cytokines, and downregulated mucosal barrier markers. Exogenous glutamine alone failed to alleviate inflammation, while combined with BPTES significantly reversed pathway activation and mitigated inflammation in inflammatory HEECs.
Conclusion: RE patients exhibit significant gut microbiota dysbiosis (dominated by Bacteroidota, Pseudomonadota, Escherichia coli, and Klebsiella pneumoniae) and abnormal glutamine metabolism (elevated serum glutamine and glutamate). Pearson analysis reveals that the glutamine-glutamate pathway correlates negatively with multiple bacterial genera (Acrocarpospora, Limnobacter, Pseudobacter, Shewanella, and Tropicimonas). The glutamine-glutamate pathway is activated in inflammatory esophageal epithelial cells, and targeted GLS inhibition by BPTES reverses pathway activation and mitigates inflammation. These findings highlight the gut microbiota-glutamine axis as potential diagnostic biomarkers and therapeutic targets for RE, providing new insights into pathogenesis and a basis for novel clinical interventions.

Keywords:  glutamine; glutamine-glutamate metabolic pathway; gut microbiota; inflammatory mechanism; reflux esophagitis

DOI:  https://doi.org/10.3389/fmicb.2026.1805181
Cell Host Microbe. 2026 Jun 10. pii: S1931-3128(26)00204-0. [Epub ahead of print]34(6): 975-977

Engineered probiotic for hepatic encephalopathy.

Cynthia L Hsu.

Hepatic encephalopathy is a devastating neuroinflammatory complication of cirrhosis driven by systemic metabolic dysregulation across the gut-liver-brain axis. In a recent article in Cell, Aggarwal et al. engineered a multi-strain bacterial cocktail to simultaneously neutralize toxic ammonia and L-glutamine while replenishing essential amino acids, offering a promising, targeted therapeutic strategy.

DOI: https://doi.org/10.1016/j.chom.2026.05.011
Pharmacol Res. 2026 Jun 11. pii: S1043-6618(26)00210-0. [Epub ahead of print]230 108295

Synergistic dual targeting of mTOR and GLS1 overcomes glutamine-driven resistance in triple-negative breast cancer.

Mengting Lyu, Liushun Wu, Yin Li, Yang Yu, Ying Li, Tongsheng Wang, Feng-Qing Xu, Deling Wu, Wuxi Zhou.

  Resistance to therapeutic agents represents a critical barrier in the clinical management of triple-negative breast cancer (TNBC), necessitating novel therapeutic strategies. We discovered that mammalian target of rapamycin (mTOR) and glutaminase 1 (GLS1) mediated glutamine metabolism-a TNBC-addicted process-critically drives aggressive proliferation and confers therapeutic resistance. The combined treatment with rapamycin (an mTOR inhibitor) and CB839 (a GLS1 inhibitor) elicited synergistic anti-tumor effects in diverse TNBC cell lines. This synergy arose from‌ inhibition of metabolic rewiring, ‌characterized by‌ perturbations in adenosine triphosphate (ATP) homeostasis, redox equilibrium, metabolite pools, and signaling cascades, ‌ultimately triggering multimodal‌ cell death mechanisms. Furthermore, ‌synergistic‌ pharmacological inhibition of mTOR and GLS1 ‌significantly suppressed‌ in vivo tumor growth and metastasis ‌in murine models‌, ‌with no overt toxic effects observed‌. Overall, our findings indicate dual inhibition of mTOR and GLS1 as a promising clinical strategy to counteract glutamine-driven resistance, enhancing therapeutic efficacy in TNBC.

Keywords:  GLS1 inhibitor; Synergistic effects; Triple-negative breast cancer; mTOR inhibitor

DOI:  https://doi.org/10.1016/j.phrs.2026.108295
Health Sci Rep. 2026 Jun;9(6): e72582

Beyond Glycolysis: Targeting Non-Glycolytic Metabolic Pathways in Brain Tumors for Therapeutic Innovation: A Narrative Review.

Iffat Islam Mayesha, Zubaier Ahmed, Ammarah Laaika Mohiuddin, Faiza Fairuz Muskan, Saiful Islam, Sharmin Jahan Sumaya.

   Background and Aims: Metabolic reprogramming is a hallmark of brain tumors, extending beyond the classical Warburg effect. While glycolysis has been extensively studied, gliomas and pediatric high-grade brain cancers demonstrate remarkable metabolic plasticity. This review aims to highlight non-glycolytic metabolic pathways that sustain tumor growth, contribute to therapy resistance, and offer translational potential in neuro-oncology.
Methods: We conducted a comprehensive synthesis of recent preclinical and translational studies focusing on non-glycolytic metabolic dependencies in brain tumors. Particular emphasis was placed on fatty acid oxidation (FAO), amino acid metabolism, mitochondrial dynamics, and immune metabolic interfaces.
Results: Emerging evidence indicates that FAO supports ATP synthesis and redox balance under hypoxic conditions. Glutaminolysis and serine/glycine metabolism maintain nucleotide and antioxidant pools essential for tumor survival. Mitochondrial fusion-fission dynamics and Complex I mutations enhance oxidative phosphorylation (OXPHOS) adaptability. Targeting these metabolic nodes, individually or in combination, reduces tumor growth, reverses drug resistance and sensitizes tumors to radiotherapy and immunotherapy. Additionally, the tryptophan-kynurenine-AHR axis contributes to immune evasion, underscoring the interplay between metabolism and tumor immunology.
Discussion: Non-glycolytic metabolism represents an emerging frontier for precision neuro-oncology. The integration of metabolic inhibitors with conventional or immune-based therapies shows promise in preclinical models. However, overcoming metabolic plasticity and therapeutic resistance will require patient stratification, blood-brain barrier penetrant inhibitors, and biomarker-guided clinical trials. These insights underscore the need to translate metabolic vulnerabilities into clinically actionable strategies.
Conclusion: Non-glycolytic metabolic pathways, including lipid, nucleotide, and amino acid metabolism, offer promising therapeutic targets to overcome tumor survival and therapy resistance in brain tumors. However, despite encouraging preclinical evidence, the clinical development of such targeted metabolic therapies remains in its early stages.

Keywords:  brain tumors; fatty acid oxidation; metabolic reprogramming; mitochondrial dynamics; non‐glycolytic pathways; precision neuro‐oncology

DOI:  https://doi.org/10.1002/hsr2.72582
J Exp Clin Cancer Res. 2026 Jun 13.

Inhibition of 5'-tiRNAGly restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer.

Xinliang Gu, Yu Zhang, Yang Li, Xun Li, Yuening Sun, Shuo Ma, Xinyue Qin, Yuejiao Huang, Xianjuan Shen, Ming Zheng, Quanhua Yi, Zhiyuan Tang, Shaoqing Ju.

   BACKGROUND: Transfer RNA-derived small RNAs (tsRNAs) have been implicated in tumor progression and immune regulation in recent years. However, the specific role of tRNA halves (tiRNAs), a subclass of tsRNAs, in modulating immunotherapy response remains unexplored.
METHODS AND RESULTS: In this study, 5'-tiRNAGly levels were examined in gastric cancer (GC) patients and found to be upregulated, especially in non-responders to anti-PD-1 therapy. Elevated 5'-tiRNAGly levels were also associated with diminished oxoglutarate dehydrogenase-like (OGDHL) expression. Further exploration revealed that 5'-tiRNAGly bound to DLST and promoted OGDHL destabilization, whereas targeted inhibition of 5'-tiRNAGly restored OGDHL stability through succinylation at lysine 910, enhanced tricarboxylic acid (TCA) cycle activity, and reduced glutamine-derived metabolic reprogramming. Additionally, 5'-tiRNAGly was found to decrease the activity of α-ketoglutarate dehydrogenase and inhibit succinylation of histone H3 at lysine 79 (H3K79suc), thereby downregulating PD-L1 transcription and reducing therapeutic responsiveness to PD-1 inhibitors. Conversely, restoration of this epigenetic modification upon 5'-tiRNAGly inhibition facilitated PD-L1 transcription, thereby sensitizing tumors to anti-PD-1 therapy.
CONCLUSION: Our findings indicate that targeting 5'-tiRNAGly may represent a promising strategy to enhance responsiveness to anti-PD-1 therapy in GC patients.

Keywords:  Gastric cancer; Glutamine metabolism; OGDHL; PD-1; Succinylation; tRNA-derived small RNAs

DOI:  https://doi.org/10.1186/s13046-026-03758-8
Cancers (Basel). 2026 May 29. pii: 1786. [Epub ahead of print]18(11):

Mitochondrial Metabolic Reprogramming in Colorectal Cancer-Associated Fibroblasts: An Up-to-Date Review.

Ying Li, Dipanjan Chanda, Seong-Woo Jeon, Jae-Han Jeon, Min-Ji Kim.

  Colorectal cancer (CRC) progression stems from dynamic metabolic crosstalk between malignant cells and the tumor microenvironment (TME). Among stromal components, cancer-associated fibroblasts (CAFs) have emerged as pivotal metabolic drivers rather than mere structural elements. Specifically, evidence indicates that mitochondrial reprogramming in CAFs significantly orchestrates tumor growth, therapeutic resistance, and immune evasion in CRC. This review synthesizes recent insights into how CAF mitochondrial dynamics and metabolic reprogramming dictate CRC biology. We first examine the functional diversity of CAF subpopulations and their distinct mitochondrial requirements. We then contrast mitochondrial dynamics-including fission-fusion balance and mitophagy-between CRC cells and CAFs, highlighting how tumor-derived signals modulate stromal mitochondrial function. We systematically evaluate key regulatory pathways of CAF mitochondrial reprogramming, including TGF-β/HIF-1α, ROS-NF-κB, PI3K-AKT-mTOR, AMPK-PGC-1α, YAP/TAZ mechanotransduction, and mtDNA-mediated cGAS-STING signaling. Furthermore, we discuss how remodeled CAF mitochondria foster metabolic symbiosis via lactate, ketone, and glutamine shuttling; maintain redox homeostasis through the NADPH-glutathione axis and UCP2; and establish immunosuppressive niches via mitochondrial stress signaling. Collectively, these mechanisms drive resistance to chemotherapy, targeted agents, radiotherapy, and immunotherapy. By integrating mitochondrial metabolism, stromal signaling, and clinical responses, this review identifies CAF mitochondria as an actionable target within the CRC TME. Targeting these CAF-specific pathways offers a novel strategy to disrupt tumor-stroma metabolic cooperation and overcome treatment resistance in colorectal cancer.

Keywords:  cancer-associated fibroblasts; colorectal cancer; metabolic reprogramming; mitochondria; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers18111786
Biosci Biotechnol Biochem. 2026 Jun 08. pii: zbag078. [Epub ahead of print]

Metabolomic Profiling of LPS-Induced Systemic Inflammation in Mice: Tryptophan as a Biomarker for Nutritional and Inflammatory Status.

Rio Kurihara, Yumi Takayama, Riyo Hidaka, Kanae Masuda, Hikono Sakata, Yukina Yumen, Tomomi Komura, Daisuke Saigusa, Masaru Yoshida.

  LPS-induced inflammation triggers metabolic reprogramming and nutritional decline. This study aimed to identify biomarkers for inflammatory and nutritional stress using GC-MS/MS-based metabolomic profiling. Male mice received LPS to induce systemic inflammation. Evaluations included liver histology (H&E, Gr-1), blood biochemistry, and metabolomic analysis of liver and plasma. LPS administration significantly increased hepatic neutrophil infiltration and liver enzymes, while decreasing nutritional markers (total protein, albumin, LDL-cholesterol). In the liver, LPS increased glycolytic and TCA cycle intermediates (e.g. 3-phosphoglycerate, citric acid) but decreased amino acids, including glutamine and tryptophan. Plasma analysis showed significant decreases in tryptophan, glucose, and succinic acid. Notably, tryptophan was significantly reduced in both compartments. Our findings demonstrate that tryptophan serves as a robust biomarker for monitoring the intersection of inflammatory response and nutritional status, reflecting synchronized metabolic shifts in the liver and plasma.

Keywords:  GC-MS/MS; amino acid; inflammation; metabolomics

DOI:  https://doi.org/10.1093/bbb/zbag078
Nat Microbiol. 2026 Jun 10.

Dietary fat alters goblet cell function and microbial bile acid metabolism to promote intestinal lipid absorption in mice.

Xinyu Liang, Yongxin Zhang, Wei Xie, Jiayi Xiong, Suqin Lin, Yingquan Wen, Yutang Cao, Shuwu Yu, Kanglong Wang, Jie Deng, Jingjie Zhao, Jingyi Xu, Yiyang Hu, Yameng Liu, Qin Feng, Yifei Zhong, Frank J Gonzalez, Cen Xie.

Dietary fat reshapes host-microbiota interactions, yet the upstream events that mediate overnutrition-driven microbiome alterations and metabolic dysfunction remain unclear. Here we compared mouse models of diet-induced and genetic obesity using multi-omics to identify the colonic mucus niche as an early, diet-sensitive driver of metabolic dysfunction. Excessive dietary lipids impaired glutamine metabolism and redox homeostasis in goblet cells, thinning the mucus layer and depleting the mucus-adapted symbiont Akkermansia muciniphila while expanding the bile-acid-transforming bacterium Clostridium scindens. Altered bile acid composition along the enterohepatic axis activates FXR-PLIN2 signalling in the small intestine and increases fat absorption. In parallel, enterocytes upregulate the PPARα-dependent uptake pathway that supports luminal lipid entry. Supplementation with glutamine restored goblet cell function and the gut microbiota-derived bile acid pool, thereby reducing intestinal FXR activation and lipid uptake. These findings reveal that dietary fat impairs colonic goblet cell function and reshapes microbial bile acid metabolism, influencing small-intestinal fat absorption.

DOI: https://doi.org/10.1038/s41564-026-02381-9
J Med Chem. 2026 Jun 12.

Design, Synthesis, and Evaluation of Bibenzyl Analogues against Hepatocellular Carcinoma by Targeting Pyruvate Carboxylase.

Zeen Qiao, Lingyu Li, Yuwen Sheng, Jinlian Yang, Jialing Yu, Fan Wu, Minghui Ji, Ruiying Xi, Linhan Yang, Guolin Zhang, Xiaoxia Lu, Xiaofeng Ma, Fei Wang.

Pyruvate carboxylase (PC) replenishes tricarboxylic acid cycle intermediates, driving cancer metabolic reprogramming. To improve the metabolic stability of erianin, a potent PC inhibitor from Dendrobium chrysotoxum Lindl, we designed and synthesized 55 derivatives, culminating in the identification of CIB-Q22, which exhibited potent PC inhibition (IC50 = 1.74 nM) and suppressed HCC cell viability (IC50 = 25.18 nM), comparable to erianin. Notably, CIB-Q22 demonstrated significantly improved in vivo stability, with a half-life (T1/2 = 1.21 h) much longer than erianin (T1/2 ∼ 0.1 h). Mechanistically, CIB-Q22 suppressed HCC proliferation and metastasis by inducing apoptosis and ferroptosis. Moreover, it promoted mitochondrial oxidative stress and inhibited glycolysis, thereby sensitizing cells to glutamine deprivation. In vivo, CIB-Q22 exhibited comparable antitumor efficacy but improved safety compared to sorafenib. With its potent PC inhibition and favorable drug-like properties, CIB-Q22 represented a promising therapeutic candidate for HCC treatment.

DOI: https://doi.org/10.1021/acs.jmedchem.6c00075
Cureus. 2026 May;18(5): e108373

Targeted Metabolic Therapy in Cancer: A Comprehensive Metabolic Treatment Strategy.

Yahia Anane.

  Cancer progression arises from the convergence of three domains: intrinsic metabolic and signaling rewiring within tumor cells, microenvironmental conditions that support survival and dissemination, and systemic metabolic dysfunction in the host. These layers collectively drive treatment resistance, immune evasion, and recurrence. Targeted metabolic therapy (TMT) is proposed as a comprehensive therapeutic framework designed to simultaneously target all three domains of cancer progression. TMT targets key metabolic pathways implicated in tumor growth and survival such as glycolysis, glutaminolysis, IGF-1/PI3K-AKT-mTOR, angiogenesis, apoptosis resistance, and Wnt/β-catenin signaling, while also disrupting microenvironmental drivers including cancer stemness, metastasis, acidosis, hypoxia, and chronic inflammation. At the systemic (host) level, TMT corrects metabolic derangements - including hyperglycemia, systemic inflammation, and cachexia - that create a permissive environment for tumor progression. The therapeutic model integrates multiple intervention categories. These include dietary and fasting strategies, repurposed pharmacological agents, nutraceuticals, and essential vitamins and minerals. Additional components encompass oxygen- and redox-modulating therapies and lifestyle optimization measures. This paper outlines the biological rationale for TMT and proposes a systems-level framework for applying coordinated metabolic pressure with the aim of improving treatment responsiveness, prolonging survival, and offering cancer patients a more durable path toward disease control and remission.

Keywords:  cancer metabolism; cancer stem cells; fasting therapy; ketogenic diet; metabolic oncology; metabolic therapy; repurposed drugs; tumor hypoxia; tumor microenvironment

DOI:  https://doi.org/10.7759/cureus.108373
Int J Mol Sci. 2026 May 23. pii: 4708. [Epub ahead of print]27(11):

The Glutamate-Glutamine Axis in Pediatric Septic Shock: Immunometabolic Mechanisms, Biomarker Potential, and Clinical Implications.

Yaru Cui, Juan Wang, Yiyao Bao.

  Pediatric septic shock remains a major cause of morbidity and mortality in critically ill children and is increasingly recognized as a syndrome of profound immunometabolic dysregulation. This narrative review synthesizes current clinical, translational, and mechanistic evidence on the glutamate-glutamine axis in pediatric septic shock. The review focuses on how glutamine and glutamate metabolism may interact with immune-cell function, mitochondrial substrate handling, redox defense, and intestinal barrier integrity, while distinguishing biological plausibility from validated clinical utility. Current evidence supports the glutamate-glutamine axis as a mechanistically relevant pathway and a source of candidate biomarkers, but pediatric-specific data remain limited and do not yet justify routine biomarker use or glutamine-based intervention in unselected children with septic shock. Future studies should use standardized sampling, reproducible analytical methods, pediatric validation cohorts, and phenotype-guided trial designs before this axis can be translated into clinical decision making.

Keywords:  biomarkers; critical care; glutamate–glutamine axis; immunometabolism; metabolic reprogramming; pediatric septic shock; prognosis

DOI:  https://doi.org/10.3390/ijms27114708
Front Immunol. 2026 ;17 1815639

HHLA2 as an emerging immune checkpoint in lung cancer: linking EGFR signaling, macrophage polarization, and CD8+ T-cell metabolic suppression.

Juan Wang, Kang Wang, Zhenhong Hu, Xueting Hu.

  Immune checkpoint blockade has revolutionized the treatment of lung cancer; however, therapeutic responses remain heterogeneous, particularly in patients harboring activating epidermal growth factor receptor (EGFR) mutations. Emerging evidence identifies human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2), a novel B7 family member, as a genotype-associated immune checkpoint enriched in EGFR-mutant lung cancer. Beyond its classical role in T-cell inhibition, HHLA2 appears to integrate tumor-intrinsic oncogenic signaling with immune microenvironment remodeling. Recent studies demonstrate that HHLA2 promotes tumor progression by enhancing EGFR/MAPK/ERK signaling, thereby supporting proliferation, invasion, and epithelial-mesenchymal transition. In parallel, HHLA2 reshapes the tumor microenvironment through interleukin-10-dependent macrophage M2 polarization, contributing to an immunosuppressive niche. Notably, the HHLA2-KIR3DL3 axis directly suppresses CD8+ T-cell glutamine metabolism, introducing a metabolic checkpoint mechanism that limits cytotoxic function and facilitates immune evasion. Clinically, lower HHLA2 expression has been associated with improved response to neoadjuvant immunotherapy and increased tissue-resident memory T-cell infiltration, suggesting predictive biomarker potential. Collectively, HHLA2 represents a multifunctional immune checkpoint that links oncogenic EGFR signaling, macrophage polarization, and metabolic suppression of CD8+ T cells. Targeting the HHLA2-KIR3DL3 axis, particularly in combination with EGFR tyrosine kinase inhibitors, may provide a rational precision immunotherapy strategy for EGFR-mutant lung cancer. Further mechanistic and translational studies are warranted to fully define its therapeutic value.

Keywords:  EGFR-mutant lung cancer; HHLA2; KIR3DL3; T-cell metabolism; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2026.1815639
Cell Death Dis. 2026 Jun 10.

Hypoxia-induced PLOD3 activates the NEDD4/GOT2 axis to exacerbate renal cell carcinoma progression.

Yan Xu, Yu Lun, Shiyue Wang, Yu Jiao, Shikai Shen, Yumeng Yan, Xiaoyu Sun.

Treating renal cell carcinoma (RCC) is clinically challenging because the characteristic hypoxic microenvironment of RCC serves as a key driver of malignant progression. High-throughput sequencing analysis across multiple models was used in this study to identify PLOD3 as a major oncogene driving RCC development. PLOD3 promoted RCC cell growth and metastatic capacity in vivo and in vitro. Mechanistically, HIF-2α and histone lactylation modification jointly upregulate PLOD3 expression levels. PLOD3 specifically binds to the C2 domain of NEDD4, hindering NEDD4 autoinhibition and triggering NEDD4 to activate E3 ubiquitin ligase function. This process affects GOT2 expression via inducing K48-linked ubiquitination, leading to GOT2 degradation via the ubiquitin-proteasome pathway. Thus, PLOD3 participates in reprogramming glutamine metabolism through influencing the stability GOT2 protein. This study establishes PLOD3 as a key oncogenic driver of RCC, with HIF-2α/PLOD3/NEDD4/GOT2 pathway potentially being a therapeutic target and providing biomarkers for treating RCC.

DOI: https://doi.org/10.1038/s41419-026-08961-1
PLoS One. 2026 ;21(6): e0351295

Metabolomics analysis identifies differential metabolites and potential diagnostic biomarkers among pediatric sepsis subtypes.

Sisi Zhuang, Lili Zuo.

BACKGROUND: Sepsis in children can be caused by a variety of pathogens, with bacteria and viruses being the most common. This study used metabolomics to identify differences in metabolic profiles and potential biomarkers among pathogens causing pediatric sepsis.
METHODS: Serum metabolomic profiles of pediatric bacterial and viral sepsis were obtained from the MetaboLights database (MTBLS563). Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal PLS-DA were employed to explore metabolic distinctions. Differential expression metabolites (DEMs) were identified using the Wilcoxon rank-sum test and variable importance in projection (VIP) scores. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, receiver operating characteristic (ROC) analysis, Extreme Gradient Boosting (XGBoost) modeling, and Shapley Additive exPlanations (SHAP) analysis were conducted to determine diagnostic metabolites and evaluate model performance.
RESULTS: PCA and PLS-DA revealed distinct metabolic profiles among bacterial pediatric sepsis (PBID_PS), viral pediatric sepsis (VID_PS), and healthy controls. Fourteen differential metabolites were identified, primarily enriched in nitrogen metabolism, arginine biosynthesis, and the metabolism of alanine, aspartate, and glutamate. Among them, choline, glutamate, and glutamine exhibited strong discriminatory ability between PBID_PS and VID_PS. XGBoost and SHAP analyses confirmed these metabolites as key diagnostic indicators, achieving excellent predictive performance and revealing distinct metabolic reprogramming underlying different etiologies of pediatric sepsis.
CONCLUSION: Metabolomic profiling revealed distinct metabolic signatures between bacterial and viral pediatric sepsis, with glutamate, glutamine, and choline serving as potential biomarkers.

DOI: https://doi.org/10.1371/journal.pone.0351295
Respir Res. 2026 Jun 09.

Benchtop NMR as a clinical tool for acute respiratory illness: metabolic signatures associated with disease severity.

Pilar Alonso-Moreno, Zuriñe Blasco-Iturri, Carolina Gotera Rivera, Raquel Murillo, Luis A de Benito-Rodríguez, Antonio Ferruelo, Álvaro Pérez-Collar, María de Los Ángeles Zambrano Chacón, Marta Beraza, Germán Peces-Barba, Raquel Herrero, Jesús Ruiz-Cabello, José A Lorente, Jose L Izquierdo-Garcia.

   BACKGROUND: Acute respiratory failure remains a major challenge in critical care, and early identification of patients at risk of clinical deterioration is essential. Metabolomics provides a systems-level characterization of disease severity but its clinical implementation is limited by the need for high-resolution Nuclear Magnetic Resonance (NMR) infrastructure. Benchtop NMR offers a compact and potentially scalable alternative. This study aimed to identify serum metabolic signatures associated with respiratory severity and evaluate agreement between benchtop and high-resolution NMR platforms.
METHODS: Serum samples from COVID-19 patients with acute respiratory failure were classified by respiratory severity (mild, moderate, severe, and very severe). Metabolomic profiling was performed using 500 MHz high-resolution and 80 MHz benchtop NMR systems. Multivariate analyses were used to identify severity-associated metabolic signatures, assess cross-platform agreement, and evaluate associations with clinical variables.
RESULTS: Both platforms identified consistent metabolic alterations across severity groups. Supervised models achieved accurate discrimination between hospitalized and non-hospitalized patients and between moderate and very severe cases. Twenty-one metabolites, including glutamine, citrate, lactate, phenylalanine, myo-inositol, glycerol, and trimethylamine N-oxide, contributed to group separation. Altered pathways included carbohydrate metabolism, amino acid turnover, lipid metabolism, and tricarboxylic acid cycle intermediates, consistent with hypoxia and immune activation. Several metabolites correlated with inflammatory markers, immune cell counts, and oxygenation parameters. Importantly, benchtop NMR reproduced the key metabolic patterns observed with high-resolution NMR.
CONCLUSIONS: Serum NMR metabolomics identifies metabolic signatures associated with respiratory severity. The agreement between high-resolution and benchtop NMR supports the feasibility of benchtop systems for clinically accessible patient stratification in acute respiratory disease, with potential applicability beyond COVID-19.

Keywords:  Acute respiratory failure; Benchtop NMR; Biomarkers; Critical care; Metabolomics; Nuclear Magnetic Resonance; Patient stratification

DOI:  https://doi.org/10.1186/s12931-026-03731-1
J Chromatogr B Analyt Technol Biomed Life Sci. 2026 May 30. pii: S1570-0232(26)00249-7. [Epub ahead of print]1281 125160

Integrated metabolomics of tumor and plasma reveals local and systemic metabolic responses to T-DM1 therapy.

Xiangyu He, Hua Sang, Guangji Wang, Hui Ye, Chang Shao.

  Comprehensive mapping of drug-induced metabolic alterations is crucial for understanding the mechanisms of targeted therapies. Antibody-drug conjugates (ADCs) such as trastuzumab emtansine (T-DM1) have revolutionized targeted cancer therapy by combining antibody specificity with cytotoxic potency. However, the metabolic reprogramming underlying their therapeutic action and systemic effects remains poorly understood. Here, we applied high-performance liquid chromatography-mass spectrometry (HPLC-MS)-based metabolomics to profile tumor and plasma metabolic alterations in a human epidermal growth factor receptor 2-positive (HER2+) xenograft model at 4- and 7-days following T-DM1 treatment, corresponding to the period of pronounced antitumor activity. A total of 32 significantly altered metabolites were identified in tumor tissues, mapping to pathways including tricarboxylic acid (TCA) cycle, pyrimidine metabolism and lipid metabolism, reflecting disruption in energy production and macromolecular biosynthesis. In plasma, 12 significantly altered metabolites were identified, predominantly affecting histidine, glutamine, taurine, tryptophan, and tyrosine metabolism. Integrated analysis further revealed two compartment-specific metabolites-hippuric acid and uric acid-showing opposite trends, with elevated levels in tumors and reduced levels in plasma. These bidirectional changes indicate a metabolic coupling between tumor and circulation, driven by differential utilization and excretion processes during T-DM1 response. Collectively, our findings demonstrate that T-DM1 elicits coordinated local and systemic metabolic reprogramming, providing mechanistic insights into its antitumor activity and the metabolic coupling between tumor and circulation.

Keywords:  Compartment-specific metabolism; Metabolomics; Plasma; T-DM1; Tumor

DOI:  https://doi.org/10.1016/j.jchromb.2026.125160
Cell Commun Signal. 2026 Jun 12.

From energy metabolic homeostasis to immune remodeling: the role and therapeutic potential of STING signaling in the tumor microenvironment.

Kui Zhao, Xiaohua Wen, Lanyu Zheng, Chaoran Wang, Ziyu Kuang, Siyuan Cui, Na Wang, Jinli Zhu, Fanming Kong.

  The stimulator of interferon genes (STING) pathway is a core regulatory axis of innate immunity. By sensing cytoplasmic DNA, it activates the transcription of type I interferons and pro-inflammatory cytokines, playing a pivotal role in mediating anti-tumor immune responses. Accumulating evidence indicates that the biological functions of STING signaling extend well beyond immune regulation, engaging in extensive and dynamic crosstalk with energy metabolic homeostasis within the tumor microenvironment (TME). The bidirectional interplay forms a central mechanism that shapes the overall immune landscape of the TME. Here, we systematically review the mechanisms by which STING signaling interacts with four core energy metabolic pathways-glycolysis, oxidative phosphorylation, lipid metabolism, and glutamine metabolism-as well as key metabolic regulators. We clarify the critical role of STING as a hub that integrates cellular metabolic stress, energy status, and innate immune responses. Building on these findings, we further elaborate on the pathological significance of crosstalk between STING signaling and the energy metabolic network in TME remodeling. Finally, we highlight combinatorial anti-tumor therapeutic strategies that target key metabolic-immune intersections within this regulatory network, offering a theoretical framework and practical insights for developing novel therapies. In conclusion, the intricate and dynamic crosstalk between STING signaling and the core energy metabolic network establishes it as a critical node linking innate immunity with metabolic homeostasis, and strategically targeting these metabolic-immune intersections represents a promising avenue for developing more effective, combination-based anti-tumor therapies.

Keywords:  Anti-tumor therapy; Energy metabolism; Immune remodeling; STING signaling; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-026-02974-1
Schizophr Res. 2026 Jun 11. pii: S0920-9964(26)00192-1. [Epub ahead of print]295 176-178

Letter to the editor: Higher anterior cingulate glutamatergic metabolites in schizophrenia with past alcohol use disorders.

Bernard A Fischer, Mohammed Saadeh, Daniel Roche, S Andrea Wijtenburg, Laura M Rowland.



Keywords:  Alcohol use disorder; Anterior cingulate cortex; Glutamate; Glutamine; Magnetic resonance spectroscopy; Schizophrenia

DOI:  https://doi.org/10.1016/j.schres.2026.06.009
J Immunother Cancer. 2026 Jun 08. pii: e013562. [Epub ahead of print]14(6):

VSIG4 suppresses antitumor T cell immunity via the SLC3A2-dependent metabolic-ionic checkpoint.

Guoling Huang, Ruirui He, Wei Wang, Heping Wang, Yangyang Li, Bo Zeng, Panyin Shu, Ting Pan, Ming Yi, Lingyun Feng, Zhihui Cui, Xi Li, Yanyun Du, Hong Jiang, Xue Xiao, Yuan Wang, Chenhui Wang.

  BackgroundImmune checkpoint blockade therapy aims to restore T-cell function within the tumor microenvironment (TME), eliciting durable antitumor responses. However, clinical response rates to PD-1/PD-L1 inhibitors remain limited, particularly in immunologically "cold" tumors such as pancreatic cancer, underscoring the need for alternative immunotherapeutic strategies. V-set and immunoglobulin domain-containing 4 (VSIG4) has been implicated in tumor progression, but its functional role in T-cell regulation and mechanisms of tumor immune evasion remain unclear.
METHODS: Syngeneic tumor models and human VSIG4 knock-in mice were employed to investigate the therapeutic effect of VSIG4 blockade. Mouse-specific and human-specific neutralizing antibodies against VSIG4 were administered across multiple tumor types, including pancreatic cancer. Tumor-infiltrating immune cells were analyzed by flow cytometry and functional assays. Mechanistic studies examined the interaction between VSIG4 and solute carrier family 3 member 2 (SLC3A2) and its impact on amino acid transport, ion flux, and T-cell activation.
RESULTS: Therapeutic blockade of VSIG4 significantly suppressed tumor growth and prolonged survival in several cancer models, with particular efficacy in pancreatic cancer. VSIG4 expression correlated with tumor aggressiveness, and its blockade reactivated CD8+ T cells within the TME, enhancing intratumoral infiltration and effector function. Mechanistically, VSIG4 directly bound to SLC3A2, a chaperone for amino acid transporters, thereby impairing glutamine uptake, disrupting sodium and calcium flux, and ultimately suppressing T-cell activation. VSIG4 blockade restored nutrient and ion availability to CD8+ T cells, thereby reinvigorating antitumor immunity.
CONCLUSIONS: These findings define a previously unrecognized metabolic-ionic checkpoint axis by which VSIG4 restricts T-cell activation through SLC3A2. Blockade of VSIG4 reprograms the TME and enhances antitumor immunity, highlighting VSIG4 as a promising therapeutic target, particularly in metabolically repressive tumors such as pancreatic cancer.

Keywords:  Antibody; Immune Checkpoint Inhibitor; Immunotherapy; Macrophage; T cell

DOI:  https://doi.org/10.1136/jitc-2025-013562
Sci Adv. 2026 Jun 12. 12(24): eaec8873

SUCNR1 coordinates metabolic flux, mitochondrial function, and nutrient-dependent adaptation in hepatocytes.

Anna Marsal-Beltran, Laura Salmerón-Pelado, Aleix Ribas-Latre, Maria Repollés-de-Dalmau, M-Mar Rodríguez-Peña, Catalina Núñez-Roa, Joan Badia, Ana Madeira, Eva Novoa, Marc Beltrà, Ana Belén Plata-Gómez, Jordi Capellades, Joan Carles Escolà-Gil, Antonio Zorzano, Óscar Yanes, Alejo Efeyan, Ruben Nogueiras, Jordi Gracia-Sancho, Joan Vendrell, Victòria Ceperuelo-Mallafré, Sonia Fernández-Veledo.

Succinate, a mitochondrial metabolite, also functions as an extracellular signal through its receptor succinate receptor 1 (SUCNR1), coordinating responses to nutrient availability. The physiological role of SUCNR1 within hepatocytes, however, is unclear. We show that hepatic succinate levels and Sucnr1 expression are dynamically regulated by nutritional status. Mice lacking Sucnr1 in hepatocytes [Hep-Sucnr1 knockout (KO)] exhibit a fasting-like phenotype characterized by enhanced gluconeogenesis, elevated amino acids, and impaired metabolic flexibility. Mechanistically, loss of Sucnr1 compromises glucose-derived oxidative flux through the tricarboxylic acid cycle, increases reliance on glutamine-dependent anaplerosis, and induces mitochondrial stress adaptations. Upon refeeding, Hep-Sucnr1 KO mice show blunted mammalian target of rapamycin activation, incomplete glycogen restoration, and an altered hepatic proteomic response. Sucnr1 expression increases during liver maturation, is enriched in pericentral hepatocytes, and its loss is associated with functional reprogramming of pericentral metabolic functions without disruption of zonation. Together, our findings establish SUCNR1 as a critical regulator of hepatic metabolic adaptation, linking succinate signaling to mitochondrial flexibility and nutrient-dependent metabolic responses.

DOI: https://doi.org/10.1126/sciadv.aec8873
Naunyn Schmiedebergs Arch Pharmacol. 2026 Jun 12.

Luteolin ameliorates cigarette smoke-induced chronic obstructive pulmonary disease by modulating gut and lung microbiota and amino acid metabolism in C57Bl/6 mice.

Tunyu Jian, Jiawei Huang, Fang Zhang, Weichen Zhang, Lina Zhou, Guanting Niu, Han Lv, Yanan Gai, Shijie Zhang, Weilin Li, Xiaoqin Ding, Jian Chen.

  Exposure to cigarette smoke (CS) is a potent and major risk factor for chronic obstructive pulmonary disease (COPD). Luteolin (Lut), a flavonoid found in many edible plants, has displayed therapeutic effects on COPD; however, the underlying mechanisms are not well comprehended. In this study, C57Bl/6 J mice were exposed to CS combined with lipopolysaccharide (LPS) to induce COPD. Examination of the levels of inflammatory markers, including TNF-α, IL-1β, IL-6, IL-18, NO, and LPS, revealed that CS exposure caused significant lung injury and inflammatory reactions, while treatment with Lut (50 and 100 mg/kg/day) significantly reversed these trends. 16S rRNA sequencing showed that mice exposed to CS not only decreased the richness and composition of the lung microbiota, but also affected the gut microbiota. Lut treatment increased the richness and modulated the composition. Lut treatment altered the abundance of Pseudomonas, Streptococcus, and Actinomyces in the lung microbiota, as well as Actinobacteria, Helicobacter, and Coprococcus in the gut microbiota. Moreover, targeted metabolomics of amino acids showed seven amino acids, which were significantly altered by Lut, including serine (Ser), threonine (Thr), asparagine (Asn), glutamine (Gln), glutamic acid (Glu), histidine (His), and tyrosine (Tyr). Our study suggests that the protection effect of Lut on CS-induced COPD probably relies on the modulation of gut and lung microbiota and amino acid metabolism.

Keywords:  Amino acid metabolism; COPD; Cigarette smoke; Gut microbiota; Lung microbiota

DOI:  https://doi.org/10.1007/s00210-026-05535-y