bims-glucam 2025-11-02 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–11–02
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

HIF2α inhibits glutaminase clustering in mitochondria to sustain growth of clear cell Renal Cell Carcinoma.
Glutamine synthetase deficiency enhances CD8 T cell survival and stress resilience in the tumor microenvironment.
Ammonia metabolism and ammonia-induced cell death: role in cancer therapy.
Immunometabolic Rewiring of Dendritic Cells to Overcome Glutamine-Driven Immune Suppression in Colorectal Cancer.
SLAMF7 promotes TCRαβ+ double negative T cell antitumor activity through enhancing glutamine metabolism.
Identification of biomarkers and therapeutic targets of schizophrenia using glutamine metabolism.
Metabolic Hostile Takeover: How Influenza Virus Reprograms Cellular Metabolism for Replication.
The cancer-induced lactate load and oncologic remodeling hypothesis: lactate as a driver of biosynthesis and epigenetics in cancer.
Salivary BCAA, Glutamate, Glutamine and Urea as Potential Indicators of Nitrogen Metabolism Imbalance in Breast Cancer.
African swine fever virus hijacks host pyrimidine metabolism to promote viral replication.
Metabolic adaptation of glucose-deprived macrophages involves partial gluconeogenesis.
GLP-1 signaling in tumor metabolism and immunity: mechanisms and strategies.
Triple-Resonance NMR Experiments for Assignment of Asparagine and Glutamine Side-Chain NH2 Groups in Intrinsically Disordered Proteins.
Unveiling Metabolic Signatures as Potential Biomarkers in Common Cancers: Insights from Lung, Breast, Colorectal, Liver, and Gastric Tumours.
Pneumococcal H₂O₂ reshapes mitochondrial function and reprograms host cell metabolism.
From sea to cure: Discovery of marine-derived therapeutics against Fusarium solani in shrimps for enhancing aquaculture sustainability.

JCI Insight. 2025 Oct 30. pii: e182711. [Epub ahead of print]

HIF2α inhibits glutaminase clustering in mitochondria to sustain growth of clear cell Renal Cell Carcinoma.

Wencao Zhao, Sara M Demczyszyn, Nathan J Coffey, Yanqing Jiang, Boyoung Kim, Schuyler Bowers, Caitlyn E Bowman, Michael C Noji, Cholsoon Jang, M Celeste Simon, Zoltan Arany, Boa Kim.

  Clear cell renal cell carcinomas (ccRCC) are largely driven by HIF2α and are avid consumers of glutamine. However, inhibitors of glutaminase1 (GLS1), the first step in glutaminolysis, have not shown benefit in phase III trials, and HIF2α inhibition, recently FDA-approved for treatment of ccRCC, shows significant but incomplete benefits. This highlights the need to better understand the interplay between glutamine metabolism and HIF2α in ccRCC. Here, we report that glutamine deprivation rapidly redistributes GLS1 into isolated clusters within mitochondria in diverse cell types, but not in ccRCC. GLS1 clustering occurs rapidly within 1 to 3 hours, is reversible, is specifically triggered by reduced intracellular glutamate, and is dependent on mitochondrial fission. Clustered GLS1 markedly enhances glutaminase activity and promotes cell death under glutamine-deprived conditions. HIF2α prevents GLS1 clustering, independently of its transcriptional activity, thereby maintaining low GLS activity and protecting ccRCC cells from glutamine deprivation-induced cell death. Forced clustering of GLS1, using constitutively clustering mutants, restores high GLS activity, promotes apoptosis, and suppresses ccRCC tumor growth in vivo. These findings reveal multiple insights into cellular glutamine handling, including a previously unrecognized process by which HIF2α promotes ccRCC: by suppressing GLS1 clustering and maintaining low GLS activity. This mechanism provides a potential explanation for the lack of clinical efficacy of GLS inhibitors in ccRCC and suggests a therapeutic avenue to combine HIF2α inhibition with strategies that restore GLS1 clustering.

Keywords:  Cancer; Cell biology; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.182711
J Immunol. 2025 Oct 31. pii: vkaf250. [Epub ahead of print]

Glutamine synthetase deficiency enhances CD8 T cell survival and stress resilience in the tumor microenvironment.

Emilie L Fisher-Gupta, Emma S Hathaway, Jeffrey M Perera, Erin Q Jennings, Channing Chi, Allison E Sewell, Spenser H Stone, Jason E Muka, Rachael C Sinard, Joseph A DeCorte, Heidi Chen, John T Wilson, Jens Meiler, Jeffrey C Rathmell.

  Cellular immunotherapy has revolutionized the treatment of hematologic malignancies yet has had limited success in the solid tumor microenvironment (TME). While insufficient nutrients can lead to T cell metabolic stress in the TME, the glutamine antagonist DON can paradoxically enhance antitumor immunity. Because DON inhibits both essential and nonessential enzymes whose impairment may contribute to dose-limiting toxicities, mechanisms underlying DON-induced antitumor activity have remained unclear. Here, we aimed to identify specific DON targets that increase T cell antitumor activity and test if more selective inhibition of glutamine metabolism could replicate the effects of DON with reduced toxicity. CRISPR screening in the TME of DON-relevant glutamine metabolizing enzymes identified some targets that were essential in tumor-infiltrating CD8 T cells, but that tumor-infiltrating CD8 T cells lacking the DON target glutamine synthetase (GS) were enriched. Upon adoptive T cell transfers, GS-deficient CD8+ T cells displayed improved survival, a higher proportion TCF-1+ Tox- stem-like cells, and greater antitumor and memory function. GS converts glutamate to glutamine and GS-deficient cells exhibited increased intracellular glutamate and reduced glutathione levels, which correlated with enhanced mitochondrial respiration and resistance to reactive oxygen species. Pharmacological inhibition of GS reduced tumor burden in multiple orthotopic murine tumor models in a manner dependent on adaptive immunity. Our findings establish GS as a key metabolic regulator of CD8+ T cells stress resilience in the TME. By preserving intracellular glutamate, GS inhibition reprograms T cells for improved survival and function, offering a promising therapeutic strategy to enhance immune-based cancer treatments.

Keywords:  T cell; antitumor immunity; glutamine; glutamine synthetase; immunometabolism

DOI:  https://doi.org/10.1093/jimmun/vkaf250
Cell Commun Signal. 2025 Oct 30. 23(1): 468

Ammonia metabolism and ammonia-induced cell death: role in cancer therapy.

Yan Xu, Jiafeng Wang, Aixiang Wu, Mengchuan Wang.

  Ammonia has long been regarded as the end-toxic product of hepatic metabolism. Under normal physiological conditions, ammonia is metabolized through the urea cycle; however, its metabolic imbalance is closely related to various diseases, including hepatic encephalopathy, liver fibrosis, and cancer. Ammonia-induced cell death, specifically the selective death of immune cells, has emerged in recent years as a new form of cell death in the field of tumor biology, offering a new perspective on the regulation of tumor cell fate. This review creatively focuses on the role of ammonia in tumorigenesis, development, and treatment resistance. We systematically reviewed the sources and dynamic balance of ammonia in the tumor microenvironment and found that it plays a key role in tumor metabolic reprogramming by regulating glutamine metabolism, mitochondrial function, and lysosomal stability in tumor cells. Ammonia can also induce the selective death of immune cells, reshape the immune cell map in the tumor microenvironment, and regulate the anti-tumor immune response. Mechanistically, we analyzed the multi-level network of ammonia metabolism regulation, including the role of glutamine synthetase, the mTOR signaling pathway, and epigenetic modification in ammonia death. In addition, this review emphasizes the importance of ammonia as a potential target for cancer therapy and proposes multimodal strategies combining metabolic regulation and immunotherapy to achieve precision in cancer treatment. Finally, the comprehensive map of ammonia in the tumor ecosystem was constructed, highlighting its potential clinical value as a new anti-cancer target.

Keywords:  Ammonia; Apoptosis; Autophagy; Immunotherapy; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-025-02504-5
Adv Sci (Weinh). 2025 Oct 31. e13986

Immunometabolic Rewiring of Dendritic Cells to Overcome Glutamine-Driven Immune Suppression in Colorectal Cancer.

Bingjie Zhang, Renming Fan, Yongrui Hai, Ye Chen, Xintong Lu, Wenhui Wang, Jiarui Dou, Jiaxin Yan, Chang Su, Yue Chen, Le Yang, Minggao Zhao, Lei Liang, Gaofei Wei.

  The immunosuppressive tumor microenvironment imposes significant metabolic constraints that impair dendritic cell (DC) maturation and antigen presentation, ultimately undermining antitumor immunity. In colorectal cancer (CRC), elevated glutamine uptake by tumor cells depletes extracellular glutamine, thereby limiting DC functionality and disrupting T cell priming. While glutamine antagonists such as JHU083 inhibit tumor metabolism, they are insufficient to fully restore DC activity. Here, the development of T26, a bifunctional immunometabolic prodrug that links JHU083 with the STING agonist MSA-2 via a cleavable amide bond, is reported, enabling synchronized intratumoral release and dual targeting of glutamine metabolism and innate immune activation. In murine CRC models, T26 restores DC maturation, promotes CD8⁺ T cell activation, and reprograms tumor cell-derived extracellular vesicles to enhance antigen presentation and immune stimulation. Importantly, T26 significantly inhibits the growth and proliferation of CRC patient-derived organoids, underscoring its translational potential in human CRC. Notably, T26 also demonstrates strong synergy with chemotherapy, immune checkpoint blockade, and anti-angiogenic therapy, significantly improving tumor control without inducing systemic toxicity. These findings position T26 as a mechanistically integrated and translationally promising strategy to overcome glutamine-driven immune suppression and enhance immunotherapy efficacy in CRC and other metabolically dysregulated malignancies.

Keywords:  STING; colorectal cancer; dendritic cells; extracellular vesicles; glutamine; immunotherapy

DOI:  https://doi.org/10.1002/advs.202513986
J Exp Clin Cancer Res. 2025 Oct 30. 44(1): 297

SLAMF7 promotes TCRαβ+ double negative T cell antitumor activity through enhancing glutamine metabolism.

Nan Xu, Peiyang Fang, Longyang Zhou, Xiaotong Han, Yuan Jiang, Xiyu Wang, Jingjing Zhu, Buer Li, Zihan Zhang, Hua Jin, Xiaonan Du, Guangyong Sun, Dong Zhang.

   BACKGROUND: TCRαβ+ double negative T cells (DNT) have recently gained attention for their antitumor activity. Adoptive DNT therapy has emerged as a promising cancer immunotherapy due to its potent cytotoxic function and lack of graft-versus-host-disease. However, the intrinsic mechanisms regulating DNT antitumor functions remain unclear.
METHODS: Signaling lymphocytic activation molecule factor 7 (SLAMF7) expression in murine and human DNT were evaluated. The antitumor activities were compared between SLAMF7+ and SLAMF7- DNT both in vivo and in vitro. Further, metabolomics analysis was performed to reveal the underlying mechanism by which SLAMF7 promotes DNT antitumor cytotoxicity.
RESULTS: The expression of SLAMF7 was markedly increased on DNT upon activation. SLAMF7+ DNT exhibited superior antitumor capacity both in vitro and in vivo compared with SLAMF7- DNT. Mechanistically, SLAMF7 enhanced antitumor activity through ligand-independent and ligand-dependent dual manners. Firstly, SLAMF7 could upregulate GPT2/SLC1A5-mediated glutamine metabolism by activating ERK signaling pathway in DNT, thereby supporting mitochondrial fitness, increasing ATP production, enhancing the expression of effector molecules such as granzyme B and perforin, and promoting antitumor activity of DNT against tumor cells independent of homotypic ligand-receptor interactions. Secondly, DNT showed superior antitumor cytotoxicity against SLAMF7-expressing tumor cells because SLAMF7-SLAMF7 interaction between DNT and SLAMF7-expressing tumor cells promoted DNT cell degranulation. Furthermore, SLAMF7 was also highly expressed in human DNT, and its dual antitumor roles in human DNT were also validated.
CONCLUSIONS: SLAMF7 is a key regulator of DNT-mediated cytotoxicity and a promising target for improving DNT cell function in cancer therapy.

Keywords:  Cancer immunotherapy; Double negative T cells; ERK; Glutamine metabolism; SLAMF7

DOI:  https://doi.org/10.1186/s13046-025-03570-w
Asian J Psychiatr. 2025 Oct 17. pii: S1876-2018(25)00367-3. [Epub ahead of print]114 104724

Identification of biomarkers and therapeutic targets of schizophrenia using glutamine metabolism.

Kun Lian, Yilan Chen, Tianhu Lv, Xiufeng Xu, Wei Yang, Yongmei Li.

   BACKGROUND: Schizophrenia (SCZ) is a major neurodevelopmental disorder that exhibits poor response to current therapeutic interventions. Dysregulation of glutamate metabolism (GM) has been strongly associated with the development of SCZ, through mechanisms involving NMDA receptor dysfunction and neuroimmune imbalance.
METHODS: This study utilized Mendelian randomization (MR) to explore the causal association between 1400 blood metabolites and SCZ. Differentially Expressed GM-related Genes (GMDEGs) were identified via GEO transcriptome data integration, and consensus clustering techniques were employed to delineate the molecular subtypes. Using the key GM genes, a diagnostic model was developed and combined with CIBERSORT and MCPcounter analyses to assess immune infiltration. Moreover, the Drug Signatures Database (DSigDB) was used to identify potential targeted drugs, with their binding stability verified through Molecular Docking (MD) and dynamics simulations.
RESULTS: Mendelian randomization identified 23 SCZ-related plasma metabolites, with glutamate exhibiting the most significant effect (P < 2.72e-31). Further analysis uncovered 25 Differentially Expressed Genes (DEGs) involved in GM, among which ASL, SLC1A5, and CLN3 were validated as the core targets. Immunoassays demonstrated that these DEGs were involved in the regulation of neutrophil and T cell infiltration. SCZ was categorized into C1 and C2 subtypes based on the expression profiles of these three hub glutamate metabolism genes. A diagnostic model integrating ASL, SLC1A5, and CLN3 was developed, which could identify potential therapeutic agents like Tanespimycin with an AUC of 0.844. Moreover, MD experiments confirmed strong binding affinities between tanespimycin and SLC1A5 (-7.7812 kcal/mol), geldanamycin and SLC1A5 (-7.1142 kcal/mol), cyclosporin A and CLN3 (-7.3049 kcal/mol). Meanwhile, molecular dynamics simulations indicated stable binding interactions.
CONCLUSIONS: This study demonstrates the potential causal association of GM-related genes in SCZ, developed a precise diagnostic model, and proposed novel targeted therapeutic strategies.

Keywords:  Glutamine Metabolism; Immune Infiltration; Mendelian Randomization; Molecular Dynamics Simulation; Schizophrenia

DOI:  https://doi.org/10.1016/j.ajp.2025.104724
Viruses. 2025 Oct 17. pii: 1386. [Epub ahead of print]17(10):

Metabolic Hostile Takeover: How Influenza Virus Reprograms Cellular Metabolism for Replication.

Xianfeng Hui, Xiaowei Tian, Shihuan Ding, Ge Gao, Xin Zhao, Jiyan Cui, Yiru Hou, Tiesuo Zhao, Hui Wang.

  Influenza viruses are adept at hijacking host cellular machinery to facilitate their replication and propagation. A critical aspect of this hijacking involves the reprogramming of host cell metabolism. This review summarizes current findings on how influenza virus infection alters major metabolic pathways, including enhanced glycolysis, suppression of oxidative phosphorylation, diversion of TCA cycle intermediates for biosynthesis, and upregulation of lipid and amino acid metabolism. Key nutrients like glucose, glutamine, and serine are redirected to support viral RNA synthesis, protein production, and membrane formation. Moreover, these metabolic changes also modulate host immune responses, potentially aiding in immune evasion. We highlight the role of transcription factors such as SREBPs in lipid synthesis and the impact of one-carbon metabolism on epigenetic regulation. Finally, we discuss how targeting virus-induced metabolic shifts, using agents like 2-deoxyglucose or fatty acid synthesis inhibitors, offers promising avenues for antiviral intervention, while emphasizing the need for selective approaches to minimize harm to normal cells.

Keywords:  amino acid metabolism; antiviral strategies; cellular metabolism; glycolysis; influenza virus; lipid biosynthesis

DOI:  https://doi.org/10.3390/v17101386
Front Oncol. 2025 ;15 1638108

The cancer-induced lactate load and oncologic remodeling hypothesis: lactate as a driver of biosynthesis and epigenetics in cancer.

Hüseyin Aydin.

   Background: Cancer cells undergo profound metabolic reprogramming to sustain proliferation, redox homeostasis, and epigenetic remodeling. While the Warburg effect and glutaminolysis have long been recognized as central paradigms, the anabolic and regulatory role of lactate under normoxic conditions remains poorly defined.
Hypothesis: The Cancer-Induced Lactate Load and Oncologic Remodeling (CILLO) hypothesis proposes that lactate, either imported through MCT1 or produced endogenously, is oxidized to pyruvate by LDHB and subsequently carboxylated to oxaloacetate (OAA) by pyruvate carboxylase. OAA then acts as a metabolic hub driving malate-dependent NADPH production, aspartate synthesis for nucleotide metabolism, activation of the serine/glycine/folate cycle, lipogenesis, and S-adenosylmethionine-mediated epigenetic modifications. In this framework, lactate is no longer a mere by-product of glycolysis but a central integrator of anabolic flux, redox balance, and chromatin dynamics.
Conclusion: The CILLO hypothesis unifies previously fragmented mechanisms into a coherent paradigm, emphasizing lactate-derived carbon skeletons as active drivers of tumor growth and metabolic plasticity. Key rate-limiting steps-MCT1-mediated uptake, LDHB-dependent oxidation, PC-driven anaplerosis, and PEPCK-M-mediated cataplerosis-emerge as therapeutic nodes for intervention. This model not only advances our understanding of cancer metabolism but also suggests novel strategies for biomarker development, metabolic imaging, and targeted therapies. By reframing lactate as a central determinant of oncologic remodeling, the CILLO hypothesis provides a foundation for translational advances in oncology and personalized medicine.

Keywords:  CILLO hypothesis; epigenetic regulation; lactate metabolism; metabolic reprogramming; oxaloacetate; pyruvate carboxylase; redox balance

DOI:  https://doi.org/10.3389/fonc.2025.1638108
Curr Issues Mol Biol. 2025 Oct 11. pii: 837. [Epub ahead of print]47(10):

Salivary BCAA, Glutamate, Glutamine and Urea as Potential Indicators of Nitrogen Metabolism Imbalance in Breast Cancer.

Elena A Sarf, Lyudmila V Bel'skaya.

  Nitrogen metabolism in the human body is in a strictly balanced state, which is disturbed in pathologies, including breast cancer. The state of nitrogen balance can be judged by the content of urea and the amount of branched-chain amino acids (BCAAs) (Val, Leu, and Ile), glutamine (Gln), and glutamate (Glu). The study involved 1438 people, including patients with breast cancer (n = 543), fibroadenomas (n = 597), and healthy controls (n = 298). Saliva samples were collected from all patients before treatment, and urea levels were determined in all 1438 samples. Salivary levels of BCAAs, Gln, and Glu were determined in 116 patients with breast cancer, 24 with fibroadenomas, and 25 healthy volunteers. An increase in the concentration of urea in saliva was shown in breast cancer, most pronounced in luminal molecular biological subtypes: luminal A 10.46 [7.69; 12.62] mmol/L (p < 0.0001), luminal B HER2-negative 9.52 [6.72; 12.52] mmol/L (p = 0.0198), and luminal B HER2-positive 8.26 [5.27; 12.07] mmol/L. The Gln/Glu ratio increased in the saliva of the control group (5.43 [3.30; 10.5]) compared with breast cancer (2.22 [0.84; 5.40], p = 0.0094) and fibroadenomas (1.94 [0.89; 6.05], p = 0.0184). For luminal B HER2-positive and TNBC, the Gln/Glu ratio increased sharply to 8.23 [3.24; 10.9] (p = 0.0327) and 11.2 [4.28; 15.2] (p < 0.0001) compared with healthy controls. Thus, an increased Gln/Glu ratio in saliva may characterize a more aggressive subtype of breast cancer.

Keywords:  BCAA; breast cancer; glutamate; glutamine; nitrogen metabolism; saliva; urea

DOI:  https://doi.org/10.3390/cimb47100837
J Virol. 2025 Oct 31. e0098525

African swine fever virus hijacks host pyrimidine metabolism to promote viral replication.

Zebu Song, Yilin Chen, Hui Guo, Guihong Zhang, Lang Gong, Zezhong Zheng.

  African swine fever (ASF) is a highly contagious disease of pigs caused by the African swine fever virus (ASFV), posing a significant threat to global swine production. As an obligate intracellular parasite, ASFV relies on host metabolic networks to fulfill its replication requirements. However, the precise mechanisms by which it manipulates nucleotide metabolism remain unclear. In this study, untargeted metabolomic analysis of ASFV-infected porcine alveolar macrophages revealed significant perturbations in purine and pyrimidine metabolism, glycolysis, the pentose phosphate pathway (PPP), and the glutamate and aspartate metabolic pathways. Functional validation demonstrated that ASFV depends on de novo pyrimidine biosynthesis for viral genome replication. Notably, ASFV employs a dual strategy to sustain the supply of nucleotide precursors: (i) it hijacks the PPP to generate ribose-5-phosphate and NADPH for redox balance, and (ii) it enhances glutamine uptake and catabolism to provide the nitrogen and carbon needed for nucleotide biosynthesis and tricarboxylic acid cycle replenishment. Furthermore, although aspartate is essential for pyrimidine synthesis, ASFV circumvents dependence on extracellular aspartate by activating a cytosolic GOT1-mediated synthesis pathway. Collectively, these findings elucidate how ASFV reprograms host nucleotide metabolism to support its replication, offering new insights into virus-host metabolic interactions and identifying potential targets for antiviral therapy.IMPORTANCEAfrican swine fever (ASF) is a devastating disease that causes substantial economic losses in the global pig industry. This study demonstrates that the African swine fever virus (ASFV) reprograms host cell metabolism to produce the essential building blocks required for its replication. Specifically, ASFV manipulates host nucleotide biosynthetic pathways to secure both the substrates for DNA synthesis and the reducing power necessary to mitigate oxidative stress. Elucidating these metabolic interactions not only deepens understanding of ASFV pathogenesis but also highlights promising metabolic targets for antiviral therapy. By elucidating how ASFV hijacks nucleotide biosynthesis within infected cells, our findings pave the way for innovative strategies to combat ASF.

Keywords:  African swine fever virus; aspartate; glutamine; metabolic hijacking; pyrimidine metabolism

DOI:  https://doi.org/10.1128/jvi.00985-25
Proc Natl Acad Sci U S A. 2025 Nov 04. 122(44): e2419568122

Metabolic adaptation of glucose-deprived macrophages involves partial gluconeogenesis.

Katharina Schindlmaier, Theresa Haitzmann, Visnja Bubalo, Barbara Konrad, Joseph Jelwan, Gabriele Bluemel, Sonja Rittchen, Vanessa Jäger, Michael A Dengler, Luka Brcic, Jörg Lindenmann, Leigh M Marsh, Thomas O Eichmann, Alexander Kirchmair, Zlatko Trajanoski, Julia Kargl, Cristina Muñoz-Pinedo, Katharina Leithner.

  Macrophages are recruited to sites of infection contributing to the killing of bacteria, but also to malignant tumors, where they promote angiogenesis and suppress antitumor immune responses. The metabolic microenvironment in tumors is frequently depleted of important nutrients such as glucose. Here, we investigated metabolic adaptation strategies of macrophages to glucose deprivation using stable isotopic tracing. Lactate production was decreased, potentially indicating a reduction of glycolysis. In contrast, the contribution of glutamine to the tricarboxylic acid cycle via α-ketoglutarate and reductive carboxylation were increased. Moreover, gluconeogenesis, the reverse pathway of glycolysis, was activated in glucose-deprived macrophages, proceeding partially to the generation of glycolytic intermediates and glycerol-3-phosphate. The partial gluconeogenesis pathway was abrogated in human and murine macrophages lacking the initial gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PCK2, mitochondrial isoform). Partial gluconeogenesis was higher in anti-inflammatory, interleukin-4-stimulated compared to proinflammatory, interferon-γ/lipopolysaccharide-stimulated macrophages. Single-cell analysis and immunostaining revealed expression of PCK2 in macrophages from both lung cancer and normal lung. Low glucose conditions only partially modulated macrophage phenotypes, leading to reduced CD80 surface marker levels in proinflammatory, and enhanced vascular endothelial growth factor expression in anti-inflammatory macrophages. Our study reveals partial gluconeogenesis in glucose-deprived macrophages and shows that this versatile type of immune cells exhibits remarkable metabolic flexibility.

Keywords:  glucose deprivation; glycolysis; macrophages; metabolism; partial gluconeogenesis

DOI:  https://doi.org/10.1073/pnas.2419568122
Food Funct. 2025 Oct 29.

GLP-1 signaling in tumor metabolism and immunity: mechanisms and strategies.

Yingzhe Luo, Huimin Xu, Yaqin Zhao, Biao Yang, Ying Zhang.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for diabetes, are now recognized to exert context-dependent effects on tumor metabolism and immunity. Here, we synthesize emerging evidence that GLP-1R signaling remodels cancer bioenergetics by reversing the Warburg effect, restoring mitochondrial function, and modulating glutamine and autophagy pathways, thereby constraining metabolic plasticity. In parallel, GLP-1RAs enhance cytotoxic T cell and natural killer (NK) cell activity, reshape macrophage polarization, and suppress myeloid-derived suppressor cells, collectively alleviating immunosuppression. However, these actions vary markedly across tumor types: prostate, liver, and colorectal cancers exhibit clear benefits, whereas breast and thyroid cancers reveal paradoxical responses, highlighting the influence of molecular subtypes, oncogenic mutations, and microenvironmental cues. Safety remains a concern, particularly regarding thyroid malignancy, although large-scale cohorts suggest an overall favorable risk-benefit balance. We propose that multi-omics biomarker discovery, innovative trial designs, and next-generation GLP-1 analogs or peptide-drug conjugates will be critical to refine patient stratification and unlock the therapeutic promise of GLP-1RAs in oncology.

DOI: https://doi.org/10.1039/d5fo03273c
Chemphyschem. 2025 Oct 26. e202500630

Triple-Resonance NMR Experiments for Assignment of Asparagine and Glutamine Side-Chain NH2 Groups in Intrinsically Disordered Proteins.

Francesco Torricella, G Marius Clore, Vitali Tugarinov.

  Complete degeneracy of aliphatic 13C chemical shifts of the same type of amino-acid residues precludes unambiguous NMR assignments of asparagine (Asn) and glutamine (Gln) carboxamide NH2 groups in intrinsically disordered proteins with conventional techniques. Here, a pair of triple-resonance NMR experiments is described that correlate the 1H/15N chemical shifts of Asn and Gln carboxamide NH2 groups with the backbone amide 15N chemical shifts of the same and the next residue. These experiments exploit a by far superior dispersion of backbone amide 15N chemical shifts, and permit unambiguous assignments of all Asn/Gln side-chain NH2 groups in the intrinsically disordered protein α-synuclein and the majority of Gln NH2 groups in the disordered huntington exon-1 protein with a 7-residue glutamine repeat, httex1Q7.

Keywords:  intrinsically disordered proteins; resonance assignments; side‐chain NH2 groups; triple‐resonance NMR spectroscopy

DOI:  https://doi.org/10.1002/cphc.202500630
Biomolecules. 2025 Sep 28. pii: 1376. [Epub ahead of print]15(10):

Unveiling Metabolic Signatures as Potential Biomarkers in Common Cancers: Insights from Lung, Breast, Colorectal, Liver, and Gastric Tumours.

Kha Wai Hon, Rakesh Naidu.

  Reprogramming is a hallmark of cancer, enabling tumour cells to sustain rapid proliferation, resist cell death, and adapt to hostile microenvironments. This review explores the expression profiles of key metabolic enzymes and transporters involved in glucose, amino acid, and lipid metabolism across the five most deadly cancers worldwide: lung, breast, colorectal, liver, and gastric cancers. Through a comparative analysis, we identify consistent upregulation of glycolytic enzymes such as LDHA, PKM2, and HK2, as well as nutrient transporters like GLUT1, ASCT2, and LAT1, which contribute to cancer progression, metastasis, and therapy resistance. The role of enzymes involved in glutaminolysis (e.g., GLS1, GDH), one-carbon metabolism (e.g., SHMT2, PHGDH), and fatty acid synthesis (e.g., FASN, ACLY) is also examined, with emphasis on their emerging relevance as diagnostic, prognostic, and predictive biomarkers. While several metabolic proteins show strong potential for clinical translation, only a few, such as tumour M2-pyruvate kinase (TuM2-PK) and serum LDH measurement, have progressed into clinical use or trials. This review addresses some of the challenges in biomarker development. Ultimately, our findings underscore the importance of metabolic proteins not only as functional drivers of malignancy but also as promising candidates for biomarker discovery. Advancing their clinical implementation could significantly enhance early detection, treatment stratification, and personalized oncology.

Keywords:  biomarker; breast cancer; colorectal cancer; gastric cancer; liver cancer; lung cancer; metabolic proteins

DOI:  https://doi.org/10.3390/biom15101376
mBio. 2025 Oct 31. e0201925

Pneumococcal H₂O₂ reshapes mitochondrial function and reprograms host cell metabolism.

Anna Scasny, Babek Alibayov, Ngoc Hoang, Ana G Jop Vidal, Kenichi Takeshita, Consuelo Bautista-Muñoz, Eva Bengten, Antonino Baez, Wei Li, Jonathan Hosler, Kurt Warncke, Kristin S Edwards, Jorge E Vidal.

  Streptococcus pneumoniae (Spn), a primary cause of pneumonia, induces acute lung parenchymal damage through a unique metabolic pathway generating hydrogen peroxide (H₂O₂) as a byproduct. This study demonstrates that Spn-derived H₂O₂, primarily produced by pyruvate oxidase (SpxB), inhibits key tricarboxylic acid (TCA) cycle enzymes (aconitase, glutamate dehydrogenase, and α-ketoglutarate dehydrogenase) in lung epithelial cells, leading to citrate accumulation and diminished NADH production for oxidative phosphorylation. RNA sequencing reveals SpxB-dependent upregulation of glycolytic genes (HIF1A, IER3, HK2, PFKP), restricting pyruvate entry into the TCA cycle and increasing glucose consumption and lactate/acetate production, indicative of a Warburg-like metabolic shift that may enhance bacterial survival. Notably, mitochondrial membrane potential remains largely preserved, with minimal apoptosis despite Spn-induced stress. These findings uncover a novel mechanism of Spn-driven host metabolic reprogramming, highlighting potential therapeutic targets for pneumococcal diseases.IMPORTANCEStreptococcus pneumoniae (Spn) remains a leading cause of community-acquired pneumonia worldwide, yet the mechanisms by which it manipulates host metabolism to promote its survival and pathogenesis are not fully understood. This study reveals a novel metabolic strategy whereby pneumococcus-derived hydrogen peroxide, generated by pyruvate oxidase (SpxB), disrupts the host tricarboxylic acid (TCA) cycle and drives a Warburg-like metabolic shift in lung epithelial cells. By inhibiting key TCA cycle enzymes and rewiring glycolytic gene expression, Spn effectively reprograms host cell metabolism to favor its persistence while minimizing host cell apoptosis and maintaining mitochondrial function. These insights expand our understanding of host-pathogen metabolic interactions and identify potential metabolic vulnerabilities that could be targeted to mitigate tissue damage and improve treatment outcomes in pneumococcal pneumonia.

Keywords:  Streptococcus pneumoniae; Warburg effect; host-pathogen interactions; mitochondrial metabolism; pneumonia

DOI:  https://doi.org/10.1128/mbio.02019-25
PLoS One. 2025 ;20(10): e0336107

From sea to cure: Discovery of marine-derived therapeutics against Fusarium solani in shrimps for enhancing aquaculture sustainability.

Abdullah Al Siam, Avijit Kumer Paul, Shanjida Akter Joyoti, Md Ifteker Hossain, Noimul Hasan Siddiquee, Bushra Binte Zaker, Al- Farabi, Shyamal Kumar Paul.

Fusarium solani, an Ascomycota filamentous fungus species, causes shell disease or mycotic infections in wild and farmed shrimps. It causes black gill disease in shrimps, which has no specific treatments, so cutting-edge pharmaceutical research to prevent glutamine synthetase is needed to stop it and reduce its negative effects on aquaculture productivity and health. In silico drug design has been evaluated as an innovative treatment for black gill disease in shrimps caused by F. solani. Initially, molecular docking targeted the Glutamine synthetase (AF-Q9UUN6-F1-v4), utilising a set of 1,191 seaweed metabolites found in the Seaweed metabolite database (SWMD). The three lead compounds, CID: 359 (Phloroglucinol), 11640528 ((6E,10E,14E)-16-(2,5-dihydroxy-3-methylphenyl)-2-hydroxy-2,6,10,14-tetramethyl hexadeca-6,10,14-trien-3-one), and 8768 (Protocatechualdehyde), have binding affinities of -5.752, -5.374, and -5.102 kcal/mol, with negative binding free energies of -16.27, -48.99, and -27.48 kcal/mol, respectively. Additionally, they have excellent ADMET properties, making them safe and effective, whereas HOMO-LUMO and QSAR studies suggest thermodynamic stability and biological activity, notably antifungal efficacy. The compounds were subsequently assessed to verify their durability and binding affinity to the target protein by conducting an MD simulation analysis. In the MD simulation, the ligands evaluated in this study exhibited notable robustness of the proteins' binding site when complexed with CID: 8768, which suggests a strong interaction between the target and lead compound. Consequently, the compound obtained from the seaweed Polysiphonia lanosa may inhibit the fungal activity of F. solani glutamine synthetase protein, revealing that the compound might be an effective novel therapeutic candidate.

DOI: https://doi.org/10.1371/journal.pone.0336107