bims-glucam 2025-06-01 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–06–01
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Stable 13C-glutamine Tracing Resolved Metabolomics for Cancer Metabolism Study.
Glutamine Transport via Amino Acid Transporter NTT4 (SLC6A17) Maintains Presynaptic Glutamate Supply at Excitatory Synapses in the CNS.
A glutamine metabolism gene signature with prognostic and predictive value for colorectal cancer survival and immunotherapy response.
Targeting Methionine Metabolism Reveals AMPK-SAMTOR Signaling as a Therapeutic Vulnerability in Prostate Cancer.
Immune-metabolic crosstalk in HNSCC: mechanisms and therapeutic opportunities.
Loss of hepatic autophagy induces α-cell proliferation through impaired glutamine-dependent gluconeogenesis.
Unlocking the Role of Metabolic Pathways in Brain Metastatic Disease.
The Metabolic Landscape of Cancer Stem Cells: Insights and Implications for Therapy.
Breaking the immune desert: Strategies for overcoming the immunological challenges of pancreatic cancer.
Metabolic flux analysis of glioblastoma neural stem cells reveals distinctive metabolic phenotypes in ketogenic conditions.
Low, Intermediate, and High Glutamine Levels Are Progressively Associated with Increased Lymphopenia, a Diminished Inflammatory Response, and Higher Mortality in Internal Medicine Patients with Sepsis.
Exploring the Molecular Mechanism and Role of Glutathione S-Transferase P in Prostate Cancer.
Nuclear PHGDH regulates macrophage polarization through transcriptional repression of GLUD1 and GLS2 in breast cancer.
Metabolomic analysis reveals paraquat-induced metabolic alternation in BV2 microglia: Focus on glutamate metabolism.
Glutamine Administration Attenuates Poly(I:C)-Induced Lung Injury by Reducing Neutrophil Infiltration and Activating the TLR-3 Antiviral Pathway.
The stiffness of extracellular matrix (ECM) in regulating cellular metabolism.

Bio Protoc. 2025 May 20. 15(10): e5322

Stable 13C-glutamine Tracing Resolved Metabolomics for Cancer Metabolism Study.

Yaogang Zhong, Liqing He, Xinmin Yin, Logan Mazik, Xiang Zhang, Deliang Guo.

  Stable isotopes have frequently been used to study metabolic processes in live cells both in vitro and in vivo. Glutamine, the most abundant amino acid in human blood, plays multiple roles in cellular metabolism by contributing to the production of nucleotides, lipids, glutathione, and other amino acids. It also supports energy production via anaplerosis of tricarboxylic acid cycle intermediates. While 13C-glutamine has been extensively employed to study glutamine metabolism in various cell types, detailed analyses of specific lipids derived from 13C-glutamine via the reductive carboxylation pathway are limited. In this protocol, we present a detailed procedure to investigate glutamine metabolism in human glioblastoma (GBM) cells by conducting 13C-glutamine tracing coupled with untargeted metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS/MS). The method includes step-by-step instructions for the extraction and detection of polar metabolites and long-chain fatty acids (LCFAs) derived from 13C-glutamine in GBM cells. Notably, this approach enables the distinction between isomers of two monounsaturated FAs with identical masses: palmitoleic acid (16:1n-7) (cis-9-hexadecenoic acid) and palmitelaidic acid (16:1n-7) (trans-9-hexadecenoic acid) derived from 13C-glutamine through the reductive carboxylation process. In addition, using this protocol, we also unveil previously unknown metabolic alterations in GBM cells following lysosome inhibition by the antipsychotic drug pimozide. Key features • Methods for analyzing the flux of the stable isotope 13C-glutamine in cancer cells and identifying its derived polar metabolites and long-chain fatty acids (LCFAs). • Distinguishes isomers of long-chain fatty acids, such as palmitoleic acid (16:1n-7) (cis-9-Hexadecenoic acid) and palmitelaidic acid (16:1n-7) (trans-9-Hexadecenoic acid), which share the exact same mass. • The method is utilized to investigate glutamine metabolism reprogramming in cancer cells following lysosome inhibition.

Keywords:  13C-glutamine; GBM cells; LC–MS/MS; Long-chain fatty acids; Lysosome; Pimozide; Polar metabolites

DOI:  https://doi.org/10.21769/BioProtoc.5322
Prog Neurobiol. 2025 May 26. pii: S0301-0082(25)00076-0. [Epub ahead of print] 102785

Glutamine Transport via Amino Acid Transporter NTT4 (SLC6A17) Maintains Presynaptic Glutamate Supply at Excitatory Synapses in the CNS.

Angela L Nicoli, A Shaam Al Abed, Sarah R Hulme, Abhijit Das, Gregory Gauthier-Coles, Angelika Bröer, Sarojini Balkrishna, Gaetan Burgio, Nathalie Dehorter, Caroline D Rae, Stefan Bröer, Brian Billups.

  The glutamate-glutamine cycle is thought to be the principle metabolic pathway that recycles glutamate at synapses. In this cycle, synaptically released glutamate is sequestered by astrocytes and forms glutamine, before being returned to the presynaptic terminal for conversion back into glutamate to replenish the neurotransmitter pool. While many aspects of this cycle are established, a key component remains unknown: the nature of the transporter responsible for the presynaptic uptake of glutamine. We hypothesise that neurotransmitter transporter 4 (NTT4/SLC6A17) plays this role. Accordingly, we generated NTT4 knockout mice to assess its contribution to presynaptic glutamine transport and synaptic glutamate supply. Using biochemical tracing of 13C metabolites in awake mice, we observe a reduction of neuronal glutamate supply when NTT4 is absent. In addition, direct electrical recording of hippocampal mossy fibre boutons reveals a presynaptic glutamine transport current that is eliminated when NTT4 is removed or inhibited. The role of NTT4 in neurotransmission was demonstrated by electrophysiological recordings in hippocampal slices, which reveal that NTT4 is required to maintain vesicular glutamate content and to sustain adequate levels of glutamate supply during periods of high-frequency neuronal activity. Finally, behavioural studies in mice demonstrate a deficit in trace fear conditioning, and alterations in anxiety behaviour and social preference. These results demonstrate that NTT4 is a presynaptic glutamine transporter, which is a central component of the glutamate-glutamine cycle. NTT4 and hence the glutamate-glutamine cycle maintain neuronal glutamate supply for excitatory neurotransmission during high-frequency synaptic activity, and are important regulators of memory retention and normal behaviour.

Keywords:  Glutamate-Glutamine Cycle; Neuronal Glutamine Uptake; Neurotransmitter; Neurotransmitter Recycling; Presynaptic Function; Presynaptic Glutamate, Supply; Transporters

DOI:  https://doi.org/10.1016/j.pneurobio.2025.102785
Front Mol Biosci. 2025 ;12 1599141

A glutamine metabolism gene signature with prognostic and predictive value for colorectal cancer survival and immunotherapy response.

Yinmeng Zhang, He Zhu, Jiawei Fan, Jiahui Zhao, Yan Xia, Nan Zhang, Hong Xu.

   Background: Colorectal cancer (CRC) remains a major cause of cancer mortality, and dysregulated glutamine metabolism has emerged as a potential therapeutic target. However, the precise role of glutamine in CRC progression and treatment response remains debated.
Methods: The authors collected transcriptome and microbiome information, from multiple sources to construct the GLMscore, a prognostic signature in CRC. To comprehensively characterize the biological features of GLMscore groups, the integration of transcriptomic profiling, KEGG pathway enrichment analysis, immune infiltration analysis, tumor immune microenvironment characterization, microbiome analysis, and tissue imaging were applied. Furthermore, CRC patients were stratified into GLMscore high and GLMscore low groups. The robustness of GLMscore was validated in both training and validation cohorts, and the predictive value for immunotherapy response was assessed. Finally, single-cell RNA sequencing (scRNA-seq) analysis was conducted to delineate the differences between GLMscore high and GLMscore low groups.
Results: High GLMscore was associated with elevated expression of pathways related to tumorigenesis, epithelial-mesenchymal transition (EMT), and angiogenesis. Furthermore, high GLMscore patients exhibited an immunosuppressive TME characterized by increased infiltration of M0 and M2 macrophages, reduced overall immune infiltration (supported by ESTIMATE and TIDE scores), and increased expression of immune exclusion and suppression pathways. Analysis of pathological whole-slide images (WSIs) revealed a lack of intratumoral tertiary lymphoid structures (TLSs) in high GLMscore patients. The GLMscore also predicted resistance to common chemotherapeutic agents (using GDSC data) and, importantly, predicted poor response to immunotherapy in the IMvigor210 cohort. Analysis of 16S rRNA gene sequencing data revealed an enrichment of potentially oncogenic microbiota, including Hungatella and Selenomonas, in high GLMscore group. Single-cell analysis further confirmed the immunosuppressive TME and identified increased cell-cell communication between inflammatory macrophages and tumor cells in high GLMscore group.
Conclusion: The authors innovatively constructed GLMscore, a robust scoring system in quantifying CRC patients, exploring the distinct biological features, tumor immune microenvironment and microbiome ecology, exhibiting high validity in predicting survival prognosis and clinical treatment efficacy.

Keywords:  colorectal cancer; glutamine metabolism; microbiome; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fmolb.2025.1599141
Biology (Basel). 2025 May 06. pii: 507. [Epub ahead of print]14(5):

Targeting Methionine Metabolism Reveals AMPK-SAMTOR Signaling as a Therapeutic Vulnerability in Prostate Cancer.

Serdar Arisan, Ayyuce Sever, Pinar Obakan-Yerlikaya, Elif Damla Arisan, Pinar Uysal-Onganer.

  Prostate cancer (PCa) is not only one of the most diagnosed malignancies in men but also a leading cause of cancer-related mortality globally. PCa exhibits unique metabolic dependencies, particularly on lipids and glutamine, unlike many solid tumors, rather than glycolysis. Methionine metabolism plays a crucial role in these metabolic pathways, contributing to polyamine biosynthesis, DNA methylation, and cellular signaling processes. Here, we demonstrate that methionine deprivation induces selective vulnerability in AMPK-deficient PC3 PCa cells by disrupting SAMTOR-mTOR signaling and triggering oxidative stress, lipid depletion, and autophagic responses. Through functional and proteomic analyses, we show that SAMTOR directly interacts with p-AMPK and modulates cell fate under methionine-limited conditions. Our findings establish a mechanistic link between methionine sensing and metabolic stress signaling in PCa, offering a new avenue for targeted intervention.

Keywords:  SAMTOR; autophagy; mTOR; methionine; prostate cancer

DOI:  https://doi.org/10.3390/biology14050507
Front Oncol. 2025 ;15 1553284

Immune-metabolic crosstalk in HNSCC: mechanisms and therapeutic opportunities.

Xiyuan Qin, Hui Wu, Jiaqi Pan, Kai Kang, Yujie Shi, Shoushan Bu.

  Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy, characterized by metabolic reprogramming. This reprogramming creates an acidic and hypoxic environment within tumor cells to adapt to metabolic changes. Experimental data indicate that in HNSCC, the metabolic reprogramming of tumor cells regulates immune cells via metabolites or signaling pathways, thereby promoting cancer progression or immune evasion. This article reviews the metabolic reprogramming in HNSCC, including glucose, fatty acids, amino acids, and nucleotide metabolism. These metabolic pathways play crucial roles in the proliferation, differentiation, and effector functions of immune cells, and influence immunosuppressive checkpoints. Additionally, this review explores the potential relationships between metabolic reprogramming, tumor immunity, and related treatments. Thus, targeting metabolic reprogramming and interactions between immune cells may help overcome therapeutic resistance in HNSCC patients.

Keywords:  HNSCC; immune; metabolic reprogramming; tumor; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2025.1553284
Physiol Rep. 2025 May;13(10): e70381

Loss of hepatic autophagy induces α-cell proliferation through impaired glutamine-dependent gluconeogenesis.

Jesse N Velasco-Silva, Joseph L Wilkerson, Daniela Ramos, Hayden K Low, Faith Bowman, Kimberley J Evason, Sihem Boudina, William L Holland, Gregory S Ducker.

  Autophagy, the highly conserved process of protein and organelle degradation, is suppressed in the liver by obesity and metabolic dysfunction-associated fatty liver disease and associated with the development of insulin resistance. We generated adult liver-inducible ATG3 knockout mice (Atg3iLKO) to characterize pathways linking hepatic autophagy with metabolic homeostasis. Genetic loss of hepatic autophagy leads to a reduction in 16-h fasted glucose levels, a decrease in endogenous glucose production rates, and an increase in serum amino acids across the fed and fasted states. These changes collectively reflect a loss of hepatic gluconeogenic enzyme activity and not a general inability to degrade amino acids in the liver. Increased circulating glutamine levels resulting from this are associated with an induction of α-cell hyperplasia, leading to constitutively elevated glucagon levels. However, the loss of hepatic gluconeogenesis renders these animals highly glucagon resistant. Collectively, our data demonstrate that loss of hepatic autophagy is sufficient to activate the hepatic α-islet cell axis, leading to hyperglucagonemia with impaired glucose production.

Keywords:  alpha cell; autophagy; glucose; hyperglucagonemia; liver metabolism

DOI:  https://doi.org/10.14814/phy2.70381
Cells. 2025 05 13. pii: 707. [Epub ahead of print]14(10):

Unlocking the Role of Metabolic Pathways in Brain Metastatic Disease.

Madalena Pinto, Sara Violante, Rita Cascão, Claudia C Faria.

  The dissemination of malignant cells to the brain is a late-stage complication of cancer, leading to significant morbidity and mortality. Brain metastases (BM) affect 20-30% of cancer patients, primarily originating from lung cancer, breast cancer, and melanoma. Despite advances in molecular-targeted therapies, brain metastatic disease remains incurable, with a poor median survival of ≤12 months if left untreated. The lack of therapeutic efficacy is mainly attributed to the presence of the blood-brain barrier (BBB) and genetic differences between BM and their primary tumors. Previously published data have identified potential driver mutations of BM. However, the mechanisms underlying brain cancer dissemination remain unknown. Recent studies emphasize the pivotal role of metabolic adaptations in supporting the metastatic process, particularly in the nutrient-poor microenvironment characteristic of the brain. Understanding the interplay between metabolism and genetic alterations associated with brain metastatic disease could unveil novel therapeutic targets that are more effective in treating patients. This review focuses on relevant metabolic pathways in cancer, particularly brain cancer dissemination, while also presenting information on current preclinical models of BM, relevant clinical trials, and preclinical studies targeting metabolic reprogramming, providing an overview for advancing therapeutic strategies in BM.

Keywords:  brain metastatic disease; cancer metabolism; metabolic reprogramming; therapeutic targets

DOI:  https://doi.org/10.3390/cells14100707
Cells. 2025 05 15. pii: 717. [Epub ahead of print]14(10):

The Metabolic Landscape of Cancer Stem Cells: Insights and Implications for Therapy.

Martina Milella, Monica Rutigliano, Savio Domenico Pandolfo, Achille Aveta, Felice Crocetto, Matteo Ferro, Antonio d'Amati, Pasquale Ditonno, Giuseppe Lucarelli, Francesco Lasorsa.

  Cancer stem cells (CSCs) are a subpopulation with self-renewal and differentiation capacities believed to be responsible for tumor initiation, progression, and recurrence. These cells exhibit unique metabolic features that contribute to their stemness and survival in hostile tumor microenvironments. Like non-stem cancer cells, CSCs primarily rely on glycolysis for ATP production, akin to the Warburg effect. However, CSCs also show increased dependence on alternative metabolic pathways, such as oxidative phosphorylation (OXPHOS) and fatty acid metabolism, which provide necessary energy and building blocks for self-renewal and therapy resistance. The metabolic plasticity of CSCs enables them to adapt to fluctuating nutrient availability and hypoxic conditions within the tumor. Recent studies highlight the importance of these metabolic shifts in maintaining the CSC phenotype and promoting cancer progression. The CSC model suggests that a small, metabolically adaptable subpopulation drives tumor growth and therapy resistance. CSCs can switch between glycolysis and mitochondrial metabolism, enhancing their survival under stress and dormant states. Targeting CSC metabolism offers a promising therapeutic strategy; however, their adaptability complicates eradication. A multi-targeted approach addressing various metabolic pathways is essential for effective CSC elimination, underscoring the need for further research into specific CSC markers and mechanisms that distinguish their metabolism from normal stem cells for successful therapeutic intervention.

Keywords:  cancer; markers; stem cells; treatment

DOI:  https://doi.org/10.3390/cells14100717
Biochim Biophys Acta Rev Cancer. 2025 May 22. pii: S0304-419X(25)00095-2. [Epub ahead of print]1880(4): 189353

Breaking the immune desert: Strategies for overcoming the immunological challenges of pancreatic cancer.

Tianming Wang, Wenjing Song, Yuan Tang, Jianfeng Yi, Haibang Pan.

  Pancreatic cancer is characterised by its highly aggressive nature and extremely poor prognosis, with a uniquely complex tumour immune microenvironment that manifests as a prototypical "immune desert." This immune-desert phenotype primarily arises from the inherently low immunogenicity of the tumour, the formation of a dense fibrotic stroma, severe deficiency in immune cell infiltration, and profound immunosuppressive effects of the metabolic landscape. Specifically, dysregulated tryptophan metabolism, such as indoleamine 2,3-dioxygenase (IDO)-mediated catabolism, and excessive lactate accumulation contribute to impaired T-cell functionality. Collectively, these factors severely limit the efficacy of current immunotherapy strategies, particularly those based on immune checkpoint inhibitors, which have demonstrated significantly lower clinical response rates in pancreatic cancer than in other malignancies. In response to these therapeutic challenges, this review explores integrated treatment strategies that combine metabolic reprogramming, tumour microenvironment remodelling, and next-generation immune checkpoint blockades, such as LAG-3, TIM-3, and VISTA. These emerging approaches hold substantial promise for clinical application. For example, targeting key metabolic pathways, including glycolysis (Warburg effect) and glutamine metabolism, may help restore T-cell activity by alleviating metabolic stress within the tumour milieu. Additionally, localised administration of immune stimulators such as interleukin-12 (IL-12) and CD40 agonists may enhance immune cell infiltration and promote tumour-specific immune activation. Future research should prioritise large-scale, multicentre clinical trials to validate the therapeutic efficacy of these innovative strategies, aiming to achieve meaningful breakthroughs in pancreatic cancer immunotherapy and significantly improve long-term survival and clinical outcomes in affected patients.

Keywords:  Fibrotic matrix; Immune microenvironment; Immunotherapy; Metabolic intervention; Pancreatic cancer

DOI:  https://doi.org/10.1016/j.bbcan.2025.189353
Sci Rep. 2025 May 28. 15(1): 18736

Metabolic flux analysis of glioblastoma neural stem cells reveals distinctive metabolic phenotypes in ketogenic conditions.

Anna Rushin, Aleezeh Shaikh, Callie Hardin, Loic P Deleyrolle, Matthew E Merritt.

  Glioblastomas (GBM) are the most prevalent primary brain tumors, affecting 5 in every 100,000 people. GBMs optimize proliferation through adaptive cellular metabolism, frequently exploiting the Warburg effect by increasing aerobic glycolysis and glucose utilization to facilitate rapid cell growth. This disproportionate reliance on glucose has driven interest in using the ketogenic diet (KD) as a treatment for GBM. In this study, we explored metabolic flux in three primary human GBM cell samples using a media simulating a KD. Flux analysis using a detailed metabolic modeling approach revealed three unique metabolic phenotypes in the patient GBMs that correlated with cell viability. Notably, these phenotypes are apparent in the flux modeling, but were not evidenced by changes in the metabolite pool sizes. This variability in metabolic flux may underlie the inconsistent results observed in preclinical and clinical studies using the KD as a treatment paradigm.

Keywords:  Cancer biology; Glioblastoma; Isotopic analysis; Ketogenesis; Metabolism

DOI:  https://doi.org/10.1038/s41598-025-02124-6
J Clin Med. 2025 May 09. pii: 3313. [Epub ahead of print]14(10):

Low, Intermediate, and High Glutamine Levels Are Progressively Associated with Increased Lymphopenia, a Diminished Inflammatory Response, and Higher Mortality in Internal Medicine Patients with Sepsis.

Filippo Mearelli, Alessio Nunnari, Federica Chitti, Annalisa Rombini, Alessandra Macor, Donatella Denora, Luca Messana, Marianna Scardino, Ilaria Martini, Giulia Bolzan, Noemi Merlo, Fabio Di Paola, Francesca Spagnol, Chiara Casarsa, Nicola Fiotti, Venera Costantino, Verena Zerbato, Stefano Di Bella, Carlo Tascini, Daniele Orso, Filippo Giorgio Di Girolamo, Gianni Biolo.

  Background: The pathophysiological mechanisms underlying altered plasma glutamine concentrations in sepsis remain poorly understood. Identifying clinical, immunological, and metabolic correlates of glutamine fluctuations is crucial to advancing precision medicine, developing targeted therapies, and improving survival outcomes in septic patients. Methods: We enrolled 469 patients with sepsis and assessed inflammatory markers-including body temperature, white blood cell count, and C-reactive protein levels-upon admission to the internal medicine unit. Lymphocyte count and plasma concentrations of glutamine, glutamic acid, 5-oxoproline, phenylalanine, tyrosine, and leucine were measured using gas chromatography-mass spectrometry. Patients were stratified into three groups based on plasma glutamine levels. Mortality was recorded at 30 days and 6 months. Results: Low, intermediate, and high glutamine levels were observed in 46% (n = 217), 47% (n = 218), and 7% (n = 34) of patients, respectively. Patients with hyperglutaminemia exhibited significantly lower body temperature, white blood cell and lymphocyte counts, C-reactive protein levels, and glutamic acid-to-5-oxoproline ratio (a surrogate marker of glutathione availability), along with elevated phenylalanine levels, leucine levels, and tyrosine-to-phenylalanine ratio (all p < 0.01). Metabolic disruption and mortality increased progressively across glutamine level groups. Kaplan-Meier analysis demonstrated significantly higher mortality in patients with elevated glutamine levels at both 30 days (log-rank p = 0.03) and 6 months (log-rank p = 0.05). Conclusions: At baseline, increasing plasma glutamine levels are associated with progressively deeper lymphopenia, more pronounced metabolic derangement, and higher short- and long-term mortality in patients with sepsis.

Keywords:  5-oxoproline; glutamic acid; glutamine; leucine; phenylalanine/tyrosine; sepsis

DOI:  https://doi.org/10.3390/jcm14103313
Biomedicines. 2025 Apr 26. pii: 1051. [Epub ahead of print]13(5):

Exploring the Molecular Mechanism and Role of Glutathione S-Transferase P in Prostate Cancer.

Shan Huang, Hang Yin.

  Aims: To investigate the effect of Glutathione metabolism in prostate cancer pathogenesis. Background: There is growing evidence that Glutathione metabolism plays an important role in prostate cancer, with genes encoding key enzymes in this pathway potentially serving as diagnostic or prognostic biomarkers. Objective: To explore whether there is a causal relationship between key enzymes in the Glutathione metabolism and prostate cancer, and to further investigate the molecular mechanisms and roles of the genes encoding their proteins in relation to prostate cancer. Method: Transcriptomic datasets from the Gene Expression Omnibus (GEO) database were analyzed to identify differentially expressed genes (DEGs) and enriched pathways in prostate cancer versus normal tissues. Two-sample bidirectional Mendelian randomization (MR) was employed to assess causal relationships between Glutathione metabolic enzymes (exposure) and prostate cancer risk (outcome). Immune infiltration analysis and LASSO regression were performed to construct a diagnostic model. Single-cell RNA sequencing (scRNA-seq) data were utilized to elucidate cell-type-specific expression patterns and functional associations of target genes. Result: The results of two-sample bidirectional MR showed that Glutathione S-transferase P (GSTP) in Glutathione metabolism could reduce the risk of prostate cancer. The Glutathione S-transferase Pi-1 (GSTP1) gene was lowly expressed in prostate cancer and was able to diagnose prostate cancer more accurately. Single-cell analysis showed that the high expression of GSTP1 in prostate cancer epithelial cells was closely associated with the upregulation of the P53 pathway and apoptosis. Conclusions: Our study reveals that GSTP in Glutathione metabolism reduces the risk of prostate cancer and further analyzes the genetic association and mechanism of action between GSTP1 and prostate cancer.

Keywords:  Glutathione S-transferase P; Mendelian randomization; causality; machine learning; prostate cancer; single-cell analysis

DOI:  https://doi.org/10.3390/biomedicines13051051
Cancer Biol Med. 2025 May 28. pii: j.issn.2095-3941.2024.0398. [Epub ahead of print]

Nuclear PHGDH regulates macrophage polarization through transcriptional repression of GLUD1 and GLS2 in breast cancer.

Pei Wang, Xin Du, Zhiren Han, Jiaxin Zhong, Jiayu Yuan, Lin Jiang, Beinan Han, Wenkui Fu, Hongde Li, Hai Hu, Zhenkun Na.

   OBJECTIVE: Tumor-associated macrophages (TAMs) exhibit heterogeneous properties including anti-tumorigenic and pro-tumorigenic phenotypes. The rate-limiting enzyme in de novo serine biosynthesis, 3-phosphoglycerate dehydrogenase (PHGDH), has a well-established role in cellular metabolism, yet its specific role in macrophages remains unknown.
METHODS: Metabolomics assays were conducted to assess metabolite composition and dynamics in macrophages. Changes in polarization and immunosuppressive markers were validated with qRT-PCR. Bioinformatics was used to analyze immune cell subsets and associated metabolic pathways. Finally, ChIP-qPCR and co-immunoprecipitation assays were performed to elucidate the downstream regulatory mechanisms of PHGDH.
RESULTS: Serine metabolism was found to be downregulated in TAMs in breast cancer. Functional studies revealed that PHGDH inhibition promotes an M2-like phenotype and immunosuppressive functions in macrophages. Furthermore, PHGDH was found to undergo nuclear translocation during macrophage polarization. Mechanistically, nuclear PHGDH was found to regulate GLUD1 and GLS2 transcription via interaction with the transcription factor STAT3. Rescue experiments demonstrated that glutamine supplementation and STAT3 inhibition reversed the effects of PHGDH on macrophage function.
CONCLUSIONS: Our findings reveal a previously unrecognized non-canonical metabolic function of PHGDH, thus providing potential therapeutic targets in the tumor microenvironment for reversing malignant progression.

Keywords:  Breast cancer; polarization; serine metabolism; tumor-associated macrophages

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2024.0398
Comp Biochem Physiol C Toxicol Pharmacol. 2025 May 26. pii: S1532-0456(25)00115-2. [Epub ahead of print] 110234

Metabolomic analysis reveals paraquat-induced metabolic alternation in BV2 microglia: Focus on glutamate metabolism.

Xutong Qin, Yaxin Han, Jiming Zhang, Zheng Wang, Qiuyun Gu, Jiayi Li, Zhijun Zhou, Xiuli Chang.

  Paraquat (PQ), a commonly used contact herbicide, is known to induce oxidative stress and energy depletion, leading to cell death. Chronic low-dose exposure to PQ has been associated with an increased risk of Parkinson's disease, with microglia playing a significant role in its pathogenesis. However, little research has been conducted on the specific effects of PQ on microglial metabolism. This study employs ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) to investigate the metabolic changes in BV2 microglial cells exposed to varying concentrations of 0, 2.5, 5, 10, and 20 μM of PQ. A dose-response fitting model was constructed to determine the effective concentrations and identify sensitive differential metabolites (DMs). Furthermore, reverse transcription-PCR (RT-PCR) was used to assess the expression levels of key genes involved in glutamate metabolism, namely SLC7A11, GLS and SLC38A1. The study identified 40 intracellular inter-group DMs, mainly enriched in amino acid metabolic pathways. d-Glucosamine 6-phosphate and pantothenic acid were identified as the most sensitive DMs. Glutamate emerged as a pivotal metabolite, with its upregulation being accompanied by a significant increase in SLC7A11 expression increasing with PQ concentration, indicating an enhanced cellular response to oxidative stress via glutathione synthesis. Moreover, increased expression of GLS and SLC38A1 was observed exclusively at the 2.5 concentration group, suggesting a shift in glutamate synthesis mechanisms depending on PQ exposure levels. These findings contribute to the understanding of PQ's impact on microglial metabolism and its potential role in neurodegenerative diseases.

Keywords:  BV2 cells; Dose-response model; Glutamate; Metabolomics; Neurodegenerative disorders; Paraquat-induced toxicity

DOI:  https://doi.org/10.1016/j.cbpc.2025.110234
Nutrients. 2025 May 16. pii: 1700. [Epub ahead of print]17(10):

Glutamine Administration Attenuates Poly(I:C)-Induced Lung Injury by Reducing Neutrophil Infiltration and Activating the TLR-3 Antiviral Pathway.

Li-Han Su, Wen-Chiuan Tsai, Hitoshi Shirakawa, Yu-Ling Tsai, Sung-Ling Yeh, Chiu-Li Yeh.

  Objectives: In this study, we investigated the effects of intravenous glutamine (GLN) administration on the Toll-like receptor 3 (TLR3) antiviral pathway and leukocyte migration in mice with poly(I:C)-induced acute lung injury (ALI). Methods: There were four groups in this study: the NC group, mice without an intratracheal injection; the SH group, mice intratracheally injected with endotoxin-free saline; the PS group, intratracheally instilled with 3 mg poly(I:C)/kg body weight (BW), followed by an intravenous (IV) injection of saline; and the PG group, intratracheally injected with poly(I:C) followed by the IV administration of 0.75 g GLN/kg BW. Mice in the SH, PS, and PG groups were sacrificed at 4, 12, and 24 h after intratracheal instillation. Results: The results showed that poly(I:C) stimulation decreased the plasma GLN concentration and increased inflammatory cytokine levels. In bronchoalveolar lavage fluid, concentrations of interferon λ3 and percentages of macrophages and M1 macrophages decreased, while neutrophils increased along with significantly elevated myeloperoxidase activity in lung tissues. The gene expressions of molecules related to leukocyte migration increased, whereas tight/adherens junction expressions in endothelial and epithelial cells were reduced. GLN supplementation upregulated the mRNA and/or protein expressions of TLR3 antiviral pathway-related factors and tight/adherens junctions while reducing inflammatory cytokines and the expressions of leukocyte migration molecules. Histological results also showed that lung injury was attenuated. Conclusions: These findings indicated that intravenous GLN administration after poly(I:C) instillation restored plasma GLN levels and alleviated ALI by activating the TLR3 antiviral pathway, suppressing leukocyte migration and neutrophil infiltration, mitigating inflammation, and improving the integrity of the alveolar-capillary barrier.

Keywords:  TLR-3 pathway; alveolar–capillary barrier; glutamine; interferon λ3; tight/adherens junction

DOI:  https://doi.org/10.3390/nu17101700
Am J Physiol Cell Physiol. 2025 May 28.

The stiffness of extracellular matrix (ECM) in regulating cellular metabolism.

Boyang Zha, Chunlei Zhang, Congying Wu.

  Cells interact dynamically with the extracellular matrix (ECM), which provides both structural support and biochemical signals that regulate various cellular processes. Among these, the mechanical properties of the ECM, particularly stiffness, play a crucial role in governing cell differentiation, migration, and survival. Recent studies have highlighted the intricate relationship between ECM stiffness and cellular metabolism, influencing key pathways such as glucose, lipid and amino acid metabolism. This review explores how ECM stiffness modulates these metabolic processes, emphasizing the underlying mechano-transduction mechanisms. Additionally, we discuss emerging techniques that enable the investigation of ECM-mediated force sensing and response, providing new insights to the mechanoregulation of metabolism and its implications in disease and therapy.

Keywords:  Amino acids metabolism; ECM stiffness; Glucose metabolism; Lipid metabolism; Mechano-transduction

DOI:  https://doi.org/10.1152/ajpcell.00913.2024