bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2025–12–28
eighteen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. GCDH Promotes Breast Cancer Glutaminolysis Reprogramming by Inducing GLS1 Expression Through Histone Crotonylation at Its Promoter Region.
  2. SLC38A3 deficiency reveals a critical role of blood-derived glutamine in brain development.
  3. Interplay Between Glutamine Metabolism and Other Cellular Pathways: A Promising Hub in the Treatment of HNSCC.
  4. Mitochondrial glutamine import sustains electron transport chain integrity independently of glutaminolysis in cancer.
  5. SLC6A14-mediated glutamine promotes SYTL4-CXCL8 axis activation to drive gemcitabine resistance and immune evasion in pancreatic cancer.
  6. Surface Avidity of Anionic Polypeptide Coatings on Layer-by-Layer Nanoparticles Target Cancer-Associated Amino Acid Transporters.
  7. Alpha-ketoglutarate promotes random-pattern skin flap survival by enhancing angiogenesis via PI3K/Akt/HIF-1α signaling pathway.
  8. NEDD4 suppresses ferroptosis in lung ischemia-reperfusion injury by ubiquitinating and degrading SLC1A5.
  9. Purpurin as a promising anticancer agent: A review of preclinical evidence.
  10. Metabolic reprogramming and immune regulation in acute myeloid leukemia.
  11. LAT1/SLC7A5-mediated amino acid uptake is regulated by redox signals triggered by formyl-peptide receptor 2.
  12. Metabolism of glioblastoma: a review of metabolic adaptations and metabolic therapeutic interventions.
  13. Recent insights into the roles and therapeutic potentials of GLS1 in inflammatory diseases.
  14. Metabolomic Markers and Pathways of Blood-Brain Barrier Damage: A Systematic Review.
  15. Multi-Omics Profiling of Intercellular Immunometabolic Heterogeneity highlights in Lung Cancer: Crosstalk mechanisms and Resistance in the Tumor-Immune Interface.
  16. Tumor-produced ammonia is metabolized by regulatory T cells to further impede anti-tumor immunity.
  17. Exosomes loaded with metabolites: Roles in crosstalk between tumor cells and their microenvironment.
  18. Mitochondrial VHL rewires cell metabolism in hypoxia.
  1. Cancer Manag Res. 2025 ;17 3185-3196
    GCDH Promotes Breast Cancer Glutaminolysis Reprogramming by Inducing GLS1 Expression Through Histone Crotonylation at Its Promoter Region.
    Jianan Zhang, Mengsha Zou.
       Objective: Glutaryl-CoA dehydrogenase (GCDH) is a mitochondrial enzyme involved in lysine and tryptophan catabolism, yet its role in cancer metabolism remains poorly understood. This study aimed to investigate the function of GCDH in regulating glutamine metabolism and proliferation in breast cancer cells, and to elucidate its molecular mechanism via epigenetic modulation of glutaminase 1 (GLS1).
    Methods: GCDH expression was silenced using siRNAs in human breast cancer cell lines MCF-7 and MDA-MB-231. Cell proliferation was assessed using CCK-8 and EdU assays. Glutamine metabolism was analyzed by quantifying intracellular levels of glutamine, glutamate, α-ketoglutarate (α-KG), and ATP. In vivo effects were evaluated using a xenograft model in BALB/c nude mice. Chromatin immunoprecipitation (ChIP), luciferase reporter assays, and Western blotting were performed to explore the epigenetic regulation of GLS1. Functional interaction between GCDH and GLS1 was further validated through overexpression and knockdown studies, and the requirement for GCDH's enzymatic activity was tested using a catalytically inactive mutant.
    Results: GCDH knockdown significantly suppressed proliferation in MCF-7 and MDA-MB-231 cells (p<0.001), decreased EdU incorporation (p<0.01), and impaired glutamine metabolism, as indicated by elevated intracellular glutamine and reduced levels of glutamate, α-KG, and ATP (all p<0.05). In vivo, GCDH depletion led to reduced tumor growth and weight (p<0.001), with altered metabolic profiles consistent with impaired glutaminolysis (decreased α-KG, p<0.05). Mechanistically, GCDH silencing reduced global and GLS1 promoter-specific H3K27 crotonylation (p<0.01), suppressing GLS1 transcriptional activity (p<0.001). Overexpression of GLS1 reversed the metabolic and proliferative deficits induced by GCDH knockdown. Furthermore, wild-type GCDH overexpression, but not a catalytically inactive mutant, partially restored glutamate production and ATP levels in GLS1-deficient cells (p<0.05), indicating a functional interplay that depends on GCDH's enzymatic activity.
    Conclusion: GCDH promotes breast cancer cell proliferation and metabolic activity by enhancing glutaminolysis through epigenetic upregulation of GLS1 via histone crotonylation. Critically, this novel metabolic-epigenetic axis requires the catalytic function of GCDH. These findings not only reveal a novel metabolic-epigenetic axis driven by a specific mitochondrial enzyme but also suggest GCDH as a potential therapeutic target in breast cancer.
    Keywords:  breast cancer; epigenetic regulation; glutamine metabolism; histone crotonylation
    DOI:  https://doi.org/10.2147/CMAR.S552195
  2. Brain. 2025 Dec 24. pii: awaf473. [Epub ahead of print]
    SLC38A3 deficiency reveals a critical role of blood-derived glutamine in brain development.
    Inna Radzishevsky, Lama Harb, Maali Odeh, Inon Maoz, Aseel Saeed, Ankita Lahkar, Bella Agranovich, Ifat Abramovich, Farrukh A Chaudhry, Avi Avital, Daniel J Liebl, Herman Wolosker.
      Biallelic mutations in SLC38A3 lead to postnatal progressive microcephaly, epilepsy, and intellectual disability. However, the underlying pathophysiology remains unknown. Here, we identified Slc38a3 expressed at the vascular endothelium as a critical glutamine transporter that mediates blood-to-brain influx of glutamine through the blood-brain barrier (BBB). Endothelial selective deletion of Slc38a3 (Slc38a3-cKO) lowered the influx of glutamine across the BBB and decreased brain glutamine levels in mouse pups. This was associated with lower transfer of glutamine carbons to glutamate and GABA, suggesting impairment of the glutamine-glutamate/GABA metabolic cycle. Like individuals with mutations in SLC38A3, Slc38a3-cKO pups developed postnatal progressive microcephaly as well as behavioural impairments and morphological alterations in synapses. Approximately 30% of Slc38a3-cKO pups fail to thrive, exhibiting motor dysfunction and preweaning lethality. Glutamine deficiency in the Slc38a3-cKO hippocampus was associated with a slower TCA cycle and a seemingly adaptive increase in glycolysis rate. Glutamine supplementation replenished brain glutamine, prevented microcephaly, and normalized motor behavior in Slc38a3-cKO pups, indicating that brain glutamine deficiency is the primary cause of the phenotype. In contrast to the dogma that all glutamine is produced locally in the brain, our data show that Slc38a3 provides blood-derived glutamine for neurotransmitter synthesis, energy metabolism, and synaptogenesis. Our findings suggest that SLC38A3 mutations cause a glutamine-related BBB aminoacidopathy and developmental disorder, which may be amenable to glutamine supplementation therapy.
    Keywords:  SN1; SNAT3; amino acid transporters; glutamatergic transmission; glutamine-glutamate/GABA cycle; microcephaly
    DOI:  https://doi.org/10.1093/brain/awaf473
  3. Cells. 2025 Dec 10. pii: 1962. [Epub ahead of print]14(24):
    Interplay Between Glutamine Metabolism and Other Cellular Pathways: A Promising Hub in the Treatment of HNSCC.
    Teresa Stefania Dell'Endice, Francesca Posa, Giuseppina Storlino, Lorenzo Sanesi, Lucio Lo Russo, Giorgio Mori.
      Head and neck squamous cell carcinoma (HNSCC) is the most common and aggressive histologic subtype of head and neck cancer (HNC), difficult to treat effectively. Here, we discuss several studies on human and mouse HNSCC cell lines arising from the mucosal epithelium of various anatomical sites, as well as recent studies using murine models, focused on targeting key checkpoints in the glutamine (Gln) metabolism pathway, either alone or in synergy with other signaling pathways, as a potential therapeutic strategy for HNSCC. Emerging evidence demonstrates a complex interplay between Gln metabolism and pathways mediating altered cellular mechanisms, including ferroptosis, immune system evasion, mitochondrial energy production, and oncogenic transcriptional control. This review examines currently available gene expression databases and protein expression analyses of Gln metabolism-related components in tissue samples from HNSCC patients. From a translational perspective, the co-administration of pharmaceutical agents and biologic products targeting distinct molecular pathways, integrated with radiotherapy (RT) or chemotherapy (CT), may produce superior anti-HNSCC efficacy, thereby improving clinical outcomes and extending patient survival. Multimodal strategies represent a key direction in precision oncology, enabling personalized therapeutic interventions to suppress metastatic dissemination and disease progression more effectively. Therefore, an integrated therapeutic approach represents a promising path to defeat HNSCC.
    Keywords:  ferroptosis; glutamine metabolism; head and neck cancer; head and neck squamous cell carcinoma; precision medicine in oncology; targeted therapy
    DOI:  https://doi.org/10.3390/cells14241962
  4. Mol Cell. 2025 Dec 22. pii: S1097-2765(25)00975-X. [Epub ahead of print]
    Mitochondrial glutamine import sustains electron transport chain integrity independently of glutaminolysis in cancer.
    Lingzhi Zhu, Kuishen Wu, Jianwei You, Wen Mi, Jie Xu, Liucheng Li, Fang Yang, Xinyi Xia, Haohang Yan, Fei Li, Li Chen, Pingyu Liu, Fuming Li.
      Oxidative phosphorylation (OXPHOS) fulfills energy metabolism and biosynthesis through the tricarboxylic acid (TCA) cycle and an intact electron transport chain (ETC). Mitochondrial glutamine import (MGI) replenishes the TCA cycle through glutaminolysis, but its broader roles in cancer remain unclear. Here, we show that MGI sustains OXPHOS independently of glutaminolysis by maintaining ETC integrity. Exogenous glutamate availability abrogates cellular dependence on glutaminolysis but not SLC1A5var-mediated MGI. Blocking MGI elicits severe mitochondrial defects, reducing mitochondrial glucose oxidation and increasing glutamine reductive carboxylation. MGI, but not glutaminolysis, is essential for mitochondrial translation by enabling biogenesis of Gln-mt-tRNAGln, the most limiting mitochondrial aminoacyl-tRNA in cancer cells. Finally, deleting SLC1A5 in mice and targeting SLC1A5var in xenograft tumors inhibit Gln-mt-tRNAGln biogenesis and mitochondrial translation and blunt tumor growth. Our findings uncover a previously unrecognized role of MGI in safeguarding ETC integrity independently of glutaminolysis and inform a therapeutic option by targeting MGI to abrogate OXPHOS for cancer treatment.
    Keywords:  SLC1A5var; glutamine; glutaminolysis; mitochondrial glutamine import; mitochondrial translation
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.001
  5. Exp Mol Med. 2025 Dec 25.
    SLC6A14-mediated glutamine promotes SYTL4-CXCL8 axis activation to drive gemcitabine resistance and immune evasion in pancreatic cancer.
    Hyeon Woong Kang, Ju Hyun Kim, Jae Woong Jeong, Sungsoon Fang, Won-Gun Yun, Hye-Sol Jung, Wooil Kwon, Jin-Young Jang, Hyo Jung Kim, Joon Seong Park.
      Chemoresistance remains a major challenge in pancreatic ductal adenocarcinoma (PDAC). Glutamine sustains drug resistance and shapes the immunosuppressive tumor microenvironment; however, the underlying mechanisms remain unclear. Identifying key regulators that drive both gemcitabine resistance and immune evasion is crucial for improving theapeutic outcomes in PDAC. Here we identified solute-carrier family 6 member 14 (SLC6A14) as the central regulator of glutamine metabolism that drives gemcitabine resistance. SLC6A14-mediated glutamine metabolism facilitated α-ketoglutarate production, activating mTOR/NF-κB signaling to upregulate PD-L1 expression, playing a central role in immune evasion. Moreover, SLC6A14 induced CXC motif chemokine ligand 8 secretion via synaptotagmin-like 4-mediated exocytosis, paracrinally activating CXCR2 signaling in cancer-associated fibroblasts to enhance mitochondrial fission and amino acid recycling, supporting PDAC progression. Targeting SLC6A14 with α-methyl-tryptophan enhanced gemcitabine sensitivity, suppressed PD-L1 driven immune evasion and reduced tumor growth, metastasis and glutamine production in vivo. These findings underscore SLC6A14 as a pivtoal mediator of glutamine-driven gemcitabine resistance and immune evasion in PDAC. Therapeutic strategies targeting SLC6A14, either alone or in combination with PD-L1 blockade, hold promise for overcoming chemoresistance and enhancing antitumor immunity in gemcitabine-resistant pancreatic cancer.
    DOI:  https://doi.org/10.1038/s12276-025-01596-w
  6. Angew Chem Int Ed Engl. 2025 Dec 22. e19203
    Surface Avidity of Anionic Polypeptide Coatings on Layer-by-Layer Nanoparticles Target Cancer-Associated Amino Acid Transporters.
    Ivan S Pires, Margaret M Billingsley, Ezra Gordon, Andrew J Pickering, Eva Cai, Gonzalo J Esparza, Mae L Pryor, Alexander D Stoneman, Aidan Kindopp, Darrell J Irvine, Paula T Hammond.
      Tumor-targeted drug delivery enhances therapeutic efficacy while minimizing toxicity. Layer-by-layer nanoparticles (LbL-NPs) coated with anionic polypeptides selectively bind to cancer cells, though the mechanisms have been unclear. Here, we integrated in silico and in vitro approaches-including gene expression analysis, receptor inhibition, and AI-based protein modeling-to show that poly(L-glutamate) (PLE)-coated LbL-NPs bind with high avidity to SLC1A5, a glutamine transporter overexpressed in cancer. We also discovered that PLE clusters SLC1A5 on the cell membrane, promoting prolonged cell surface retention. Poly(L-aspartate) (PLD)-coated NPs similarly bind SLC1A5 but also interact with faster internalizing transporters of anionic amino acids. Correlation analyses across cancer cell lines confirmed a strong link between transporter expression and nanoparticle (NP) association. These findings demonstrate that dense glutamate or aspartate presentation through electrostatically adsorbed polypeptides enables selective targeting of overexpressed transporters, providing a mechanistic framework for receptor-targeted delivery that leverages metabolic characteristics of a range of solid tumor types.
    Keywords:  Cancer targeting; Drug delivery; Layer‐by‐layer; Nanoparticles; Polymer coating
    DOI:  https://doi.org/10.1002/anie.202519203
  7. Cell Regen. 2025 Dec 22. 14(1): 54
    Alpha-ketoglutarate promotes random-pattern skin flap survival by enhancing angiogenesis via PI3K/Akt/HIF-1α signaling pathway.
    Jiefeng Huang, Shuangmeng Jia, Yitong Ji, Yingjia Zhu, Yishu Lu, Yiming Tang, Jiajie Yang, Guangpeng Liu, Lei Cui, Shuaijun Li.
      Random-pattern skin flaps are widely employed in tissue reconstruction, however, their survival is frequently hindered by ischemia, leading to necrosis. Metabolic alterations have been implicated in playing critical roles in angiogenesis during tissue repair. Using RNA sequencing analysis in a mouse model, we identified significant disruptions in glutamine metabolism, which substantially impaired angiogenesis within random-pattern skin flaps. Although local glutamine repletion failed to alleviate ischemia, administering α-ketoglutarate (α-KG) markedly promoted angiogenesis, as evidenced at both gene and protein levels. In human umbilical vein endothelial cells,α-KG enhanced the stability of hypoxia-inducible factor (HIF-1) alpha through activation of the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway. Notably, α-KG treatment improved flap viability by augmenting blood perfusion, an effect correlated with upregulation of vascular endothelial growth factor expression. Together, these results reveal a novel mechanism by which α-KG enhances random-pattern skin flap viability via promoting angiogenesis through the PI3K/Akt/HIF-1α pathway, offering promising therapeutic insights for improving flap survival.
    Keywords:  Alpha-ketoglutarate; Angiogenesis; Glutamine metabolism; PI3K/Aktpathway; Skin fap
    DOI:  https://doi.org/10.1186/s13619-025-00264-8
  8. Sci Rep. 2025 Dec 23.
    NEDD4 suppresses ferroptosis in lung ischemia-reperfusion injury by ubiquitinating and degrading SLC1A5.
    Jianchao Li, Fanwei Meng, Xiaoliang Qian, Shuchen Chen.
      Lung ischemia-reperfusion injury (LIRI) is a critical complication in thoracic surgery and transplantation, driven partly by ferroptosis. While the E3 ubiquitin ligase neural precursor cell expressed, developmentally down-regulated 4 (NEDD4) mitigates ferroptosis in other organs, its role in pulmonary ferroptosis remains unexplored. We screened screened NEDD4 interactors in pulmonary epithelial cells through TurboID proximity proteomics. And functional validation was utilized, including murine LIRI models (WT/NEDD4-/-), hypoxia/reoxygenation (H/R) in vitro, Co-IP, ubiquitination assays, cycloheximide chase, and rescue experiments. The research indicated that NEDD4 expression was downregulated in murine LIRI and H/R-injured pulmonary epithelia. NEDD4 deficiency exacerbated LIRI-induced lung injury, apoptosis, inflammation, and ferroptosis. NEDD4 overexpression rescued H/R-induced ferroptosis by reducing ROS, lipid peroxidation, and iron overload. TurboID identified glutamine transporter solute carrier family 1 member 5 (SLC1A5) as a NEDD4-specific interactor. Mechanistically, NEDD4 ubiquitinated SLC1A5 primarily via K48-linked chains and promoted its proteasomal degradation in a manner dependent on NEDD4's catalytic activity. SLC1A5 overexpression reversed NEDD4-mediated protection against ferroptosis in vitro. In conclusion, NEDD4 attenuates ferroptosis in LIRI by ubiquitinating and degrading the pro-ferroptotic transporter SLC1A5. Targeting the NEDD4-SLC1A5 axis offers therapeutic potential for LIRI.
    Keywords:  Ferroptosis; Glutamine metabolism; Lung ischemia-reperfusion injury; NEDD4; SLC1A5; Ubiquitination
    DOI:  https://doi.org/10.1038/s41598-025-32479-9
  9. Fitoterapia. 2025 Dec 22. pii: S0367-326X(25)00679-3. [Epub ahead of print] 107052
    Purpurin as a promising anticancer agent: A review of preclinical evidence.
    Fui-Ling Voon, Yu Zhao Lee, Xiao Ying Ooi, Charlotte Zi Ern Tay, Ji Wei Tan, Chau Ling Tham, Yu-Cheng Ho, Ming Tatt Lee.
      Purpurin, a naturally occurring anthraquinone pigment, has gained attention for its promising anticancer properties. This systematic-narrative hybrid review summarises current preclinical evidence on its mechanisms of action, pharmacology, and translational potential. Literature searches were conducted using PubMed, Web of Science, Scopus, and Google Scholar up to June 2025. Purpurin demonstrates selective cytotoxicity across multiple cancer models through redox imbalance, mitochondrial dysfunction, inhibition of PI3K/AKT signalling, and upregulation of the tumour suppressor LHPP. It also interferes with amino acid and glutamine metabolism and suppresses oncogenic protein aggregation. As a photosensitiser, purpurin enhances photodynamic therapy through light-activated ROS generation. Despite these promising mechanistic insights, its clinical applicability remains limited by poor aqueous solubility, rapid metabolism, and insufficient pharmacokinetic and toxicological data. Early in vivo studies indicate favourable safety, and emerging nanoparticle-based delivery systems show potential to improve bioavailability and tumour targeting. Collectively, current findings highlight purpurin as a compelling candidate for further development in oncology, particularly as part of combination or photo-enhanced therapeutic approaches. Continued research is required to address existing pharmacological gaps and to evaluate purpurin in clinically relevant models.
    Keywords:  Anthraquinone; PI3K/AKT signalling; Photodynamic therapy; Preclinical studies; Purpurin; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.fitote.2025.107052
  10. Front Immunol. 2025 ;16 1655005
    Metabolic reprogramming and immune regulation in acute myeloid leukemia.
    Xiaogang Hao, Chenyang Fan, Lixiang Yan, Reaila Jianati, Yifei Guo, Xinli Zhou, Gengda Zhu, Yucheng Zhang, Chengyulong Zheng, Ying Zhang, Zhexin Shi.
      The most prevalent kind of acute leukemia in adults is acute myeloid leukemia (AML). While some individuals have had better effectiveness due to advancements in targeted medications, recurrence after remission and inadequate treatment specificity continue to be significant therapeutic problems. By controlling essential metabolic pathways and metabolites, metabolic reprogramming, a crucial strategy for cellular adaptability to energy needs, modifies cellular metabolic rhythms. In addition to being involved in immune cell proliferation, differentiation, and effector function, this pathway is also essential for leukemogenesis and survival signaling in AML. By altering the expression of immune molecules, the release of certain metabolites (such as lactate, ROS, glutamine, etc.) has a significant impact on the immune response to tumors. It is noteworthy that the metabolic interactions between immune cells and AML cells form a distinct pattern of energy competition in the tumor microenvironment. This study examined the new approach of targeting metabolic pathways to improve immunotherapy, systematically clarified the regulatory mechanism of metabolic reprogramming between AML cells and immune cells to counteract tumor immunity, and concentrated on the synergistic effect of current therapies and metabolic interventions. These findings offered a fresh perspective on how to fully realize the potential of metabolic therapy for AML.
    Keywords:  AML; immune regulation; metabolic reprogramming; metabolism; review
    DOI:  https://doi.org/10.3389/fimmu.2025.1655005
  11. FEBS J. 2025 Dec 21.
    LAT1/SLC7A5-mediated amino acid uptake is regulated by redox signals triggered by formyl-peptide receptor 2.
    Myrhiam Cassese, Chiara Brignola, Stefano Marrone, Gabriella Esposito, Rosario Ammendola, Fabio Cattaneo.
      The rewiring of amino acid (AA) metabolism is a key characteristic of cancer metabolism. Cells can only synthesize nonessential AAs, but if the demands of highly proliferating cells don't meet the endogenous synthesis capacity, AAs must be acquired from outside. SLC7 belongs to the solute carrier transporters (SLC) superfamily and acts as a passive facilitative or secondary AA active transporter. LAT1/SLC7A5 acts as an antiporter that mediates the influx of several AAs into cells in exchange for the efflux of intracellular substrates. In tumor cells, LAT1/SLC7A5 overexpression is closely associated with proliferation, invasion, metastasis, and poor clinical prognosis. Formyl peptide receptor 2 (FPR2) belongs to the FPR family of GPCRs. Its activation regulates several biological processes and triggers NADPH oxidase assembly and, consequently, reactive oxygen species (ROS) generation. FPR2 stimulation also induces an increase in SLC1A5/ASCT2 and SLC7A11/xCT expression, which correlates with enhanced glutamine and cystine uptake, respectively. Herein, we analyze the LAT1/SLC7A5-mediated uptake of several essential AAs in FPR2-stimulated CaLu-6 and HCC1937 cells and prove: (i) the redox regulation of both LAT1/SLC7A5 and 4F2hc/SLC3A2/CD98, which form a heterodimer on the plasma membrane; (ii) the redox activation of the mTOR pathway and, in turn, of S6K1 and 4E-BP1, which stimulate protein synthesis; (iii) c-Myc and miR-126 regulation, which control LAT1/SLC7A5 synthesis at the transcriptional and post-transcriptional level, respectively. These findings provide new approaches for the development of novel therapeutic strategies for the treatment of human cancers.
    Keywords:  LAT1/SLC7A5; NADPH oxidase; SLC3A2/CD98; formyl peptide receptor 2; miR‐126; reactive oxygen species
    DOI:  https://doi.org/10.1111/febs.70370
  12. Front Oncol. 2025 ;15 1712576
    Metabolism of glioblastoma: a review of metabolic adaptations and metabolic therapeutic interventions.
    James Chung, Jawad Saad, Ahmad Kafri, Julien Rossignol, Maxwell Verbrugge, Jesse Bakke.
      Glioblastoma (GBM) is the most common and aggressive primary malignancy of the central nervous system, marked by profound metabolic reprogramming that promotes growth, invasion, and therapeutic resistance. This review examines metabolic adaptations that sustain GBM progression and summarizes current and emerging strategies that target these pathways. GBM cells display increased aerobic glycolysis, glutaminolysis, lipid and cholesterol synthesis, and mitochondrial remodeling. These processes are regulated by oncogenic alterations such as EGFR amplification, PTEN loss, and HIF-1α stabilization, which allow tumor cells to thrive in hypoxic and nutrient-poor environments. Accumulation of lactate further supports metabolic flexibility and promotes an immunosuppressive microenvironment. Recent studies have focused on exploiting these metabolic vulnerabilities through dietary, pharmacologic, and oxygen-modulating interventions. The ketogenic diet has been explored as an adjuvant therapy to reduce glucose availability and enhance treatment sensitivity. Pharmacologic approaches include inhibition of key metabolic enzymes such as hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase, and glutaminase. Additional strategies aim to disrupt mitochondrial function through VDAC1 blockade or to reduce tumor hypoxia using hypoxia-activated prodrugs, hyperbaric oxygen therapy, and oxygen-transporting agents. Preclinical findings suggest these approaches can suppress tumor proliferation and improve responsiveness to radiation and chemotherapy, although clinical evidence remains limited. Combining metabolic interventions with standard therapies may help overcome GBM's intrinsic resistance and metabolic plasticity. Overall, the review highlights metabolism as a key determinant of GBM pathophysiology and a promising target for therapeutic innovation, emphasizing the importance of continued translational research to identify and exploit context-specific metabolic vulnerabilities in this highly lethal disease.
    Keywords:  brain cancer; cancer; cancer signaling; glioblastoma; metabolic therapeutics; metabolism
    DOI:  https://doi.org/10.3389/fonc.2025.1712576
  13. J Pharm Anal. 2025 Dec;15(12): 101292
    Recent insights into the roles and therapeutic potentials of GLS1 in inflammatory diseases.
    Jian-Xiang Sheng, Yan-Jun Liu, Jing Yu, Ran Wang, Ru-Yi Chen, Jin-Jin Shi, Guan-Jun Yang, Jiong Chen.
      Glutaminase 1 (GLS1) is a crucial enzyme that serves as the initial rate-limiting factor in glutaminolysis, a metabolic process that releases various factors that influence biological processes such as development, differentiation, and immune responses. Several studies have systematically investigated the crucial role of GLS1 in cancer. However, there is a lack of a comprehensive understanding of the relationship between GLS1 and inflammation. In this review, we present a detailed examination of GLS1, and discuss its structure, function, and role in inflammatory pathways. Here, we summarize the evidence supporting GLS1's involvement in several inflammatory diseases and explore the potential therapeutic applications of GLS1 inhibitors. We found that GLS1 plays a crucial regulatory role in inflammation by mediating glutaminolysis. Targeting GLS1, such as through the use of GLS1 inhibitors, can effectively alleviate inflammation induced by GLS1. Furthermore, we highlight the challenges and opportunities associated with investigating GLS1 function and developing targeted inhibitors, and propose practical solutions that offer valuable insights for the functional exploration and discovery of potential therapeutics aimed at treating inflammatory diseases.
    Keywords:  Glutaminase 1; Glutaminolysis; Inflammation; Inhibitor
    DOI:  https://doi.org/10.1016/j.jpha.2025.101292
  14. Compr Physiol. 2025 Dec;15(6): e70086
    Metabolomic Markers and Pathways of Blood-Brain Barrier Damage: A Systematic Review.
    Andrzej Wasilewski, Agata Serrafi, Igor Działak, Krzysztof Ksawery Gofron, Leszek Szenborn, Jolanta Jasonek, Eliza Wasilewska, Bernarda Kazanowska.
       OBJECTIVES: This study aimed to identify metabolites and metabolic pathways associated with blood-brain barrier (BBB) dysfunction in human and animal metabolomic research.
    METHODS: PubMed, Scopus, Web of Science, and Embase were searched (last search: 24 November 2025) without date limits. Original studies applying metabolomic techniques (1H-NMR, LC-MS, GC-MS) to CSF, serum, or plasma and reporting metabolites linked to BBB damage were included. Study selection, full-text assessment, and data extraction were performed independently by two reviewers, with disagreements resolved by a third. Risk of bias was evaluated using SYRCLE and ROBINS-I tools. Metabolites reported in ≥ 2 studies were mapped to metabolic pathways using MetaboAnalyst with hypergeometric testing and Holm-Bonferroni and FDR corrections.
    RESULTS: Of 12,182 records identified, eight studies (four human, four animal) met the inclusion criteria. Across these, 157 metabolites were identified, 25 of which were reported in more than one study. Frequently observed metabolites included glutamate, glutamine, alanine, choline, creatine, and branched-chain amino acids (valine, leucine, isoleucine). Pathway analysis revealed significant enrichment of alanine, aspartate and glutamate metabolism, nitrogen metabolism, and BCAA biosynthesis (FDR = 0.01). Glutamate and glutamine most consistently correlated with BBB dysfunction and neuroinflammatory processes. Substantial heterogeneity was observed, partly due to differences in analytical platforms, sample types, and reporting standards.
    CONCLUSIONS: Metabolites and pathways related to glutamate, nitrogen metabolism, and BCAA may play key roles in BBB impairment. Metabolomics shows promise for identifying BBB biomarkers, but larger, methodologically standardized studies are required.
    TRIAL REGISTRATION: OSF identifier: dapu9.
    Keywords:  biomarkers; blood–brain barrier; inflammation; metabolomics; neurological disorders
    DOI:  https://doi.org/10.1002/cph4.70086
  15. Crit Rev Oncol Hematol. 2025 Dec 24. pii: S1040-8428(25)00482-2. [Epub ahead of print] 105094
    Multi-Omics Profiling of Intercellular Immunometabolic Heterogeneity highlights in Lung Cancer: Crosstalk mechanisms and Resistance in the Tumor-Immune Interface.
    Praise Audax Rukonge, Vincent Kawuribi, Yifan Sheng, Qishu Wei, Yan Kun, Pascaline Niyodukunda, Tianyu Wang, Zhimeng Lu, Yiyan Miao, Kuang Xu, Guiping Yu.
      Lung cancer's tumor microenvironment (TME) is shaped by metabolic crosstalk between malignant and immune cells, driving immune evasion, heterogeneity, and resistance to immunotherapy. Tumor-derived metabolites such as lactate, adenosine, and kynurenine impair cytotoxic T cells and dendritic cells while promoting regulatory and suppressive immune subsets, creating a metabolically hostile niche that limits checkpoint inhibitor efficacy. Advances in multiomics including single-cell transcriptomics, proteomics, metabolomics, and spatial profiling have enabled high-resolution mapping of tumor-immune metabolic communication. Available evidence from various studies reveals metabolic subtypes, immune states, and spatial niches linked to resistance, including lactate accumulation, glutamine dependence, and adenosine signaling. This review uniquely synthesizes findings from latest literature (2009-2025) obtained from electronic database including PubMed, Google Scholar, Scopus and Web of Science, which integrates multi-omics data to define immunometabolic phenotypes (LM-high, CD73^high, KEAP1/NRF2^mutation) and pathways in lung cancer and highlights therapeutic strategies such as CD73/adenosine blockade, arginase and glutaminase inhibition, and metabolically engineered immune cells. Collectively, available evidence from various studies positions multi-omics profiling as a critical clinical tool. It enables the classification of tumors by dominant immunometabolic phenotype, thereby paving the way for biomarker-driven trials that rationally combine metabolic inhibitors with immunotherapy to overcome resistance.
    Keywords:  Adenosine–CD73 Axis; Immune Checkpoint Inhibitor Resistance; Immunometabolism; Metabolic Heterogeneity; Multi-Omics; Non–Small Cell Lung Cancer (NSCLC); Tumor Microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.105094
  16. Cell. 2025 Dec 24. pii: S0092-8674(25)01369-8. [Epub ahead of print]
    Tumor-produced ammonia is metabolized by regulatory T cells to further impede anti-tumor immunity.
    Jian Gu, Yu Li, Qiuyang Chen, Ziyan Song, Qufei Qian, Yuan Liang, Tianning Huang, Lei Qiao, Xiangyu Li, Miao Yu, Mu Liu, Jinren Zhou, Qing Shao, Xiaozhang Xu, Robert Zeiser, Ling Lu.
      Mechanisms of adaptation of regulatory T cells (Tregs) to harsh tumor metabolic microenvironments for suppression of anti-tumor immunity remain largely unclear. Here, using spatial metabolomics and transcriptomics, we show that human hepatocellular carcinoma harbored metabolically heterogeneous subregions characterized by high glutaminolysis and ammonia contents, where Tregs were frequently present but CD8+ and CD4+ effector T cells die. We found Tregs used the urea cycle to detoxify ammonia by upregulating argininosuccinate lyase (ASL); meanwhile, ammonia was also converted to spermine by the FOXP3 transcription factor regulated spermine synthase (SMS). A direct interaction between spermine and PPARγ was verified by X-ray crystallography, leading to comprehensively modulating the transcription of multiple mitochondrial complex proteins to enhance oxidative phosphorylation and immunosuppression of Tregs. Clinically, anti-PD-1-treated dying tumor cells used transdeamination to release ammonia, which reinforced Treg function, leading to immunotherapeutic resistance. Targeting ammonia production to suppress Tregs presents a potential strategy for anti-tumor immunotherapy.
    Keywords:  Tregs; ammonia; cancer immunotherapy; glutaminolysis; metabolic adaptation; polyamine metabolism; urea cycle
    DOI:  https://doi.org/10.1016/j.cell.2025.11.034
  17. Eur J Pharmacol. 2025 Dec 24. pii: S0014-2999(25)01264-6. [Epub ahead of print] 178510
    Exosomes loaded with metabolites: Roles in crosstalk between tumor cells and their microenvironment.
    Ping Ye, Mingjun Sun, Jia Wang, Xianzhao Bai, Zihan Li, Qiang Lin, Ran Liu.
      Exosomes, small endosome-derived vesicles, mediate intercellular crosstalk among cancer cells within the tumor microenvironment (TME), while metabolic reprogramming directly drives these phenotypic changes. Recently, the application of nanoparticle tracking analysis and mass spectrometry to exosome identification and metabolite detection has brought exosome-loaded metabolites in the TME into sharp research focus. In this study, we compared the exosomal metabolites derived from cancer versus normal cells, and elucidated how these differences modulate communication between tumor and stromal or immune cells. The differences in oncometabolites associated with tumors mainly include changes in fatty acids and amino acids. Tumor metabolic shifts reflected by exosomal amino-acids alterations center on glutamate metabolism and arginine biosynthesis. Tumor-associated alterations in exosomal fatty acids centered around the biosynthesis and metabolism of phosphatidylcholine and ceramide. Like nucleic acids and proteins, exosomal metabolites serve as non-invasive, efficient biomarkers for cancer detection.
    Keywords:  Exosomal metabolites; Intercellular communication; Precision therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178510
  18. Cell Metab. 2025 Dec 22. pii: S1550-4131(25)00527-3. [Epub ahead of print]
    Mitochondrial VHL rewires cell metabolism in hypoxia.
    Guobang Li, Wenfeng Pan, Long Wu, Zhiliang Cai, Haoming Chen, Xingui Wu, Tiantian Yu, Kun Liao, Hui Zhang, Xingqiao Wen, Bo Li.
      Under normoxia, von Hippel-Lindau (VHL) protein targets the oxygen-induced, hydroxylated α subunits of hypoxia-inducible factors (HIFs) for degradation to orchestrate mammalian oxygen sensing. However, whether VHL plays non-canonical roles in hypoxia, when protein hydroxylation is attenuated, remains elusive. Here, we show that most cytosolic VHL is degraded under chronic hypoxia, with the remaining VHL pool primarily translocating to the mitochondria. Mitochondrial VHL binds and inhibits 3-methylcrotonyl-coenzyme A carboxylase subunit 2 (MCCC2), an essential subunit of the leucine catabolic machinery. Accumulated leucine allosterically activates glutamate dehydrogenase to promote glutaminolysis, generating sufficient lipids and nucleotides to support hypoxic cell growth. Furthermore, SRC-mediated VHL phosphorylation and protein arginine methyltransferase 5 (PRMT5)-mediated MCCC2 methylation synergistically regulate the VHL-MCCC2 interaction and concomitant metabolic changes, which are recapitulated in animal models of ischemic injury and functionally associated with VHL mutations in cancer. Our study highlights VHL as a bona fide regulator of hypoxic metabolism within mitochondria, rather than a solely "standby adaptor" for HIFs under hypoxia.
    Keywords:  VHL; hypoxia; leucine; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.013
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