bims-glucam 2025-06-29 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–06–29
twenty-two papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine Metabolism: Molecular Regulation, Biological Functions, and Diseases.
The metabolic shift of glutaminase 2 to glutaminase 1 promotes LGR5 + progenitor cell proliferation in liver cirrhosis.
The Landscape of Cancer Metabolism as a Therapeutic Target.
TFDP1 activates SPC25-mediated glutamine metabolism to repress anti-tumor immunity of NK cells in lung adenocarcinoma.
Landscape of metabolic alterations and treatment strategies in breast cancer.
Targeting Glutamine Metabolism Transporter SLC25A22 Enhances CD8+ T-Cell Function and Anti-PD-1 Therapy Efficacy in Cervical Squamous Cell Carcinoma: Integrated Metabolomics, Transcriptomics and T-Cell-Incorporated Tumor Organoid Studies.
Optimizing Cellular Metabolism Through Mass Balance Analysis to Improve Skin Wound Healing.
Trained Immunity Induced by Oxidized Low-Density Lipoprotein Is Dependent on Glutaminolysis.
Metabolic Assays for Brain Cancer Cells.
ATF4 in proximal tubules modulates kidney function and modifies the metabolome.
Resistance of HEK-293 and COS-7 cell lines to oxidative stress as a model of metabolic response.
Ablation of LAT2 Transporter Causes Intramuscular Glutamine Accumulation and Inhibition of Fasting-Induced Proteolysis.
Long-Term Exposure to 6-PPD Quinone Inhibits Glutamate Synthesis and Glutamate Receptor Function Associated with Its Toxicity Induction in Caenorhabditis elegans.
Integrated functional genomics-identified DEAF1 in oxidative stress and hepatocellular carcinoma development.
The Identification of a Key Regulator of Mitochondrial Metabolism, the LRPPRC Protein, as a Novel Therapeutic Target in SDHA-Overexpressing Ovarian Tumors.
Unlocking the Distinct Roles of the Three Mammalian VDAC Isoforms in Mitochondrial Respiration and Cancer Cell Metabolism.
The Overlapping Biology of Sepsis and Cancer and Therapeutic Implications.
Endothelial Metabolic Zonation in the Vascular Network: A Spatiotemporal Blueprint for Angiogenesis.
SLC4A11 Revisited: Isoforms, Expression, Functions, and Unresolved Questions.
CcpA-mediated regulation of cellular energy metabolism in the ruminal bacterium Streptococcus bovis.
Cellular Uptake of Hybrid PLGA-Lipid Gadolinium Nanoparticles Functionalized for Magnetic Resonance Imaging of Pancreatic Adenocarcinoma Cells.
Metabolic communication in colorectal cancer liver metastasis: The role of l-glutamine and SLC3A2.

MedComm (2020). 2025 Jul;6(7): e70120

Glutamine Metabolism: Molecular Regulation, Biological Functions, and Diseases.

Mudasir A Kumar, Sana Khurshid Baba, Inamu Rashid Khan, Mohd Shahnawaz Khan, Fohad Mabood Husain, Saheem Ahmad, Mohammad Haris, Mayank Singh, Ammira S Al-Shabeeb Akil, Muzafar A Macha, Ajaz A Bhat.

  Glutaminolysis, the metabolic process of converting glutamine into key intermediates, plays an essential role in cellular energy production, signaling, biosynthesis, and redox balance. Deregulation of glutamine metabolism significantly influences various pathological conditions, including cancers and metabolic and neurological diseases. Emerging evidence shows that long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and oncogenic alterations in glutamine transporters and enzymes enhance glutamine's role as an alternative energy source, supporting cell survival and proliferation under nutrient and oxygen deprivation conditions. To combat the pathogenic effects of altered glutamine metabolism, researchers are developing targeted inhibitors of key enzymes and transporters involved in glutaminolysis. By interfering with the mechanisms that support the growth of cancer cells, these inhibitors may be able to stop the growth of tumors and treat metabolic and neurological conditions. This review provides a comprehensive overview of existing inhibitors and ongoing clinical trials targeting glutamine metabolism, focusing on its potential as a cancer therapeutic strategy. Additionally, the role of lncRNAs and circRNAs in regulating glutamine metabolism is explored, revealing novel avenues for therapeutic intervention in cancer and other diseases.

Keywords:  cancer; circular RNAs; glutamine metabolism; glutaminolysis; long noncoding RNAs; therapeutic targeting

DOI:  https://doi.org/10.1002/mco2.70120
Cell Mol Life Sci. 2025 Jun 23. 82(1): 251

The metabolic shift of glutaminase 2 to glutaminase 1 promotes LGR5 + progenitor cell proliferation in liver cirrhosis.

Defu Kong, Qi Zhou, Kang He, Janette Heegsma, Hans Blokzijl, Vincent E de Meijer, Klaas Nico Faber.

   BACKGROUND AND AIM: Liver regeneration is impaired in end-stage liver disease characterized by advanced fibrosis and cirrhosis, where metabolic reprogramming is considered as a therapeutic target. The shift in glutaminolysis from liver-type Glutaminase 2 (GLS2) to kidney-type Glutaminase 1 (GLS1) is crucial in different liver diseases, though its role in liver progenitor cell-mediated regeneration remains unclear. This study aimed to analyze the expression of glutamine-metabolizing enzymes in fibrotic human livers and investigate the role of GLS1 in LGR5+-progenitor cell expansion in liver regeneration.
METHODS: Healthy and chronically diseased human liver tissue from patients with alcoholic liver disease, viral hepatitis, biliary atresia, primary biliary cholangitis or non-alcoholic steatohepatitis were immunostained for GLS1, GLS2 and glutamine synthetase (GS), and co-stained for LGR5. GLS1 was inhibited in adult progenitor cell-rived human liver organoids to evaluate its role in stemness and cell proliferation pathways.
RESULTS: GLS1 expression was enhanced and GLS2 decreased in chronic liver diseases compared to healthy liver. GLS1 was expressed in parenchymal, including hepatocytes, and non-parenchymal cells. In cirrhotic livers, GLS1+ hepatocytes showed a spatial distribution comparable to the progenitor cell marker LGR5. The GLS1 inhibitor CB839 suppressed progenitor cell markers (LGR5 and AXIN2) via the ROS-Wnt/β-Catenin pathway, which was rescued by glutathione (GSH). The CB839-mediated decrease in cell proliferation in human liver organoids was rescued by non-essential amino acids.
CONCLUSIONS: This study identifies GLS1 as a metabolic regulator of progenitor cell expansion aiding liver regeneration in various etiologies of human liver cirrhosis.

Keywords:  GSH; Glutaminase 1; Glutamine metabolism; Liver fibrosis; Liver organoids; Proliferation

DOI:  https://doi.org/10.1007/s00018-025-05772-z
Pathol Int. 2025 Jun 24.

The Landscape of Cancer Metabolism as a Therapeutic Target.

Kenji Ohshima.

  Cancer cells reprogram their metabolism during progression to adapt to the tumor microenvironment, which is characterized by distinct differences in nutrient availability, oxygen concentrations, and acidity. This metabolic reprogramming can simultaneously create metabolic vulnerabilities unique to cancer cells, making cancer metabolism a promising therapeutic target. Since the clinical application of folate antimetabolites in the 1940s, numerous therapeutic strategies targeting cancer metabolism have been developed. In recent years, advancements in technologies such as metabolome analysis have facilitated the development of agents that more specifically target cancer cell metabolism. However, these newly developed agents often face challenges in demonstrating efficacy as monotherapies in clinical trials. Nevertheless, combination therapies, designed based on precise mechanistic insights and incorporating agents such as immune-checkpoint and signaling-pathway inhibitors, have shown promising efficacy. This review provides an overview of the current landscape of therapeutic strategies targeting cancer metabolism, with a particular focus on approaches targeting amino acid, fatty acid, and glucose metabolism in cancer cells.

Keywords:  amino acid metabolism; cancer metabolism; cancer therapy; combination therapy; fatty acid metabolism; glucose metabolism

DOI:  https://doi.org/10.1111/pin.70034
Expert Rev Clin Immunol. 2025 Jun 25. 1-11

TFDP1 activates SPC25-mediated glutamine metabolism to repress anti-tumor immunity of NK cells in lung adenocarcinoma.

Bin Huang, Keng Chen, Mingjiang Huang, Zhangyong Yin, Wei He, Xuyang Peng, Gongzhi Wu, Jianyang Ding, Congxiong Peng, Xuhui Wu.

   OBJECTIVES: The main purpose of this study is to investigate the specific role of SPC25 in the anti-tumor immune process of Natural killer (NK) cells in lung adenocarcinoma (LUAD).
METHODS: The differentially expressed gene SPC25 was screened by the Cancer Genome Atlas database. The effect of SPC25 on the anti-tumor immunity of NK cells was evaluated by immunofluorescence, flow cytometry, lactate dehydrogenase kit, and enzyme-linked immunosorbent assay. The influence of SPC25 on glutamine (GLN) metabolism was examined by the GLN metabolism-related kit and Western blot. The interaction between SPC25 and TFDP1 was assessed by luciferase reporter gene detection and ChIP.
RESULTS: SPC25 was overexpressed in LUAD (p < 0.0001), being capable of reducing levels of cytotoxicity and cytokines in NK cells. SPC25 repressed the function of NK cells by activating GLN metabolism (p < 0.0001). Mechanistically, TFDP1 was a transcriptional activator of SPC25. Knocking down TFDP1 hindered GLN metabolism (p < 0.05) and potentiated NK cell killing ability against LUAD cells, while overexpression of SPC25 reversed the effects of TFDP1 knockdown.
CONCLUSION: This study intended to verify the inhibitory effect of TFDP1 on NK cell anti-tumor immunity by activating SPC25-mediated LUAD glutamine metabolism.

Keywords:  SPC25; TFDP1; glutamine metabolism; lung adenocarcinoma; natural killer cells

DOI:  https://doi.org/10.1080/1744666X.2025.2524469
Genes Dis. 2025 Sep;12(5): 101521

Landscape of metabolic alterations and treatment strategies in breast cancer.

Xiujuan Wu, Xuanni Tan, Yangqiu Bao, Wenting Yan, Yi Zhang.

  Breast cancer, the most prevalent cancer in women, poses a significant threat to their health. One of the prominent characteristics of malignant transformation in breast cancer cells is metabolic reprogramming, which encompasses glucose, lipid, and amino acid metabolism. Notably, breast cancer cells exhibit augmented energy metabolism and heightened glycolysis. In addition, there is an escalated demand for glutamine, which is met through intrinsic synthesis, uptake from extracellular sources via membrane transport proteins, or up-regulation of key metabolic enzymes in the glutamine metabolism pathway. Lipids not only serve as an energy source for tumor cells but also function as signaling molecules for intercellular communication. Extensive research in recent years has focused on unraveling the intricate mechanisms underlying metabolic reprogramming. Consequently, genes implicated in these processes have emerged as clinical therapeutic targets for cancer treatment. This review provides a comprehensive summary of the common metabolic alterations observed in cancer cells, discusses the factors and regulatory mechanisms influencing these changes, and explores potential therapeutic targets and strategies within the realm of cancer metabolism.

Keywords:  Amino acid metabolism; Breast cancer; Glucose metabolism; Lipid metabolism; Metabolic alterations

DOI:  https://doi.org/10.1016/j.gendis.2025.101521
Adv Sci (Weinh). 2025 Jun 27. e02225

Targeting Glutamine Metabolism Transporter SLC25A22 Enhances CD8+ T-Cell Function and Anti-PD-1 Therapy Efficacy in Cervical Squamous Cell Carcinoma: Integrated Metabolomics, Transcriptomics and T-Cell-Incorporated Tumor Organoid Studies.

Tingting Ren, Junjun Qiu, Fanghua Chen, Qian Jiang, Qinqin Liu, Tong Wu, Hua Jiang, Keqin Hua.

  Cervical squamous cell carcinoma(CSCC) represents formidable challenge in clinical oncology, exacerbated by poor prognosis and resistance to current treatments, including anti-PD-1 therapy, highlighting the urgent need for alternative therapeuties. Metabolic characteristics have emerged as potential drivers of treatment resistance and immune evasion. Herein, 1) based on metabolomic and transcriptomic analyses of 44 CSCC and 18 normal tissues, glutamine-enriched and immunosuppressive microenvironment is identified in CSCC. 2) Integrative metabolomic and transcriptomic analyses revealed the glutamine metabolism transporter SLC25A22 as a key mediator in high glutamine metabolism, immune checkpoint activation and CD8+T-cell cytotoxicity. 3) Immunohistochemistry(IHC), multiplex IHC, and flow cytometry validation with clinical CSCC samples revealed not only increased SLC25A22, PD-1 expression and reduced CD8+T-cell cytotoxicity in CSCC but also increased SLC25A22 expression in high PD-L1 expressed CSCC patients, suggesting the potential of targeting SLC25A22 for enhancing CD8+T-cell cytotoxicity and improving anti-PD-1 efficacy, especially in high PD-L1 expressed patients. 4) Novelly, 3D-CSCC organoids are constructed, replicating parental tumor features, and 3D-T-cell-incorporated CSCC organoid models, replicating the interaction between tumor cells and CD8+T cells, for in vitro experiments. 5) Importantly, it is validated through in vitro 3D T-cell-incorporated CSCC organoid models and in vivo animal experiments that targeting the glutamine metabolism transporter SLC25A22, showed promise in enhancing CD8+T-cell cytotoxicity and sensitizing anti-PD-1 therapy. These findings provided insights for future clinical trials exploring metabolic modulation to improve immunotherapy responses in CSCC patients.

Keywords:  Cervical squamous cell carcinoma; anti‐PD‐1 therapy; glutamine metabolism; metabolic profiling; transcriptional analysis

DOI:  https://doi.org/10.1002/advs.202502225
Biology (Basel). 2025 Jun 18. pii: 722. [Epub ahead of print]14(6):

Optimizing Cellular Metabolism Through Mass Balance Analysis to Improve Skin Wound Healing.

Luis Ramirez Agudelo, Gabriel Yarmush, Suneel Kumar, Francois Berthiaume.

  Accelerating healing is a clinical goal in both acute and chronic non-healing skin wounds. We leveraged the public Recon database, which seeks to aggregate all of the metabolic pathways in the human body, to uncover whether increasing the supply of specific metabolites can bolster cellular metabolism and, in turn, enhance wound healing. The database was reduced to a set of 357 reactions and 339 metabolites that were better suited for human cells in culture. Monte Carlo simulations were performed to identify the impact of 25 different inputs on the metabolic fluxes within the cellular biochemical network. Biomass and ATP production were used as surrogate markers for cell proliferation and cell migration (an energy-intensive process), respectively, both of which are critical to wound healing. The subset of simulations yielding the highest ATP production or biomass production were those where glycine and/or glutamine uptake was increased. Maximizing ATP and biomass also generally increased oxygen uptake. Due to its low availability in chronic wounds, another set of simulations was carried out in which oxygen uptake was held constant to mimic the effect of a limited oxygen supply. However, even with this constraint, glycine and glutamine remained the most promising interventions. The predictions were tested in vitro using immortalized human keratinocytes. Amino acid uptake was tentatively increased by supplementing the base culture media with additional glycine and/or glutamine, with valine supplementation with a similar nitrogen load as a control. Glycine supplementation significantly increased cellular proliferation above the base media and accelerated wound closure rate in wound scratch assay. However, glutamine and valine supplementation did not improve these parameters above base media, and glutamine even suppressed the benefit of glycine in cultures supplemented with both amino acids. In conclusion, glycine supplementation enhances cellular processes that are associated with wound healing.

Keywords:  ATP synthesis; cell proliferation; keratinocytes; metabolic flux analysis; wound healing

DOI:  https://doi.org/10.3390/biology14060722
FASEB J. 2025 Jul 15. 39(13): e70774

Trained Immunity Induced by Oxidized Low-Density Lipoprotein Is Dependent on Glutaminolysis.

Alice Scarpa, Yerin Jung, Arslan Hamid, Vasiliki Matzaraki, Tushar More, Alexander Heinz, Laszlo Groh, Siroon Bekkering, Karsten Hiller, Leo A B Joosten, Mihai G Netea, Katarzyna Placek, Niels P Riksen.

  Atherosclerosis is a chronic inflammatory disease of the arterial wall that causes cardiovascular disease. Monocyte-derived macrophages are an important contributor to atherogenesis. Monocytes can become primed for higher responsiveness to secondary, unrelated stimuli-a phenomenon known as trained immunity-a process driven by intracellular metabolic and epigenetic reprogramming. Oxidized low-density lipoprotein (oxLDL) induces trained immunity by enhancing glycolysis and oxidative phosphorylation (OXPHOS). Glutamine is known to enter the Krebs cycle through glutaminolysis where it can be used for ATP synthesis via OXPHOS. We therefore explored the role of the glutaminolysis pathway in oxLDL-induced trained immunity. Primary human monocytes from healthy donors were exposed to oxLDL for 24 h, followed by differentiation into macrophages over 6 days in culture medium. Thereafter, cytokine production capacity was assessed by stimulating them with Toll-like receptor agonist. Co-administration of the glutaminase inhibitor CB-839 during oxLDL exposure reduces glutamine anaplerosis. This prevented oxLDL-induced trained immunity, with diminished cytokine production capacity, associated with a reduced oxygen consumption rate (OCR), and glycolysis rate (ECAR). The role of glutaminolysis for induction of trained immunity was validated genetically, by showing significant associations between several single-nucleotide polymorphisms in genes related to glutaminolysis and ex vivo cytokine production in oxLDL-trained monocytes from 243 healthy volunteers. Finally, we identified a positive correlation between glutamate and Krebs cycle metabolites with inflammatory circulating biomarkers and monocyte counts in an independent cohort of 302 obese individuals. Altogether, these data suggest a crucial role of glutaminolysis in the establishment of oxLDL-induced trained immunity.

Keywords:  Krebs cycle; atherosclerosis; glutamine; glutaminolysis; oxLDL; trained immunity

DOI:  https://doi.org/10.1096/fj.202500802R
Methods Mol Biol. 2025 ;2944 49-64

Metabolic Assays for Brain Cancer Cells.

Emma Martell, Harshal Senthil, Esha Kaul, Helgi Kuzmychova, Tanveer Sharif.

  Metabolism is a fundamental foundation of all living organisms. However, cancer cells can modulate their metabolic activity to maintain their enhanced bioenergetic needs associated with uncontrolled proliferation. Some hallmarks of cancer metabolism include enhanced glucose uptake capacity and aberrations in mitochondrial metabolic activity and ATP production. In this chapter, we will outline several methods for studying critical metabolic parameters in brain cancer cells.

Keywords:  ATP; Cancer; Glucose uptake; Metabolism; Oxygen consumption

DOI:  https://doi.org/10.1007/978-1-0716-4654-0_5
J Mol Med (Berl). 2025 Jun 21.

ATF4 in proximal tubules modulates kidney function and modifies the metabolome.

Yuling Chi, Eduardo Mere Del Aguila, Tuo Zhang, Charles D Warren, Helen R Hoxie, Qiuying Chen, Steven S Gross, Jacob B Geri, David M Nanus, Lorraine J Gudas.

  Activating transcription factor 4 (ATF4) is a transcription factor that mediates the response to stress at the cellular, tissue, and organism level. We deleted the gene encoding ATF4 in the proximal tubules of the mouse kidney by using a temporal and cell type-specific approach. We show that ATF4 plays a major role in regulating the transcriptome and proteome, which, in turn, influences the metabolome and kidney functions. Genome-wide transcriptomics and single-plot, solid-phase-enhanced sample preparation (SP3)-proteomics studies reveal that ATF4 deletion changes more than 30% of transcripts and, similarly, corresponding proteins in the proximal tubules. Gene Set Enrichment Analysis indicates major changes in transporters, including amino acid transporters. Metabolomic analyses show that these changes in transporters are associated with altered profiles of amino acids in the blood, kidney, and urine. Stable isotope glutamine tracing in primary tubule cells isolated from kidney cortices confirms that ATF4 regulates glutamine transport and metabolism. We suggest that even in the absence of additional stresses, such as kidney injury, ATF4 in the proximal tubules modulates both retention of specific nutrients and excretion of catabolic products like creatinine to maintain normal kidney function. KEY MESSAGES: Activating transcription factor 4 (ATF4) deletion changed more than 30% of genome-wide transcripts and corresponding proteins in the proximal tubules. One set of the profound changes occurred in amino acid transporters and Slc22 family transporters. Changes in transporters were accompanied by altered profiles of amino acids and wastes in the blood, kidney, and urine. ATF4 in the kidney proximal tubules plays a key role in regulating both the reabsorption of nutrients and the excretion of wastes.

Keywords:  Activating transcription factor 4 (ATF4); Kidney proximal tubules; Metabolomics; Proteomics; Transcriptomics; Transporters

DOI:  https://doi.org/10.1007/s00109-025-02559-4
Acta Biochim Pol. 2025 ;72 14164

Resistance of HEK-293 and COS-7 cell lines to oxidative stress as a model of metabolic response.

Monika Sapeta-Nowińska, Katarzyna Sołtys, Katarzyna Gębczak, Ewa Barg, Piotr Młynarz.

  Oxidative stress (OS), arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, plays a pivotal role in cellular dysfunction and the pathogenesis of numerous diseases. This study evaluates the impact of oxidative stress induced by hydrogen peroxide on the metabolomic profiles of the human embryonic kidney (HEK-293) and African green monkey kidney (COS-7) cell lines. Viability (MTT) and free radical accumulation (DCF-DA) assays confirmed a dose-dependent cytotoxic effect of hydrogen peroxide, with COS-7 cells exhibiting greater resistance and producing lower levels of intracellular ROS compared to HEK-293. Metabolomic profiling was conducted using nuclear magnetic resonance spectroscopy (1H NMR) to identify and quantify metabolic changes. Exposure to a free radical inducer significantly altered both intracellular and extracellular metabolites compared to control H2O2-free samples. The analysis revealed common changes in intracellular metabolites between the two lines, including glutamate, NAD+, glutathione, ATP/ADP, AMP, and pyruvate - key molecule for mitochondrial function, as well as extracellular metabolites such as glutamate, glutamine, acetate, lactate, and pyruvate. Metabolomic differences observed in COS-7 cells suggest a potentially greater capacity for metabolic adaptation to oxidative stress. These included elevated levels of branched-chain amino acids (BCAA), supporting energy production, and increased formate production, which may aid purine synthesis and cellular resilience. These findings highlight the distinct metabolic adaptations of COS-7 cells to oxidative stress in comparison to the HEK-293 cell line. They also provide insights into the direct cellular responses to altered redox potential, offering possible therapeutic strategies aimed at targeting metabolic pathways to mitigate oxidative stress.

Keywords:  TCA cycle; cell culture; metabolomics; oxidative stress; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3389/abp.2025.14164
J Cachexia Sarcopenia Muscle. 2025 Jun;16(3): e13847

Ablation of LAT2 Transporter Causes Intramuscular Glutamine Accumulation and Inhibition of Fasting-Induced Proteolysis.

Meritxell Espino-Guarch, Susie Shih Yin Huang, Clara Vilches, Esther Prat, Rana El Nahas, Ghalia Missous, Susanna Bodoy, Abbirami Sathappan, Mohammad Ameen Al-Aghbar, Clara Mayayo, Montse Olivé, Silvia Busquets-Rius, David Sebastián, Antonio Zorzano, Manuel Palacin, Nicholas van Panhuys, Virginia Nunes.

   BACKGROUND: The neutral amino acid transporter SLC7A8 (LAT2) has been described as a key regulator of metabolic adaptation. LAT2 mutations in human populations have been linked to the early onset of age-related hearing loss and cataract growth. As LAT2 was previously found to be highly expressed in skeletal muscle, here we characterised its role in the regulation of skeletal muscle amino acid flux and metabolic adaptation to fasting.
METHODS: Wild-type (WT) and LAT2 knock-out (LAT2KO) mice were exposed to short- and long-periods of fasting (16 and 48 h). The impact of the absence of LAT2 on amino acid content, gene expression, proteolysis activity, muscle tone, and histology was measured. To characterise the impact on muscle degradation, we tested LAT2 KO mice in cancer-associated cachexia, streptozocin-induced Type-1 diabetes, and ageing models.
RESULTS: LAT2KO mice experienced a notable reduction in body weight during fasting (WT:14% and LAT2KO:18%, p = 0.02), with a greater reduction in fat mass (0.5-fold, p = 0.013) and a higher relative retention of muscle mass (1.3-fold, p = 0.0003) compared with WT. The absence of LAT2 led to increased intramuscular glutamine (Gln) accumulation (6.3-fold, p < 0.0001), accompanied by a reduction in skeletal muscle proteolysis during fasting (0.61-fold, p = 0.0004) primarily due to decreased proteasomal and autophagic activity (0.45-fold, p = 0.016 and 0.7-fold, p = 0.002, respectively). Ex vivo incubation of LAT2KO muscle with rapamycin recovered proteolysis function, demonstrating a mTORC1-dependent pathway. Decreased proteolysis in LAT2KO animals was associated with increased mTORC1 translocation to the lysosome (mTORC1-Lamp1 colocalization in fasted LAT2KO muscles was 1.23-fold, p < 0.0001). Of the three muscle loss models tested, differences were observed only during ageing. Young LAT2KO mice (3 M) exhibited muscle tone and MurF1 expression levels comparable to those of older WT mice (12 M) (0.44-fold, p = 0.02 and 0.48-fold, p = 0.04, respectively).
CONCLUSION: LAT2 has a critical role in regulating Gln efflux from skeletal muscle. The absence of LAT2 led to elevated intracellular Gln levels, impairing muscle proteolysis by inducing mTORC1 recruitment to the lysosome. Further, chronic Gln accumulation and decreased proteolysis were found to induce the early onset of an age-related muscle phenotype.

Keywords:  LAT2; ageing; glutamine; mTORC1; proteolysis; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13847
Toxics. 2025 May 26. pii: 434. [Epub ahead of print]13(6):

Long-Term Exposure to 6-PPD Quinone Inhibits Glutamate Synthesis and Glutamate Receptor Function Associated with Its Toxicity Induction in Caenorhabditis elegans.

Wei Wang, Yunhui Li, Dayong Wang.

  6-PPD quinone (6-PPDQ) is widely distributed in environments. In Caenorhabditis elegans, we first examined the effects of 6-PPDQ on glutamate synthesis and receptor function by analyzing glutamate content, related gene expression, and phenotypes after RNAi of these genes. Moreover, we performed glutamate treatment after 6-PPDQ exposure to determine the potential pharmacological effects of glutamate against 6-PPDQ toxicity. After exposure, the glutamate content was reduced by 0.1-10 μg/L 6-PPDQ, which was due to decreased expression of W07E1.1, glna-1/2/3, and alh-6 governing glutamate synthesis from α-ketoglutarate, glutamine, and proline. RNAi of W07E1.1, glna-1/2/3, and alh-6 decreased glutamate content in 6-PPDQ-exposed nematodes, and caused susceptibility to 6-PPDQ toxicity. Among glutamate transporter genes, glt-1 expression was decreased by 0.1-10 μg/L 6-PPDQ. Moreover, 0.1-10 μg/L 6-PPDQ decreased glutamate receptor genes (glr-1, glr-2, and glr-4), and their expression was decreased by RNAi of W07E1.1, glna-1/2/3, alh-6, and glt-1. RNAi of these receptor genes resulted in susceptibility to 6-PPDQ toxicity, and daf-7, jnk-1, and dbl-1 were identified as targets of neuronal glr-1, glr-2, and glr-4. Furthermore, 5 mM glutamate suppressed 6-PPDQ toxicity and increased expression of glr-1, glr-2, and glr-4. Our results demonstrated the risk of 6-PPDQ exposure in disrupting glutamate synthesis and affecting function of glutamate receptors, which was related to 6-PPDQ toxicity induction.

Keywords:  6-PPDQ toxicity; glutamate metabolism; glutamate receptor; nematode

DOI:  https://doi.org/10.3390/toxics13060434
Carcinogenesis. 2025 Jun 24. pii: bgaf032. [Epub ahead of print]

Integrated functional genomics-identified DEAF1 in oxidative stress and hepatocellular carcinoma development.

Linying Huang, Xinyuan Yu, Ziqi Zhang, Yanfei Huo, Long Zhang, Nasha Zhang, Ming Yang.

  Hepatocellular carcinoma (HCC) is the third most common cause of death for cancer patients globally, with the overall 5-year survival rate of only 16%. The molecular mechanisms leading to malignant progression of HCC patients remain largely unclear. Hepatocyte nuclear factor 4α (HNF4α) functions as a tumor suppressive transcription factor (TF) in HCC. In this study, we aimed to identify functional HCC susceptibility single nucleotide polymorphisms (SNPs) in HNF4α-binding sites throughout the human genome. We identified 1,274 HNF4α-binding site polymorphisms via a genome-wide screening using TUIFGA (The Updated Integrative Functional Genomics Approach) which we previously developed to recognize cancer susceptibility SNPs within genome-wide TF-binding sites. Among these SNPs, the DEAF1 rs11246280 SNP was significantly associated with HBV-related HCC susceptibility in several case-control studies. Importantly, the rs11246280 SNP could interrupt HNF4α-binding to the DEAF1 promoter and enhance DEAF1 expression. Oncogenic TF DEAF1 binds to the SLC38A3 promoter, elevates glutamine transporter SLC38A3 expression, enhances influx of glutamine and GSH production, leads to reduced ROS levels in cells and, thereby, promotes HCC progression. Our findings highlighted the role of DEAF1 during HCC development via maintaining redox balance, which sheds light on the development of novel cancer therapeutics.

Keywords:  DEAF1; HNF4α; genetic susceptibility; hepatocellular carcinoma; reactive oxygen species

DOI:  https://doi.org/10.1093/carcin/bgaf032
Cancers (Basel). 2025 Jun 11. pii: 1942. [Epub ahead of print]17(12):

The Identification of a Key Regulator of Mitochondrial Metabolism, the LRPPRC Protein, as a Novel Therapeutic Target in SDHA-Overexpressing Ovarian Tumors.

Anna Szulta, Lin Wang, Ameera Hasan, Michael Kinter, Atul Pranay, Jie Zhu, Kenneth M Humphries, Brooke Loveland, Timothy M Griffin, Magdalena Bieniasz.

  Background: Ovarian cancer is the deadliest of all gynecologic malignancies due to limited therapeutic options. Our data show that the tumor-specific metabolism of ovarian cancer could be effectively targetable, which highlights a path for new anti-cancer therapies. Methods and Results: Our work shows that the upregulation of mitochondrial enzyme SDHA is particularly prevalent in ovarian carcinoma. SDHA overexpression significantly induced orthotopic ovarian tumor growth, reducing mouse survival. We showed that SDHA-overexpressing tumors depend on glutaminolysis and increased activity of the tricarboxylic acid (TCA) cycle coupled with mitochondrial oxidative phosphorylation (OXPHOS), which are essential for high-energy metabolism and cell survival. We identified a distinctive vulnerability of SDHA-overexpressing tumors to agents targeting regulators of the OXPHOS pathway, particularly the LRPPRC protein. LRPPRC is a key regulator of mitochondrial energy metabolism, promoting OXPHOS and ATP generation. However, when overexpressed, the LRPPRC acts as a tumor oncogene. Our analysis of SDHA and LRPPRC gene and protein expression patterns in precursor lesions and established ovarian cancer demonstrated that the upregulation of SDHA is accompanied by LRPPRC overexpression, notably in advanced tumors. Our novel findings highlight for the first time a potential functional interaction between SDHA and LRPPRC in the development and progression of ovarian malignancy. Importantly, our in vivo data showed that pharmacological inhibition of LRPPRC results in a lasting therapeutic benefit and can be an effective therapy in SDHA- and LRPPRC-overexpressing ovarian tumors. Conclusions: Overall, our study underlines an understudied role of concomitant overexpression of SDHA and LRPPRC in ovarian cancer pathogenesis, highlighting new paths for therapeutic development.

Keywords:  LRPPRC; OXPHOS; SDHA; high-grade serous ovarian cancer; metabolism; ovarian cancer; patient-derived xenograft; shikonin; succinate dehydrogenase

DOI:  https://doi.org/10.3390/cancers17121942
bioRxiv. 2025 Apr 07. pii: 2025.02.20.639106. [Epub ahead of print]

Unlocking the Distinct Roles of the Three Mammalian VDAC Isoforms in Mitochondrial Respiration and Cancer Cell Metabolism.

Megha Rajendran, William M Rosencrans, Wendy Fitzgerald, Diana Huynh, Bethel G Beyene, Baiyi Quan, Julie Hwang, Nina A Bautista, Tsui-Fen Chou, Sergey M Bezrukov, Tatiana K Rostovtseva.

The Voltage Dependent Anion Channel (VDAC) is the most ubiquitous protein in the mitochondrial outer membrane. This channel facilitates the flux of water-soluble metabolites and ions like calcium across the mitochondrial outer membrane. Beyond this canonical role, VDAC has been implicated, through interactions with protein partners, in several cellular processes such as apoptosis, calcium signaling, and lipid metabolism. There are three VDAC isoforms in mammalian cells, VDAC 1, 2, and 3, with varying tissue-specific expression profiles. From a biophysical standpoint, all three isoforms can conduct metabolites and ions with similar efficiency. However, isoform knockouts (KOs) in mice lead to distinct phenotypes, which may be due to differences in VDAC isoform interactions with partner proteins. To understand the functional role of each VDAC isoform within a single cell type, we created functional KOs of each isoform in HeLa cells and performed a comparative study of their metabolic activity and proteomics. We found that each isoform KO alters the proteome differently, with VDAC3 KO dramatically downregulating key members of the electron transport chain (ETC) while shifting the mitochondria into a glutamine-dependent state. Importantly, this unexpected dependence of mitochondrial function on the VDAC3 isoform is not compensated by the more ubiquitously expressed VDAC1 and VDAC2 isoforms. In contrast, VDAC2 KO did not affect respiration but upregulated ETC components and decreased key enzymes in the glutamine metabolic pathway. VDAC1 KO specifically reduced glycolytic activity linked to decreased hexokinase localization to mitochondria. These results reveal non-redundant roles of VDAC isoforms in cancer cell metabolic adaptability.

DOI: https://doi.org/10.1101/2025.02.20.639106
Biomedicines. 2025 May 23. pii: 1280. [Epub ahead of print]13(6):

The Overlapping Biology of Sepsis and Cancer and Therapeutic Implications.

Amit Kumar Tripathi, Yogesh Srivastava.

  Sepsis and cancer, though distinct in their clinical manifestations, share profound pathophysiological overlaps that underscore their interconnectedness in disease progression and outcomes. Here we discuss the intricate biological mechanisms linking these two conditions, focusing on the roles of inflammation, immune dysregulation, and metabolic alterations. In sepsis, an uncontrolled immune response to infection leads to a cytokine storm, tissue damage, and immune paralysis, while cancer exploits chronic inflammation and immunosuppressive pathways to promote tumor growth and metastasis. Both conditions exhibit metabolic reprogramming, such as the Warburg effect in cancer and glycolysis-driven immune cell activation in sepsis, which fuels disease progression and complicates treatment. Sepsis can exacerbate cancer progression by inducing genomic instability, epigenetic modifications, and a pro-tumorigenic microenvironment, while cancer increases susceptibility to sepsis through immunosuppression and treatment-related complications. The shared pathways between sepsis and cancer present unique opportunities for therapeutic intervention, including anti-inflammatory agents, immune checkpoint inhibitors, and metabolic modulators. Anti-inflammatory therapies, such as IL-6 and TNF-α inhibitors, show promise in mitigating inflammation, while immune checkpoint inhibitors like anti-PD-1 and anti-CTLA-4 antibodies are being explored to restore immune function in sepsis and enhance antitumor immunity in cancer. Metabolic modulators, including glycolysis and glutaminolysis inhibitors, target the metabolic reprogramming common to both conditions, though their dual roles in normal and pathological processes necessitate careful consideration. Additionally, antimicrobial peptides (AMPs) represent a versatile therapeutic option with their dual antimicrobial and antitumor properties. In this review, we also highlight the critical need for integrated approaches to understanding and managing the complex interactions between sepsis and cancer. By bridging the gap between sepsis and cancer research, this work aims to inspire interdisciplinary collaboration and advance the development of targeted therapies that address the shared mechanisms driving these devastating diseases. Ultimately, these insights may pave the way for novel diagnostic tools and therapeutic strategies to improve outcomes for patients affected by both conditions.

Keywords:  cancer; cytokines; immune response; immunosuppression; inflammation; sepsis; therapeutic targets; tumor microenvironment

DOI:  https://doi.org/10.3390/biomedicines13061280
Am J Physiol Heart Circ Physiol. 2025 Jun 27.

Endothelial Metabolic Zonation in the Vascular Network: A Spatiotemporal Blueprint for Angiogenesis.

Kesha K Dalal, Venkatesh Katari, Narendra Kondapalli, Sailaja Paruchuri, Charles K Thodeti.

  Angiogenesis, a cornerstone of vascular development, tissue regeneration, and tumor progression, is critically orchestrated by the metabolic behavior of endothelial cells (ECs). Recent discoveries have redefined ECs not as metabolically uniform entities, but as spatially and functionally heterogeneous populations whose metabolic states govern their angiogenic potential. This review presents a comprehensive synthesis of metabolic zonation in ECs, spanning arterial, venous, and capillary domains, and highlights cell-type-specific programs during sprouting angiogenesis-including tip, stalk, and phalanx cells. We explore how distinct metabolic pathways-glycolysis, oxidative phosphorylation, fatty acid oxidation, and glutaminolysis-are differentially utilized across tissue contexts such as the brain, skeletal muscle, kidney, and tumor microenvironments. We discuss technological breakthroughs in spatial metabolomics, temporal (circadian) regulation of endothelial metabolism, and emerging clinical strategies to target EC metabolic vulnerabilities in cancer and ischemic diseases. Furthermore, we advocate for spatiotemporal modeling of EC metabolism using computational and machine learning frameworks to predict angiogenic behavior and accelerate therapeutic discovery. This integrative perspective underscores the need for precision-targeted angiogenic interventions and establishes metabolic zonation as a foundational principle in vascular biology.

Keywords:  angiogenesis; endothelial cell; energy; glycolysis; metabolism

DOI:  https://doi.org/10.1152/ajpheart.00352.2025
Biomolecules. 2025 Jun 16. pii: 875. [Epub ahead of print]15(6):

SLC4A11 Revisited: Isoforms, Expression, Functions, and Unresolved Questions.

Polina Alekseevna Kovaleva, Elena Sergeevna Kotova, Elena Ivanovna Sharova, Liubov Olegovna Skorodumova.

  The SLC4A11 gene encodes a membrane transporter implicated in congenital hereditary endothelial dystrophy, Harboyan syndrome, and certain cancers. Despite its clinical importance, current data on SLC4A11 expression patterns, transcript variants, and functional roles remain inconsistent and sometimes contradictory. We have systematized existing data, identified areas of consensus, and highlighted discrepancies. This review addresses SLC4A11 transcript and isoform diversity and how this complexity influences both the interpretation of its tissue expression patterns (particularly in the corneal endothelium) and the investigation of its functional roles in health and disease. Our review also untangles the evolving understanding of SLC4A11 function, from its initial classification as a bicarbonate transporter to its established roles in NH3- and pH-regulated H+/OH- transport, lactate efflux, cellular stress responses, and adhesion. The review details how pathogenic mutations disrupt protein maturation, membrane localization, or transport activity, contributing to corneal fluid imbalance and disease. We also discuss the emerging role of SLC4A11 in cancer metabolism and the common metabolic features of dystrophic corneas and tumors. Methodological challenges are appraised, encouraging caution in interpretation and the need for isoform-specific studies. Overall, this review provides a comprehensive update on SLC4A11 biology and identifies key gaps for future research.

Keywords:  Fuchs endothelial corneal dystrophy; Harboyan syndrome; SLC4A11; ammonia; cancer; congenital hereditary endothelial dystrophy; cornea; corneal endothelium; glutamine; lactate; variants

DOI:  https://doi.org/10.3390/biom15060875
Microbiol Spectr. 2025 Jun 25. e0215024

CcpA-mediated regulation of cellular energy metabolism in the ruminal bacterium Streptococcus bovis.

Yunan Weng, Yaqian Jin, Wenze Zhang, Lihong Wang, Hongrong Wang.

  This study investigated the cellular energy metabolite profiles of Streptococcus bovis S1. Glucose concentrations of 5 or 50 mM and the presence or absence of ccpA were applied during the cultivation of S. bovis S1. Results revealed the identification of 51 metabolites categorized into seven types: amino acid derivatives, amino acids, coenzymes and vitamins, nucleotides and their metabolites, organic acids and their derivatives, phosphate sugars, and phosphoric acids. Each group exhibited distinct cellular energy metabolite profiles, as evidenced by principal component analysis showing unique metabolite compositions. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) further distinguished between each pair of groups. KEGG prediction indicated that the abundance and enrichment of metabolites were primarily involved in carbon metabolism, amino acid metabolism, and nucleotide metabolomics. Based on the random forest algorithm, glutamine and UDP-GlcNac were identified as biomarkers under varying glucose conditions and in the presence or absence of ccpA. Further analysis reveals that low glucose restricts carbon flux to the Embden-Meyerhof-Parnas (EMP) pathway, while ccpA knockout further reduces flux through this pathway. Glucose and CcpA might regulate fructose-1,6-bisphosphate (FBP) concentration to modulate lactate dehydrogenase and pyruvate formate-lyase enzyme activity, thereby influencing the fermentation direction of pyruvate. In low-glucose environments, glutamine serves to alleviate glucose deficiency, and the interaction between glucose and CcpA may mediate the fate of amino acids differently. Low glucose limits guanine synthesis but not adenine, cytosine, or thymine synthesis, while ccpA knockout disrupts both synthesis pathways by inhibiting the pentose phosphate pathway (PPP). Overall, this study provides insights into the intricate interplay between glucose concentration, ccpA knockout, and cellular energy metabolism in Streptococcus bovis S1.IMPORTANCES. bovis S1 plays a pivotal role in lactate production in the rumen, increasing the risk of rumen acidosis. Modulating the fermentation profile of S. bovis S1 could reduce lactate accumulation, potentially improving rumen health. In this study, ccpA knockout decreased fermentation fluid lactate concentration but increased formate concentration. Liquid chromatography tandem mass spectrometry characterized the metabolic activity of S. bovis S1 under varying glucose concentrations. We found that CcpA regulates central carbon metabolism, including the EMP pathway, gluconeogenesis, and the PPP in S. bovis S1. Additionally, glucose and CcpA likely influence pyruvate fermentation, directing it toward lactate or formate production by modulating FBP concentrations. These findings underscore the regulatory roles of glucose concentration and CcpA in metabolic pathways, particularly in fermentation and energy metabolism in S. bovis S1.

Keywords:  KEGG pathway; Streptococcus bovis S1; catabolite control protein A; ccpA; energy metabolism; random forest

DOI:  https://doi.org/10.1128/spectrum.02150-24
ACS Nanosci Au. 2025 Jun 18. 5(3): 184-195

Cellular Uptake of Hybrid PLGA-Lipid Gadolinium Nanoparticles Functionalized for Magnetic Resonance Imaging of Pancreatic Adenocarcinoma Cells.

Alessandro Amaolo, Hanieh Sadeghi, Carla Carrera, Sergio Padovan, Fabio Carniato, Enza Di Gregorio, Giuseppe Ferrauto.

  Pancreatic adenocarcinoma (PDAC) presents significant diagnostic challenges, necessitating improved imaging techniques. Here, we develop hybrid poly-(lactic-co-glycolic acid) (PLGA)-phospholipid nanoparticles (NPs) loaded with gadolinium (Gd) chelates and functionalized with albumin, adenosine, or glutamine to boost their internalization in PDAC cells and increase the detectability by magnetic resonance imaging (MRI). Gd-PLGA NPs were synthesized using an oil-in-water emulsion solvent extraction method and incorporating DSPE-PEG(2000)-methoxy and DPPE-PEG(2000) N-Hydroxysuccinimide (NHS) for surface functionalization with albumin, adenosine, or glutamine. NPs were characterized by dynamic light scattering for particle size and ζ potential measurements, in addition to 1H NMR and proton nuclear magnetic relaxation dispersion to assess relaxivity and contrastographic properties, and stability studies were conducted in both HEPES-buffered saline and human serum. Reported studies demonstrated that all the preparations display a good stability, a hydrodynamic diameter lower than 200 nm, and a slight negative surface charge, with good potential for applications in cells and in vivo. In vitro studies on MiaPaca2 and Panc1 cell lines confirmed that functionalized NPs display higher cellular uptake and stronger MRI signal enhancement than unconjugated controls, with albumin-PLGA-lipid NPs leading to the greatest uptake. Our findings highlight a promising route toward a more sensitive, targeted MRI of PDAC, calling for in vivo studies to assess diagnostic potential and therapeutic applications.

Keywords:  PLGA; magnetic resonance imaging; molecular imaging; nanoparticles; pancreatic cancer; theranostic

DOI:  https://doi.org/10.1021/acsnanoscienceau.5c00010
Int Immunopharmacol. 2025 Jun 20. pii: S1567-5769(25)01105-1. [Epub ahead of print]162 115115

Metabolic communication in colorectal cancer liver metastasis: The role of l-glutamine and SLC3A2.

Yang Li, Feng Mo, Hua Mu, Jie Zhi, Zhifei Xin, Wujie Zhao, Qingxia Li, Yitao Jia.

  Colorectal cancer (CRC) liver metastasis involves complex interactions between tumor cells and the microenvironment, but the mechanisms remain unclear. This study identified macrophage-derived l-glutamine as a key metabolite driving communication between macrophages and CRC cells in liver metastases. Macrophages produced l-glutamine, which CRC cells sensed through the metabolic regulatory role of SLC3A2. This sensing process influenced the activation of genes linked to cell adhesion, including enhancer-driven genes regulated by the transcription factor FOXA2. Knocked down SLC3A2 in metastatic CRC cells reduced FOXA2 expression, impairing cell proliferation and adhesion to hepatocytes. Overexpressed FOXA2 in these cells partially restored their proliferation and adhesion abilities. These findings highlight that macrophage-derived l-glutamine promoted CRC cell proliferation and adhesion by regulating FOXA2 activity through SLC3A2-mediated metabolic sensing. This study has uncovered a novel mechanism of metabolite-mediated communication and epigenetic regulation in CRC liver metastases, providing potential therapeutic targets.

Keywords:  Colorectal Cancer; FOXA2; Liver metastasis; Macrophages; SLC3A2; l-glutamine

DOI:  https://doi.org/10.1016/j.intimp.2025.115115