bims-glucam 2025-10-26 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–10–26
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells.
Suppressing glutamine metabolism in the pancreatic cancer microenvironment can enhance the anti-tumor effect of CD8 T cells and promote the efficacy of immunotherapy.
Targeting glutamine catabolism suppresses eosinophil expansion and activation to alleviate allergic airway inflammation.
Inhibition of glutamine synthetase enhances hepatocellular carcinoma radiosensitivity through ROS-induced excessive mitophagy.
KRAS/ACTN4/p65-NR2A axis mediates glutamine-glutamate metabolic coupling between schwann cells and pancreatic cancer promoting perineural invasion.
SIRT6 promotes intrahepatic cholangiocarcinoma development by reprogramming glutamine metabolism via enhanced GLUL.
Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia.
Glutamine synthetase loss in β-catenin-mutant hepatocellular carcinoma promotes tumor burden through macrophage metabolic reprogramming.
Combined supplementation of leucine and glutamine acts as a novel therapeutic approach to alleviate hyperglycemia and oxidative stress by targeting insulin signalling genes in a drosophila model of type 2 diabetes.
Metabolic reprogramming in diabetes and other endocrine and metabolic disorders: exploring the Warburg effect, ketones, and SGLT2 inhibitors.
Dual metabolic targeting liposomes potentiate triple-negative breast cancer radiosensitivity via glucose and glutathione starvation.
Genome-scale metabolic modeling and machine learning unravel metabolic reprogramming and mast cell role in lung cancer: a multi-level analysis.
PMP2 Enhances Schwann Cell Metabolism and Promotes Myelination.
The Emerging Role of Metabolic Interventions in Uveal Melanoma.
Glutamine Potentiates Cefoperazone-Sulbactam Activity against Acinetobacter baumannii by Increasing Drug Uptake and ROS.
Genome-wide CRISPR screening identifies genes in recombinant human embryonic kidney 293 cells for increased ammonia resistance.
Kir5.1-modulated potassium flux stimulates an anabolic kidney phenotype.

Sci Rep. 2025 Oct 23. 15(1): 37028

Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells.

Martina Spada, Cristina Piras, Vera Piera Leoni, Mattia Casula, Gabriella Simbula, Antonio Noto, Katia Lilliu, Karolina Krystyna Kopeć, Gabriele Serreli, Federica Murgia, Federica Etzi, Tinuccia Dettori, Luigi Atzori, Paola Caria.

  Colorectal cancer (CRC) cells are 'addicted' to glutamine to satisfy energy and biosynthetic needs. Inhibiting glutamine metabolism enzymes, like glutaminase, is a potential cancer therapy strategy. Although the GLS inhibitor CB-839 is being evaluated in clinical trials, a comprehensive assessment of its antitumor activity in CRC cells is crucial. The present study aimed to evaluate the impact of CB-839 treatment on different CRC cell lines in terms of survival and proliferation. Furthermore, metabolic adaptations resulting from CB-839 treatment, particularly in energetic pathways, were investigated. Three CRC cell lines (HCT116, HT29, and SW480) were treated with different CB-839 concentrations. Cytotoxicity was assessed via MTT assay, proliferation capacity by flow cytometry, and ATP production rates by Seahorse XF analysis. Moreover, metabolomic profile was explored with untargeted GC-MS and 1H-NMR, and targeted analysis of the Krebs cycle was conducted using GC-MS/MS. HT29 cells exhibited the highest sensitivity to CB-839. Subsequent experiments focused on HT29 and SW480 cells. CB-839 treatment altered cell cycle progression and increased glycolytic ATP production in HT29 cells. Metabolomic analysis revealed changes in Krebs cycle and glutaminolysis in both cell lines, along with alterations in amino acids, sugars, antioxidants, and organic acid levels. This study highlighted glutamine's key role in CRC cells and provided a foundation for elucidating the mechanisms of response and resistance to CB-839.

Keywords:  CB-839; Colorectal cancer; Energetic metabolism; Glutaminase-1 inhibition; Glutamine metabolism; Glutaminolysis

DOI:  https://doi.org/10.1038/s41598-025-20528-2
Front Immunol. 2025 ;16 1599252

Suppressing glutamine metabolism in the pancreatic cancer microenvironment can enhance the anti-tumor effect of CD8 T cells and promote the efficacy of immunotherapy.

Jun Fan, Jianfei Chen, Rui Wang, Yisheng Peng, Sunde Tan, Xi Zhang, Hao Tang, Maoshan Chen, Bo Li, Xiaoli Yang.

   Objective: This study aims to investigate the relationship between tumor cell glutamine metabolism and CD8 T cells, with the goal of providing new insights to improve immunotherapy for pancreatic cancer.
Methods: Using the The Cancer Genome Atlas - Pancreatic Adenocarcinoma (TCGA-PAAD) cohort, we computed gene expression scores related to glutamine metabolism and stratified patients into high- and low-score groups. Prognosis and differences in immune cell anti-tumor activity were compared between these groups. We further utilized single-cell RNA sequencing data to quantitatively assess the expression of glutamine metabolism-related pathways in tumor cells. Based on tumor-specific glutamine metabolism gene expression, patients were again classified into high- and low-score groups. The immune remodeling effects exerted by tumor cell glutamine metabolism on CD8 T cells were subsequently investigated. To examine the impact of perturbing glutamine metabolism within the tumor microenvironment on CD8 T cell phenotype and the efficacy of PD-1 inhibitors, we conducted in vivo animal experiments.
Results: we analyzed the pancreatic cancer dataset in the cancer gene atlas database. We found that tumor glutamine metabolism was negatively correlated with patient prognosis and anti-tumor activity. Next, we defined two types of CD8 effector T cells in single-cell RNA sequencing data, namely, effector memory T cells (CD8-Tem) and terminally differentiated effector memory T cells (CD8-Temra). Under the pressure of high glutamine metabolism in tumor cells, the cytotoxicity of the CD8-Tem subset was reduced, and its immaturity score increased, while the exhaustion score of the CD8-Temra subset increased. Pseudotime analysis showed that CD8-Tn in the low-scoring group mainly developed into CD8-Tem subset, and its immune activation pathway was significantly upregulated. In addition, we found that the glutamine metabolism inhibitor JHU083 promoted the infiltration of CD4 and CD8 T cells and T lymphocyte differentiation, and increased the efficacy of PD-1 inhibitors. Glutamine inhibitors can inhibit the apoptosis of immune cells in the tumor microenvironment, while promoting CD8 T cells activation and cytotoxicity increase.
Conclusion: Inhibition of glutamine metabolism within the pancreatic cancer microenvironment results in reduced apoptosis of immune cells, heightened activation and cytotoxicity of CD8 T cells, and a substantial enhancement in the therapeutic efficacy of immunotherapy.

Keywords:  CD8 T cells; JHU083; glutamine; immunotherapy; pancreatic cancer

DOI:  https://doi.org/10.3389/fimmu.2025.1599252
Biochem Pharmacol. 2025 Oct 20. pii: S0006-2952(25)00708-7. [Epub ahead of print]242(Pt 4): 117443

Targeting glutamine catabolism suppresses eosinophil expansion and activation to alleviate allergic airway inflammation.

Xufei Du, Yuejue Wang, Jiaqi Huang, Niv Vigder, Taili Jin, Zhengyuan Liu, Wen Hua, Wen Li, Fei Li.

  Eosinophils are central immunoregulatory and effector cells in type 2 immunity and play a pivotal role in asthma pathogenesis. However, the metabolic mechanisms that govern eosinophil expansion and activation remain poorly defined. Here, we show that glutamine metabolism is extensively reprogrammed during eosinophil expansion and activation, as revealed by unbiased RNA-seq transcriptomics, liquid chromatography mass spectrometry (LC-MS)-based metabolomics and stable isotope tracing analyses. Through targeted screening, we found that pharmacological inhibition of glutaminase (GLS1) or pan-transaminase activities using CB839 or aminooxyacetic acid (AOA), respectively, attenuates eosinophil expansion potently in vitro. Using transcriptomic, proteomic, and cytokine array analyses, we reveal that glutamine drives a coordinated transcriptional and translational response that supports a pro-inflammatory signature in cytokine-activated eosinophils in vitro, and that this process is dependent on glutaminase and transaminase enzyme activity. Notably, the AOA-induced inhibition of eosinophil activation was reversed completely by supplementation of cells with non-essential amino acids (NEAAs) in vitro, consistent with its lack of efficacy in attenuating airway inflammation in an ovalbumin (OVA)-induced asthma model in vivo. In contrast, CB839 significantly decreased eosinophil infiltration, tissue pathology, and inflammatory cytokine expression in vivo. Together, these findings uncover an essential role for glutamine metabolism in eosinophil biology and identify GLS1 inhibition by CB839 as a promising therapeutic strategy for eosinophilic asthma.

Keywords:  Asthma; CB839; Eosinophil; Glutamine metabolism; Multi-omic

DOI:  https://doi.org/10.1016/j.bcp.2025.117443
Mol Biol Rep. 2025 Oct 23. 53(1): 5

Inhibition of glutamine synthetase enhances hepatocellular carcinoma radiosensitivity through ROS-induced excessive mitophagy.

Rao Liu, Guangyu Ju, Yijun Lu, Xiao Liu, Qi Ding, Kaiwei Wang, Hongcang Gu, Junchao Qian.

   BACKGROUND: Glutamine' synthetase (GS) plays a central role in glutamine metabolism and has been implicated in the progression and treatment resistance of hepatocellular carcinoma (HCC). Although previous studies have explored GS in tumor metabolism, its role in modulating mitophagy and radiosensitivity in HCC cells remains unclear.
METHODS: We analyzed GS expression in HCC using data from the TCGA database, followed by treatment of HepG2, Hep3B and Huh7 cells with the GS inhibitor L-methionine sulfoximine (MSO) and exposure to ionizing radiation. Cellular responses were evaluated through CCK-8 assays, Western blotting, immunofluorescence, flow cytometry, colony formation assays, and mitochondrial membrane potential measurements.
RESULTS: Correlation analysis revealed a positive association between GS expression and mitophagy-related genes in HCC. MSO treatment enhanced the effects of radiotherapy, leading to increased ROS production, reduced antioxidant capacity, and aggravated mitochondrial damage. Mitophagy activation was confirmed by LC3-II accumulation and upregulation of the PINK1/Parkin pathway. Notably, the radiosensitizing effect of MSO was partially reversed by Mdivi-1, indicating that mitophagy contributes to MSO-mediated radiosensitization.
CONCLUSION: These findings indicate that inhibition of GS enzyme activity enhances oxidative stress and mitophagy, thereby promoting radiosensitivity in HCC cells. This study provides new insights into the role of GS in overcoming radiotherapy resistance and highlights its potential as a therapeutic target to improve radiotherapeutic outcomes in HCC.

Keywords:  Glutamine synthetase; Hepatocellular carcinoma; Mitophagy; Radiosensitizing

DOI:  https://doi.org/10.1007/s11033-025-11172-0
J Adv Res. 2025 Oct 22. pii: S2090-1232(25)00826-4. [Epub ahead of print]

KRAS/ACTN4/p65-NR2A axis mediates glutamine-glutamate metabolic coupling between schwann cells and pancreatic cancer promoting perineural invasion.

Zhenfeng Tian, Mingxin Su, Miao Yu, Enlai Huang, Bingrong Hu, Yinting Chen.

   INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) exhibits aggressive perineural invasion (PNI), a hallmark of poor prognosis observed in 70-100% of cases. Schwann cells (SCs), key components of the tumor microenvironment, drive PNI via multiple pathways, yet the underlying mechanisms remain unclear.
OBJECTIVES: This study investigates the hypothesis that PDAC cells and SCs establish a glutamine-glutamate metabolic symbiosis to fuel PNI.
METHODS: Integrated approaches, including LC-MS metabolomics, isotopic tracing, co-culture systems, and in vivo models, were employed to analyze bidirectional metabolite exchange. Molecular assays and functional studies elucidated signaling pathways. The therapeutic potential of targeting glutamine transporters (SLC1A5/SLC7A5) and glutamate receptor NR2A was tested using inhibitors V9302 and PEAQX.
RESULTS: SCs secreted glutamine, which PDAC cells internalized via SLC1A5 and converted to glutamate. Glutamate activated SCs through NR2A, inducing ROS/NRF2-expression and upregulating glutamine synthetase (GS) and GLT-1, thereby regenerating glutamine to sustain the metabolic loop. KRAS-ACTN4-p65 signaling amplified this cycle by transcriptionally activating SLC1A5/SLC7A5 and GLS, while leucine uptake via SLC7A5 activated mTORC1 to promote invasion and PNI. In vivo, dual inhibition of SLC1A5/SLC7A5 (V9302) and NR2A (PEAQX) synergistically reduced tumor growth, PNI length, and improved sciatic nerve function in mice.
CONCLUSION: This study identifies a reciprocal glutamine-glutamate metabolic symbiosis between PDAC cells and SCs as a driver of PNI, orchestrated by KRAS-ACTN4-NF-κB signaling and glutamate-NR2A-ROS-NRF2 pathways. Disrupting this axis with V9302 and PEAQX offers a novel therapeutic strategy to target PDAC's metabolic adaptability and neurotrophic microenvironment.

Keywords:  Glutamate; Glutamine; Pancreatic cancer; Perineural invasion; Schwann cells

DOI:  https://doi.org/10.1016/j.jare.2025.10.030
Gut. 2025 Oct 23. pii: gutjnl-2025-335729. [Epub ahead of print]

SIRT6 promotes intrahepatic cholangiocarcinoma development by reprogramming glutamine metabolism via enhanced GLUL.

Mi Zhang, Chanyuan Chen, Haifeng Zhang, Tanqing Long, Tingjie Wang, Nanjin Ding, Ruitao Long, Hua Wu, Zhilu Ma, Zhongyu Cheng, Junyan Tao, Dong Kuang, Lei Li, Chuanrui Xu.

   BACKGROUND: SIRT6 acts as a tumour suppressor in multiple cancers by regulating glucose and lipid metabolism, but its role in intrahepatic cholangiocarcinoma (ICC) remains unclear.
OBJECTIVE: We investigated the role and molecular mechanisms of SIRT6 in ICC development and progression.
DESIGN: Spatial transcriptome and single-cell sequencing data from public ICC cohorts and clinical specimens were used to establish the clinical relevance of SIRT6 overexpression. B/R cell-established allografts and AKT/YAP-induced primary ICC mouse models were used to investigate the oncogenic role of SIRT6. The function of SIRT6 in metabolic regulation was assessed using seahorse analysis, metabolomics and isotope tracing. The transcriptional targets of SIRT6 were screened by RNA sequencing and confirmed by dual-luciferase assay and chromatin immunoprecipitation, and the molecular interactions and deacetylation activity of SIRT6 were analysed via co-immunoprecipitation.
RESULTS: SIRT6 was highly expressed in both human and mouse ICC tissues and cell lines. SIRT6 knockdown significantly inhibited ICC cell growth in vitro and ICC development in mouse models. Hydrodynamic co-injection of SIRT6 and AKT resulted in ICC formation in mice. SIRT6 promoted glutamine synthesis by enhancing GLUL transcription and stabilising GLUL protein degradation. SIRT6 silencing decreased glutamine levels, subsequently reducing the levels of nucleotides and amino acids in ICC cells. Thus, SIRT6 or GLUL inhibitors can suppress ICC progression and significantly enhance the sensitivity to chemotherapy.
CONCLUSIONS: Our findings establish SIRT6 as an oncogenic driver in ICC by orchestrating glutamine metabolic reprogramming and highlight the SIRT6-GLUL axis as a potential therapeutic target for ICC.

Keywords:  CELL GROWTH; HEPATOBILIARY CANCER; LIVER METABOLISM; MOLECULAR ONCOLOGY

DOI:  https://doi.org/10.1136/gutjnl-2025-335729
Nat Commun. 2025 Oct 21. 16(1): 9312

Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia.

Jacquelyne Ka-Li Sun, Ronald P Hart, Karl Herrup, Amy Zexuan Peng, Genper Chi-Ngai Wong, Deng Wu, Kin-Ming Kwan, Kim Hei-Man Chow.

The maintenance of metabolic homeostasis relies on the ability to flexibly transit between catabolic and anabolic states in response to insulin signaling. Here we show insulin-activated ATM is a critical mediator of this process, facilitating the swift transition between catabolic-and-anabolic fates of glucose by regulating the functional status of PKM2 and HIF1α. In Ataxia-Telangiectasia (A-T), these mechanisms are disrupted, resulting in intrinsic insulin resistance and glucose intolerance. Consequently, cells exhibit a compensatory dependence on glutamine as an alternative metabolite for energy metabolism. Cerebellar degeneration, a hallmark of A-T, is characterized by the pronounced vulnerability of Purkinje cells, attributed to their unexpected sensitivity to insulin. Supplementation with α-ketoglutarate, the α-keto acid backbone of glutamine, has demonstrated potentials in alleviating glutamine dependence and attenuating Purkinje cell degeneration. These findings suggest that peripheral metabolic deficiencies may contribute to sustained neurodegenerative changes in A-T, underscoring the importance of screening, monitoring and addressing these metabolic disruptions in patients.

DOI: https://doi.org/10.1038/s41467-025-64360-8
Hepatology. 2025 Oct 23.

Glutamine synthetase loss in β-catenin-mutant hepatocellular carcinoma promotes tumor burden through macrophage metabolic reprogramming.

Evan R Delgado, Panari Patel, Junyan Tao, Yekaterina Krutsenko, Silvia Liu, Daniel Green, Raghad Alzubali, Brandon M Lehrich, Jai-Jun Liu, Tyler Yasaka, Minakshi Poddar, Sucha Singh, Vik Meadows, Aaron W Bell, Xin Chen, Aatur Singhi, Satdarshan P Monga.

   BACKGROUND AIMS: Activating β-catenin gene (CTNNB1) mutations are seen in 30% of all hepatocellular cancer (HCC). These tumors are a molecularly distinct subclass characterized in majority of cases by the presence of tumor-wide glutamine synthetase (GS), increased glutamine, mTOR activation, and susceptibility to mTOR inhibitors. Here, we investigate impact of GS loss from β-catenin-mutated HCCs.
APPROACH: TCGA was assessed for CTNNB1-mutated HCCs with differential Glul (encoding GS) expression for survival. Glul was conditionally deleted from hepatocytes and/or macrophages in HCCs co-expressing mutant-CTNNB1 (T41A) and mutant Nrf2 in mice. Macrophage depletion was also performed by Clodranate treatment. Tumors were characterized by histology and single cell spatial transcriptomics.
RESULTS: CTNNB1-mutated HCC patients with low Glul showed poor survival. β-Catenin-mutated HCCs lacking GS exhibited aggressive disease due to altered glutamate/glutamine availability, forcing metabolic adaptation through upregulation of macrophage Glul permitting mTOR activation and susceptibility to mTOR inhibitors, but switching macrophage function from immunosurveillance to immunosuppression. Glul loss from tumors did not interfere with β-catenin-dependent tumor zonation and responsiveness to β-catenin inhibition. Depleting macrophages using clodronate or conditionally deleting Glul from macrophages in GS-deficient, β-catenin-mutant HCCs, both decreased tumor burden and improved survival.
CONCLUSIONS: We demonstrate unique metabolic dependency of β-catenin-mutated HCCs on GS in tumor cells which is diverted to macrophages upon GS elimination in tumor cells. This adaptation alters macrophage metabolism and function leading to compromised immunosurveillance and greater tumor burden. Our study reveals a metabolic dynamic between HCC cells and macrophages with impact on tumor biology.

Keywords:  glutamine; hepatocellular carcinoma; immune microenvironment; macrophage; metabolic heterogeneity

DOI:  https://doi.org/10.1097/HEP.0000000000001591
Mol Biol Rep. 2025 Oct 24. 53(1): 8

Combined supplementation of leucine and glutamine acts as a novel therapeutic approach to alleviate hyperglycemia and oxidative stress by targeting insulin signalling genes in a drosophila model of type 2 diabetes.

Kalpanarani Dash, Monalisa Mishra.

   OBJECTIVE: To evaluate the therapeutic potential of leucine and glutamine, individually and in combination, in alleviating metabolic dysfunction associated with Type 2 Diabetes (T2D) using a high sucrose diet-induced Drosophila model of T2D.
METHODS: T2D was induced in flies by feeding a high-sucrose diet (35%). Optimal nontoxic doses of leucine and glutamine were administered to T2D flies for seven days. The therapeutic effects were assessed in individual and combined doses through biochemical, histological, and molecular analyses.
RESULTS: Combined leucine and glutamine supplementation demonstrated superior efficacy over individual treatments. Biochemical analysis revealed that supplementation alleviates hyperglycemia and hyperlipidemia. Improved oxidative stress markers are indicated by increased thiol levels, DPPH radical scavenging, antioxidant enzyme activity, decreased protein carbonylation, and lipid peroxidation. Histological assessment found less lipid droplet accumulation in the gut, reduced reactive oxygen species accumulation, restoration of actin filament architecture, and decreased apoptotic cell death in the gut and malpighian tubules. Efflux activity in malpighian tubules was significantly improved post-treatment. qPCR studies indicate that the combination therapy of Leucine and Glutamine predominantly targets downstream components of insulin signaling pathways, including chico and Akt, while secondarily stimulating insulin secretion, which typically diminishes in the later stages of chronic hyperglycemia. The elevation of cytoskeletal genes Actin 57B and Actin 88 F and elevated mRNA expression of sns and kirre, essential for nephrocyte-mediated hemolymph detoxification, underscores the multifaceted treatment strategy.
CONCLUSION: The current study underscores the potential of leucine and glutamine co-supplementation as a promising intervention to mitigate metabolic dysregulation in T2D.

Keywords:  Drosophila melanogaster; Glutamine; Leucine; Malpighian tubules; ROS; Type 2 diabetes

DOI:  https://doi.org/10.1007/s11033-025-11171-1
Rev Endocr Metab Disord. 2025 Oct 23.

Metabolic reprogramming in diabetes and other endocrine and metabolic disorders: exploring the Warburg effect, ketones, and SGLT2 inhibitors.

Pedro Carrera-Bastos, Marcel H A Muskiet, Fernando Mata-Ordoñez, Leo Pruimboom, Alejandro Lucia, Raul M Luque, Frits A J Muskiet.

  The "Warburg effect", a metabolic adaptation observed in dividing cells, involves a shift from mitochondrial oxidative phosphorylation to cytoplasmic glucose metabolism. This metabolic process is characterized by increased cellular uptake of glucose and glutamine, elevated intracellular pH and sodium levels, enhanced protection against oxidative stress, altered autophagy, and increased lactate production. Initially identified by Otto Warburg in cancer cells, the Warburg effect is now recognized as a common feature of all dividing cells, prioritizing biomass production for cell proliferation over energy generation for specialized cellular functions. Indeed, the Warburg effect is emerging as an important feature not only in cancer but also in a range of metabolic, endocrine, and neurological chronic disorders, including type 2 diabetes, heart and kidney failure, therapy-refractory epilepsy, Alzheimer's and Parkinson's diseases, chronic fatigue syndrome, and post-viral syndromes. The prevailing notion that "dysfunctional mitochondria" are the primary cause of the "energy deficit" observed in these conditions may be misleading. Instead, this "energy deficit" can result from cells reprogramming their metabolism to support cell division. Additionally, in these disorders, senescent cells are abundant, exhibiting a Warburg-like metabolism with cell cycle arrest and enhanced anabolic activity. This review explores the multifaceted role of the Warburg effect in type 2 diabetes and other metabolic and endocrine chronic disorders and examines the therapeutic potential of different interventions such as intermittent fasting, ketogenic diets, ketone supplements, and sodium/glucose co-transporter 2 inhibitors. Through a comprehensive analysis of existing literature, we aim to shed light on the mechanisms underlying these interventions and their potential impact on disease progression and patient outcomes.

Keywords:  Diabetes; Heart failure; Ketones; Senescent cells; Sodium/glucose cotransporter; Warburg effect

DOI:  https://doi.org/10.1007/s11154-025-09996-z
Nanomedicine. 2025 Oct 19. pii: S1549-9634(25)00071-1. [Epub ahead of print] 102870

Dual metabolic targeting liposomes potentiate triple-negative breast cancer radiosensitivity via glucose and glutathione starvation.

Henan Zhang, Yanbin Liu, Xuezhi Gao, Guoli Ji, Yanzhen Zheng, Fei Luo, Xing Qi, Shasha Zhao, Shanghui Guan, Cong Wang, Ming Lu.

  Triple-negative breast cancer (TNBC) frequently develops resistance to radiotherapy, while its metabolic reliance on glucose and glutamine presents new therapeutic targets for radiotherapy sensitization. This study developed a targeted nanoliposome (G/B-Lip-R) co-delivering glucose oxidase (GOD) and buthionine sulfoximine (BSO) to enhance radiotherapy through dual metabolic intervention. GOD catalyzes glucose oxidation to generate hydrogen peroxide (H2O2) while depleting tumor energy supplies, whereas BSO inhibits glutathione (GSH) synthesis to disrupt redox homeostasis. Their synergistic action significantly elevates intracellular reactive oxygen species (ROS) levels, thereby potentiating radiosensitivity. Both in vitro and in vivo studies demonstrated that G/B-Lip-R effectively targets tumors and significantly improves radiotherapy outcomes. This work innovatively combines nanocarriers with dual metabolic pathway modulation, offering a novel strategy to overcome TNBC radioresistance with important clinical translation potential.

Keywords:  Cancer therapy; Glutathione depletion; Nanomaterials; Radiotherapy sensitization; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.nano.2025.102870
Transl Lung Cancer Res. 2025 Sep 30. 14(9): 3951-3974

Genome-scale metabolic modeling and machine learning unravel metabolic reprogramming and mast cell role in lung cancer: a multi-level analysis.

Masoud Tabibian, Tahereh Razmpour, Rajib Saha.

   Background: Lung cancer remains a leading cause of cancer-related deaths worldwide. Immune interactions, particularly involving mast cells, play a crucial role in cancer progression through their influence on immune modulation, angiogenesis, and tissue remodeling. Mast cells exhibit both pro-tumorigenic and anti-tumorigenic activities, but their metabolic adaptations in the lung cancer microenvironment remain poorly understood. The objective of this study is to elucidate the metabolic reprogramming in lung cancer cells and mast cells using genome-scale metabolic modeling (GSM) and machine learning through a multi-level approach, and to identify metabolic vulnerabilities and potential therapeutic targets.
Methods: We conducted a comprehensive multi-level analysis of metabolic alterations in lung cancer using GSM and machine learning approaches. Forty-three paired lung tissue samples (healthy and cancerous) were used to develop metabolic models of lung cancer and mast cells. A random forest classifier was employed to distinguish between healthy and cancerous states and identify key metabolic signatures. We also developed a novel metabolic thermodynamic sensitivity analysis (MTSA) to assess metabolic vulnerabilities across physiological temperatures (36-40 ℃).
Results: Our analysis revealed a significant reduction in resting mast cells in cancerous tissues. The random forest classifier accurately distinguished between healthy and cancerous states based on metabolic signatures. Lung cancer cells selectively upregulated valine, isoleucine, histidine, and lysine metabolism in the aminoacyl-tRNA pathway to support elevated energy demands. Mast cell metabolism exhibited enhanced histamine transport and increased glutamine consumption in the tumor microenvironment, suggesting a shift towards immunosuppressive activity. MTSA demonstrated impaired biomass production in cancerous mast cells across physiological temperatures, indicating specific metabolic vulnerabilities.
Conclusions: Our study elucidates the metabolic adaptations of mast cells and lung cancer cells, highlighting their interplay in tumor progression. The identified metabolic signatures provide potential therapeutic targets and diagnostic markers for future investigation. The novel MTSA approach offers a framework for identifying temperature-dependent metabolic vulnerabilities in cancer cells that could be exploited for therapeutic interventions.

Keywords:  Lung cancer; genome-scale metabolic modeling (GSM); machine learning; mast cells; metabolic thermodynamic sensitivity analysis (MTSA)

DOI:  https://doi.org/10.21037/tlcr-2025-555
J Neurochem. 2025 Oct;169(10): e70265

PMP2 Enhances Schwann Cell Metabolism and Promotes Myelination.

Gustavo Della-Flora Nunes, Jiayue Hong, Rebekah Garfolo, Acheta Jenica, Amanda S Mondschein, Olivia M Harris, Khushi Panchal, Frances L Jourd'heuil, David Jourd'heuil, Yannick Poitelon, Sophie Belin.

  Myelinating Schwann cells depend on precise metabolic regulation to support axonal function and maintain peripheral nerve integrity. Peripheral Myelin Protein 2 (PMP2), a fatty acid-binding protein enriched in myelinating Schwann cells, has been implicated in lipid metabolism and mitochondrial energy production. Here, we examine the role of PMP2 in regulating Schwann cell bioenergetics and myelination. Using both immortalized and primary Schwann cells, we show that PMP2 overexpression enhances mitochondrial ATP production. We also reveal that PMP2 alters metabolic dependencies during high metabolic demand, reducing Schwann cell reliance on glutamine while promoting greater metabolic adaptability under substrate restriction. Finally, PMP2 overexpression significantly increases myelination in vitro, indicating that PMP2-driven metabolic modulation supports the energetic demands of myelination. These findings position PMP2 as a key regulator of Schwann cell metabolism and a potential therapeutic target for demyelinating neuropathies.

Keywords:  ATP; PMP2; Schwann cell; seahorse

DOI:  https://doi.org/10.1111/jnc.70265
Semin Cancer Biol. 2025 Oct 17. pii: S1044-579X(25)00126-9. [Epub ahead of print]

The Emerging Role of Metabolic Interventions in Uveal Melanoma.

Yuki Kuranaga, Yasmin Hatem, Hans E Grossniklaus, Sameh S Ali, Erwin G Van Meir.

  Uveal Melanoma (UM) is the most common primary intraocular malignancy in adults, presenting significant clinical challenges due to its aggressive nature and metastatic potential, which results in poor prognosis in some patients. Despite recent therapeutic advances, the survival rate for metastatic UM remains unsatisfactory, underscoring the need for innovative intervention strategies. A promising direction involves the exploitation of differentially activated metabolic pathways, which are increasingly recognized for their crucial roles in cancer cell growth and metastasis. UM exhibits significant metabolic plasticity, enabling adaptation to microenvironmental stresses. While solid tumors often depend on glycolysis for energy-a phenomenon known as the Warburg effect-recent studies highlight the role of mitochondrial oxidative phosphorylation (OXPHOS), glutaminolysis, as well as fatty acid oxidation (FAO) in UM progression and therapy resistance. This diverse reliance suggests that targeting metabolic plasticity-either alone or in combination with current treatments-could offer a viable therapeutic strategy. Emerging research connects the metabolic profile of UM cells to genetic and epigenetic changes, including through oncogenic pathways driven by GNAQ and GNA11 mutations, which affect mitochondrial function and energy metabolism. This metabolic reprogramming may confer survival advantages, particularly in the nutrient- and oxygen-limited ocular environment. Here, we review recent advances on how molecular aberrations in UM alter cancer cell metabolic and mitochondrial functions, and whether these represent opportunities for therapeutic targeting. Furthering our understanding of the specific metabolic and mitochondrial changes that drive UM progression and metastasis will lead to the discovery of novel metabolic and mitochondrial biomarkers for early diagnosis, prognosis, and treatment guidance, ultimately enabling the development of more effective therapeutic strategies that exploit the unique metabolic vulnerabilities of UM cells.

Keywords:  (OXPHOS); Fatty acid oxidation (FAO); GNAQ/GNA11 mutations; Glycolysis; Metabolic plasticity; Metabolic reprogramming; Oxidative phosphorylation; Therapy resistance; Uveal melanoma

DOI:  https://doi.org/10.1016/j.semcancer.2025.10.002
ACS Infect Dis. 2025 Oct 21.

Glutamine Potentiates Cefoperazone-Sulbactam Activity against Acinetobacter baumannii by Increasing Drug Uptake and ROS.

Shi-Wen Wang, Zheng-Qi Shi, Jia-Xin Zhu, Jiao Xiang, Yue-Tao Chen, Shao-Hua Li, Xian-Liang Zhao, Ying-Yue Zeng, Yuan Tao, Huan-Zhe Fu, Hui-Yin Lin, Jin Tang, Xiao-Xia Huang, Xin Wang, Xuan-Xian Peng, Kui-Hai Wu, Tian-Tuo Zhang, Hui Li.

  The combination of an antibiotic with a metabolic reprogramming agent is anticipated to emerge as a promising therapeutic strategy against antibiotic-resistant bacteria, although this hypothesis requires validation through preclinical pharmacodynamic studies. This study evaluated the preclinical pharmacodynamic profile of cefoperazone-sulbactam (SCF) combined with glutamine against 237 Acinetobacter baumannii clinical isolates, including 26 antibiotic-sensitive (S-AB), 8 multidrug-resistant (MDR-AB), and 203 carbapenem-resistant strains (CR-AB). The combination demonstrated synergistic efficacy in 224 cases (94.51%), equivalence in 10 (4.22%), and no interaction in 3 (1.27%) compared with SCF monotherapy. Time-kill assays, bacterial load quantification, and murine infection models consistently validated these findings, with therapeutic effects remaining stable despite variations in calcium concentrations and pH gradients. Glutamine slows the development of SCF resistance, prolongs the postantibiotic effect, and reduces mutation frequency. Mechanistically, glutamine reprograms bacterial metabolism from an antibiotic-resistant state to an antibiotic-sensitive state, thereby enhancing reactive oxygen species (ROS) production, which combines with increased drug uptake to potentiate SCF killing. This accelerated drug influx surpasses the clearance capacity mediated by efflux pumps and enzymatic degradation, resulting in increased bacterial eradication through synergy with ROS. These findings suggest that the synergistic combination holds the potential for developing therapeutic candidates against MDR-AB and CR-AB.

Keywords:  Acinetobacter baumannii; carbapenem resistance; cefoperazone/sulbactam; glutamine; multidrug resistance; preclinical pharmacodynamics

DOI:  https://doi.org/10.1021/acsinfecdis.5c00616
Metab Eng. 2025 Oct 21. pii: S1096-7176(25)00163-6. [Epub ahead of print]93 184-193

Genome-wide CRISPR screening identifies genes in recombinant human embryonic kidney 293 cells for increased ammonia resistance.

Sang Yoon Lee, Hyun Seung Kim, Yeon Gu Kim, Seunghyeon Shin, Seokchan Kweon, Jae Jun Lee, Gyun Min Lee.

  Ammonia, a byproduct of glutamine metabolism, inhibits cell growth and reduces product yield and quality in mammalian cell culture. To identify novel genes associated with ammonia resistance, a genome-wide CRISPR knockout screening was conducted in monoclonal antibody (mAb)-producing human embryonic kidney 293 (HEK-mAb) cells using a virus-free, recombinase-mediated cassette exchange-based gRNA interrogation method. The knockout cell library was subcultured for five consecutive passages under 20 mM NH4Cl, enriching cells with a sgRNA that conferred a proliferation advantage under high-ammonia conditions. Next-generation sequencing analysis of the enriched population identified three target genes -WNT3, TSPAN1, and CYHR1-among 19,114 genes. Knockout of these genes in HEK-mAb cells resulted in a 1.33- to 1.56-fold increase in maximum viable cell concentration and a 1.28- to 1.58-fold increase in maximum mAb concentration under 20 mM NH4Cl. Notably, WNT3 knockout maintained N-glycan galactosylation proportions of mAb despite ammonia stress. These findings highlight the effectiveness of genome-wide CRISPR knockout screening in identifying novel gene targets for ammonia-resistant HEK293 cell, offering a promising strategy for improving mAb production.

Keywords:  Ammonia stress; CRISPR/Cas9 screening; HEK293 cell engineering; Monoclonal antibody; WNT3

DOI:  https://doi.org/10.1016/j.ymben.2025.10.008
iScience. 2025 Oct 17. 28(10): 113601

Kir5.1-modulated potassium flux stimulates an anabolic kidney phenotype.

Aihua Wu, Masa-Ki Inoue, Yahua Zhang, Clinton M Hasenour, Juan Pablo Arroyo, Fabian Bock, Alina Yu, Mohammed Z Ferdaus, Yvette Blackwell, Roman M Lazarenko, Jamey D Young, Jerod S Denton, Eric Delpire, Ming-Zhi Zhang, Raymond C Harris, Andrew S Terker.

  The kidney maintains systemic potassium (K+) balance through energy-intensive epithelial transport processes. Under K+-restricted conditions, kidney epithelial cells proliferate to accommodate profound increases in transport. Tissue reorganization to minimize systemic K+ loss is essential for survival, yet metabolic details remain obscure. Here, we demonstrate that the most-activated kidney pathways under low K+ conditions are those governing metabolism, including carbohydrate- and glutamine-based processes and fatty acid synthesis. We identify that reduced K+ intake stimulates glycolytic flux in the renal cortex to increase amino acid abundance, de novo fatty acid synthesis, and organ expansion. Using a novel mouse model harboring a dominant-negative Kir5.1 channel, we show that each of these steps is dependent on intact basolateral Kir channel flux to initiate rapid kidney growth. Results identify details of a low K+-simulated anabolic kidney program requiring Kir channel function and highlight a therapeutic role for targeting Kir channels to modulate cell physiology and metabolism.

Keywords:  Cellular physiology; Metabolic flux analysis; Technical aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.113601