bims-glucam 2026-02-15 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–02–15
twenty papers selected by
Sreeparna Banerjee, Middle East Technical University

The Glutamine-α-Ketoglutarate Metabolic Axis Controls Vascular Smooth Muscle Cell Function.
Overview of glutamine metabolism in stromal components of the tumor microenvironment and potential anti-tumor therapies.
Integrated analysis of glutamine metabolism and immune microenvironment identifies GOT2 as a prognostic gene in head and neck squamous cell carcinoma.
Dendrimer-Conjugated Glutamine Antagonist, D-TTM020, Ameliorates Brain Immune Dysregulation and Improves Neurobehavioral Deficits in the Mecp2-Deficient Mouse Model.
Glutamine supports human cytomegalovirus induced lipidome remodeling through reductive carboxylation.
Editorial: Metabolism in the tumour microenvironment: implications for pathogenesis and therapeutics.
miR-4652-3p suppresses glutamine metabolism induced by the inflammatory microenvironment in non-small cell lung cancer by regulating MYC/SLC1A5.
Metabolic Flexibility and Energy Substrate Utilization Regulate Contractility in the Human Myometrium.
Impaired Arginine, Citrulline and Glutamine Metabolism in Type 2 Diabetes: Insights from a Stable Isotope Study.
Metabolic permissiveness: how tissue context shapes cancer.
MTFP1 drives pancreatic cancer liver metastatic colonisation by regulating mitochondrial metabolism reprogramming.
Evaluation of gene editing in CHO cells using the Cas-CLOVER system.
HPLC-MS/MS Method for Monitoring of L-Asparaginase Activity by Using Asparagine and Aspartic Acid Plasma Levels.
Single-Mitochondrion ATP Profiling Directs Discovery of Targetable OXPHOS Dependency in Cancers.
Innovative methodology for flexible monitoring of various bioprocesses by using pre-existing Raman data coupled with automated transfer learning technique.
Transcriptomic profiling reveals T cell-mediated Glutamine immunomodulation via CD8A / LCK / LAT signaling in the liver model of piglets.
Neurochemical Changes Following Botulinum Toxin Type A in Chronic Migraine: An LC-MS/MS and HPLC Evaluation of Plasma and Urinary Biomarkers.
On why cancer cells require a great amount of glucose.
Genomic alterations and their correlation with metabolic-related genes in lung cancer.
Statins halt polycystic liver disease by reprogramming metabolism and normalizing mitochondrial bioenergetics in cystic cholangiocytes.

Cells. 2026 Jan 26. pii: 230. [Epub ahead of print]15(3):

The Glutamine-α-Ketoglutarate Metabolic Axis Controls Vascular Smooth Muscle Cell Function.

Kelly J Peyton, Xiao-Ming Liu, Giovanna L Durante, William Durante.

  Glutamine is a known regulator of vascular smooth muscle cell (VSMC) function, but the molecular pathways underlying this response remain incompletely understood. This study investigated how glutamine metabolism influences VSMC behavior and identified the responsible enzymes and metabolites. Glutamine deprivation markedly reduced VSMC proliferation, migration, and collagen synthesis, while modestly decreasing viability. Pharmacological inhibition of glutaminase-1 (GLS1) or aminotransferases (AT) similarly suppressed these cellular functions, whereas inhibiting glutamate dehydrogenase 1 (GLUD1) had no effect. Metabolite analysis revealed that glutamine deprivation or AT inhibition, but not GLUD1 inhibition, reduced intracellular α-ketoglutarate (αKG) concentrations, establishing AT as the primary enzyme converting glutamine-derived glutamate to αKG. To identify which metabolite drives VSMC responses, glutamine-starved cells were supplemented with various glutamine-derived molecules. The cell-permeable αKG analog dimethyl-αKG significantly restored VSMC proliferation, migration, collagen synthesis, and survival, while ammonia only enhanced viability, demonstrating αKG's primary role in mediating glutamine-dependent functions. These findings establish that glutamine metabolism via the GLS1-AT-αKG pathway is a critical driver of VSMC activation and survival. Targeting this glutamine-αKG metabolic axis through GLS1 inhibition, AT blockade, or downstream αKG disruption offers a compelling therapeutic strategy for ameliorating fibroproliferative vascular diseases, including atherosclerosis, post-angioplasty restenosis, and pulmonary hypertension.

Keywords:  aminotransferase; collagen; glutaminase; glutamine; migration; proliferation; vascular smooth muscle cells; viability; α-ketoglutarate

DOI:  https://doi.org/10.3390/cells15030230
Genes Dis. 2026 May;13(3): 101834

Overview of glutamine metabolism in stromal components of the tumor microenvironment and potential anti-tumor therapies.

Zizhuo Li, Jiapeng Deng, Hai Wang, Tao Liu, Yuyang Zhou, Pei Ouyang, Xuan Liang, Xian Zhang, Songtao Qi, Yaomin Li.

  As a critical metabolite in the tumor microenvironment, glutamine plays a crucial role in tumor progression, and its dual effects on promoting and inhibiting tumors have garnered increasing attention in recent years. Glutamine metabolism in tumor cells has been extensively studied; however, there is currently a lack of a comprehensive description of how it interacts with tumor stromal components in the tumor microenvironment. This review focuses on the interaction of glutamine metabolism and a range of tumor stromal components, such as macrophages, dendritic cells, T cells, fibroblasts, collagen, and blood vessels in the tumor microenvironment, as well as a summary of current prospective anti-tumor therapeutics targeting glutamine metabolism. Furthermore, this study discusses the shortcomings of mechanism research, metabolic complexity, and metabolic therapy for glutamine metabolism and proposes future research directions that are expected to provide a theoretical foundation for clinical cancer treatment strategies.

Keywords:  Anti-tumor therapy; Glutamine; Glutamine metabolism; Stromal cells; Tumor microenvironment; Tumor stromal components

DOI:  https://doi.org/10.1016/j.gendis.2025.101834
Discov Oncol. 2026 Feb 12.

Integrated analysis of glutamine metabolism and immune microenvironment identifies GOT2 as a prognostic gene in head and neck squamous cell carcinoma.

Xikong Pan, Tingbo Ye, Jianjun Liu, Xucai Zheng.

  Glutamine metabolism plays a key role in cancer initiation and progression. This study aims to explore the independent and interactive roles of glutamine metabolism-related genes and immune characteristic in head and neck squamous cell carcinoma (HNSCC). Clinical and gene expression data from HNSCC patients were downloaded from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA). A comprehensive evaluation of 21 glutamine metabolism-related genes in HNSCC tissues was conducted. A risk model based on glutamine metabolism-related genes was constructed using Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. The association between glutamine metabolism-related genes and immune infiltration was assessed using the Estimation of STromal and Immune cells in MAlignant Tumors using Expression data (ESTIMATE) method. The expression levels of the hub gene were verified in vitro models. Four glutamine metabolism-related genes (GOT2, FAH, LAT, and SLC7A11) were identified for constructing a risk score model for HNSCC patients. High expression levels of GOT2 were identified as a poor prognostic factor in HNSCC, as demonstrated by Kaplan-Meier analysis (HR:1.006, p < 0.001). Patients with a low-risk score exhibited higher ESTIMATE scores and Immune Scores compared to those with a high-risk score. GOT2 emerged as a hub gene associated with the survival of HNSCC patients. In vitro functional experiments demonstrated that downregulation of GOT2 expression suppresses proliferation, invasion, and metastasis. In conclusions, we developed and validated a prognostic risk scoring system based on four glutamine metabolism-associated genes, which demonstrated robust predictive capacity for clinical outcomes and immune infiltration patterns in HNSCC. Mechanistically, GOT2 emerged as a central regulator interfacing with the immunosuppressive tumor microenvironment, potentially driving oncogenesis through dual metabolic-immune reprogramming. These findings highlight GOT2 as a novel therapeutic target, offering a promising strategy to overcome immunotherapy resistance in HNSCC.

Keywords:  GOT2; Glutamine metabolism; Head and neck squamous cell carcinoma; Immunotherapy

DOI:  https://doi.org/10.1007/s12672-026-04485-4
Cells. 2026 Feb 01. pii: 272. [Epub ahead of print]15(3):

Dendrimer-Conjugated Glutamine Antagonist, D-TTM020, Ameliorates Brain Immune Dysregulation and Improves Neurobehavioral Deficits in the Mecp2-Deficient Mouse Model.

Preeti Vyas, Elizabeth Smith Khoury, Nirnath Sah, Anjali Sharma, Javier Allende Labastida, Elizabeth L Wilkinson, Kathleen Lac, Nerketa N L Damiba, Amanda Fowler, Jinhuan Liu, Ashley Bedner, Pavel Majer, Tomás Tichý, Ajit G Thomas, Rana Rais, Barbara S Slusher, Rangaramanujam M Kannan, Sujatha Kannan.

  Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by mutations in the MeCP2 gene, predominantly affecting females. Recent work with MeCP2-deficient mouse models showed a significant role in glutamatergic transmission, specifically microglia-produced glutamate and glutaminase upregulation, in RTT pathology. The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) is a potent glutaminase inhibitor; however, its use is limited due to systemic toxicities arising from its non-specific inhibition of glutamine-utilizing reactions. In this work, we determined whether dendrimer conjugation of a DON analog, TTM020 (or D-TTM020), results in targeted microglial glutaminase inhibition and behavioral changes in Mecp2 KO and heterozygous mice upon systemic administration. D-TTM020 at 1 mg/kg (drug basis) selectively and significantly inhibits glutaminase enzyme activity in the microglia of Mecp2 KO mice. Biweekly systemic treatment with 1 mg/kg of D-TTM020 improved the neurobehavioral phenotype in symptomatic Mecp2 KO and het mice. D-TTM020 also restored long-term retrieval of conditioned fear memory and improved cue responses during fear extinction after 8 weeks of treatment in symptomatic Mecp2 het mice. Our data indicate that selectively targeting glutamine metabolism in dysregulated glia using dendrimers represents a promising strategy that may offer a therapeutic approach for addressing glutamate dysregulation in RTT.

Keywords:  D-TTM020; Rett Syndrome; dendrimer; glutaminase; glutaminergic pathway; microglia; nanomedicine; nanotherapy; neurobehavioral studies; targeted therapy

DOI:  https://doi.org/10.3390/cells15030272
bioRxiv. 2026 Jan 27. pii: 2026.01.26.701865. [Epub ahead of print]

Glutamine supports human cytomegalovirus induced lipidome remodeling through reductive carboxylation.

Rebekah L Mokry, Caleb B de Lacy, John G Purdy.

Lipidome remodeling during human cytomegalovirus (HCMV) replication is a complex process that requires induction of lipogenic proteins and altered metabolite flow to support synthesis of fatty acids and lipids. HCMV infection increases the utilization of glucose and acetate to provide enough carbons to support increased demand for lipogenesis during virus replication, but other carbon contributors have not been studied. Here, we identify glutamine as a carbon source for lipogenesis during HCMV infection. Metabolic tracing with 13 C-labeled glutamine revealed carbons from glutamine are enriched in phospholipids and neutral lipids during infection, including phosphatidylcholine, phosphatidylethanolamine, diacylglycerol, and triacylglycerol. Additional metabolic tracing demonstrates that HCMV infection promotes glutamine flow to fatty acid synthesis primarily through reductive carboxylation, i.e., conversion of glutamine to citrate through isocitrate. Through the use of two different 13 C-labeled forms of glutamine, we found that ∼30% of the carbons from glutamine are delivered to fatty acid synthesis through additional metabolic means. Our current understanding of metabolite utilization during HCMV replication is based on cell culture models where there is an excess amount of glucose, suggesting that deriving carbons from glutamine might be needed when glucose levels are low. To determine if concentrations of glucose and glutamine change their contributions to fatty acid synthesis, we investigated lipogenesis when glucose and glutamine are at physiological levels (5 mM and 0.55 mM, respectively). We determined that physiological levels of glucose and glutamine are sufficient to support the increased demand for fatty acid synthesis caused by HCMV infection, despite a reduction in virus production. Using metabolic tracing with 13 C-labeled forms of glucose or glutamine, we determined that both carbon sources still contribute to fatty acid synthesis when present at physiological levels. Overall, our results identify viral activation of reductive carboxylation that increases glutamine flow to lipogenesis during infection. This work provides additional insight into metabolic reprogramming that supports HCMV-induced lipidome remodeling.
Author Summary: Many viruses hijack cellular metabolic processing to obtain the components needed for replication. Human cytomegalovirus (HCMV) uses several mechanisms to reprogram lipid metabolism and remodel the lipidome of infected cells. HCMV promotes synthesis of very long chain fatty acids that are found in phospholipids and triacylglycerol. Glucose and acetate contribute carbon to fatty acid synthesis and elongation following HCMV infection. In this work, we demonstrate that glutamine is an additional carbon source for fatty acid and lipid synthesis. Phospholipids and neutral lipids are enriched with carbons from glutamine during HCMV infection. Mechanistically, HCMV induces reductive carboxylation to increase glutamine flow to fatty acid synthesis and increased metabolite availability supports additional carbon flow to fatty acids. Overall, this study provides additional insight into virus-induced metabolic remodeling that supplies the molecular building blocks for virus replication.

DOI: https://doi.org/10.64898/2026.01.26.701865
Front Immunol. 2026 ;17 1788008

Editorial: Metabolism in the tumour microenvironment: implications for pathogenesis and therapeutics.

Adil Rasheed, Fabrizio Fontana.



Keywords:  cancer immunotherapy; glutamine; immunoediting; immunometabolism; lactate; metabolism; tumor; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1788008
Hereditas. 2026 Feb 07.

miR-4652-3p suppresses glutamine metabolism induced by the inflammatory microenvironment in non-small cell lung cancer by regulating MYC/SLC1A5.

Yihua Que, Yan Song, Deng Huang, Xianzhen Wu, Yang Pan.



Keywords:  Inflammatory microenvironment; Metabolic reprogramming; Non-small cell lung cancer; miR-4652-3p; miR-4652-3p/MYC/SLC1A5 pathway

DOI:  https://doi.org/10.1186/s41065-026-00649-y
bioRxiv. 2026 Feb 04. pii: 2026.02.02.702681. [Epub ahead of print]

Metabolic Flexibility and Energy Substrate Utilization Regulate Contractility in the Human Myometrium.

Kevin K Prifti, Ritu M Dave, Kaci T Mitchum, Jordan L Rich, Ruth M Gill, Magdaleena N Mbadhi, Antonina I Frolova.

The uterus requires energy for sustained contractility during labor, to deliver the fetus and diminish the risk of postpartum hemorrhage. Our objective was to define energy requirements and assess metabolic flexibility in quiescent and contractile myometrial cells. Cells were treated with oxytocin to stimulate myometrial contractility. We found that myometrial cells rely on oxidative phosphorylation during quiescence and, when treated with oxytocin, can adapt to higher energy demands by shifting their energy production to glycolysis. Treatment with mitochondrial oxidation inhibitors revealed that in quiescent myometrial cells basal oxygen consumption rate decreased when treated with glucose oxidation inhibitor UK5099, but not the long chain fatty acid oxidation inhibitor etomoxir or the glutamine oxidation inhibitor BPTES. In oxytocin treated myometrial cells, this decrease was also observed upon BPTES treatment in addition to UK5099, suggesting that contractile myometrial cells can shift energy production from glucose to glutamine. Functionally, myometrial contractility was significantly reduced by UK5099 but not by etomoxir, further indicating dependence on glucose utilization.

DOI: https://doi.org/10.64898/2026.02.02.702681
J Clin Endocrinol Metab. 2026 Feb 07. pii: dgag055. [Epub ahead of print]

Impaired Arginine, Citrulline and Glutamine Metabolism in Type 2 Diabetes: Insights from a Stable Isotope Study.

Mustafa Tosur, Raven A Wierzchowska-McNew, Nicolaas E P Deutz, Mariëlle P K J Engelen.

   CONTEXT: Arginine (Arg) is an important amino acid in T2D as a potent insulin secretagogue and precursor for nitric oxide (NO). Citrulline (Cit), the substrate for de novo Arg synthesis, is mostly produced from glutamine (Gln).
OBJECTIVE: We aimed to investigate their metabolism in T2D using novel stable isotope tracer approach.
METHODS: We studied 42 individuals (21 with T2D, 21 controls). After overnight fasting, blood samples were collected following pulse administration of stable amino acid tracers. Plasma concentrations and isotopic enrichments were measured by LC-MS/MS, and compartmental analyses were performed to calculate their whole-body production (WBP) rates and kinetics.
RESULTS: The cohort was 59.5% female, with a mean age of 64.4 (7.5) years and a BMI of 33.0 (4.3) kg/m2 (all p>0.05). After adjusting for sex and age, the T2D group had lower plasma concentrations of Arg (p=0.007), Cit (p=0.002), and Gln (p=0.002) than the control group. In T2D, WBP was lower for Cit (p=0.004) but higher for Gln (p=0.037) and glutamate (p=0.017) after controlling for age, sex and lean soft tissue mass. The T2D group also had lower Cit intracellular production, but higher Gln clearance and intracellular pool size, and a trend towards higher Arg clearance.
CONCLUSION: Significant dysregulation exists in Arg-Cit-Gln metabolism in T2D. Our findings suggest a working model in which increased Gln turnover stimulates gluconeogenesis, increases Gln consumption, and reduces Cit availability for Arg and NO synthesis, thereby contributing to metabolic dysregulation in T2D. Interventions targeting Gln-driven gluconeogenesis while increasing Cit availability may benefit T2D management.

Keywords:  arginine; citrulline; stable tracer; type 2 diabetes; whole-body production rate

DOI:  https://doi.org/10.1210/clinem/dgag055
Genes Dev. 2026 Feb 09.

Metabolic permissiveness: how tissue context shapes cancer.

Chrysanthi Moschandrea, Christian Frezza.

  An emerging paradox in cancer metabolism is that identical oncogenic mutations produce profoundly different metabolic phenotypes depending on tissue context, with many mutations exhibiting striking tissue-restricted distributions. Here we introduce metabolic permissiveness as the inherent capacity of a tissue to tolerate, adapt to, or exploit metabolic disruptions, providing a unifying framework for explaining this selectivity. We examine tissue-specific metabolic rewiring driven by canonical oncogenes (MYC and KRAS), tumor suppressors (p53, PTEN, and LKB1), and tricarboxylic acid (TCA) cycle enzymes (FH, SDH, and IDH), demonstrating that baseline metabolic architecture, nutrient microenvironment, redox buffering, and compensatory pathways determine whether mutations confer a selective advantage or metabolic crisis. We further discuss how the tumor microenvironment shapes metabolic adaptation and therapeutic vulnerability. This framework reveals shared principles of tissue-specific metabolic vulnerability in cancer and provides a mechanistic basis for precision metabolic therapies.

Keywords:  cancer; metabolism; permissiveness

DOI:  https://doi.org/10.1101/gad.353516.125
Gut. 2026 Feb 09. pii: gutjnl-2025-336323. [Epub ahead of print]

MTFP1 drives pancreatic cancer liver metastatic colonisation by regulating mitochondrial metabolism reprogramming.

Yang Chen, Gao-Wei Jin, Li-Hong He, Yu Dong, Yan-Na Zhang, Han-Xiang Guo, Yi-Ting Xu, Zi-Yang Wei, Bin-Fei Dang, Chun-Yang Mu, Wan-Yue Cao, Yi-Ze Zhang, Xiao-Bao Wei, Yu-Xiong Feng, Yun-Hua Liu, Qi Zhang, Ting-Bo Liang.

   BACKGROUND: Liver metastasis is a common and fatal event for patients with pancreatic ductal adenocarcinoma (PDAC). Dysregulated mitochondrial dynamics reshape biological processes, including metabolism reprogramming, which disrupts immune cell function and promotes metastatic progression.
OBJECTIVE: To identify key drivers that reprogramme PDAC mitochondrial function and its role in remodelling the immunosuppressive tumour microenvironment (TME) during PDAC liver colonisation.
DESIGN: Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) loss-of-function screening, in vivo mouse model screening and in vitro anoikis-resistant cell selection were employed to identify key drivers during PDAC liver colonisation. PDAC organoids, metabolic flux analysis, single-cell RNA sequencing, spatial metabolomics and glutathione S-transferase (GST) pull-down assay were used to explore the regulation of mitochondrial fission process protein 1 (MTFP1) on PDAC liver colonisation and unravel the underlying mechanism.
RESULTS: We revealed MTFP1, a protein that plays an important role in cell viability and mitochondrial dynamics, as a driver of PDAC liver colonisation. Mechanistically, MTFP1 is recognised as a novel ATP synthase modulator through its interaction with numerous ATP synthase subunits, thereby enhancing oxidative phosphorylation (OXPHOS). Increased mitochondrial fission and subsequent redox signalling (ROS production) upregulates solute carrier family A1 member 5 (SLC1A5) expression by activating the PI3K/AKT/c-MYC pathway, competing for glutamine uptake and impaired antitumour responses of CD8+ T cells. By performing virtual screening, we identified KPT 9274 (ATG-019) as an effective inhibitor of MTFP1. Limitation of glutamine uptake in PDAC cells or MTFP1 inhibition reverses the immunosuppressive TME and reduces liver colonisation of PDAC.
CONCLUSION: Our data demonstrate that the enhanced MTFP1 expression leads to an upregulated glutamine-OXPHOS axis in PDAC liver colonisation. This metabolic shift is triggered by the ROS/PI3K/AKT/c-MYC/SLC1A5 pathway. Targeting MTFP1 may be a potential therapeutic strategy for PDAC patients with liver metastasis.

Keywords:  CANCER IMMUNOBIOLOGY; LIVER METASTASES; OXIDATIVE METABOLISM; PANCREATIC CANCER

DOI:  https://doi.org/10.1136/gutjnl-2025-336323
Biotechnol Prog. 2026 Feb 08. e70108

Evaluation of gene editing in CHO cells using the Cas-CLOVER system.

Tiffany McLamarrah, Efecan Aral, Michael Hoffman, Jennifer Tedstone, Thomas King, Jason Vitko, Maria João Sebastião, Jose M Escandell, Mafalda M Dias, Iona McCall, Daniel Machado, Victor Cairns, Christine DeMaria, John J Scarcelli.

  Recent advances in gene editing technologies have transformed the genetic engineering of Chinese hamster ovary (CHO) hosts, enabling the development of cell lines with improved stability and productivity. In this study, we employed the programmable nuclease (PN) Cas-CLOVER to precisely target the Glutamine synthetase (GS) locus in CHO cells. A total of 30 unique serum-free, suspension-adapted CHO-K1 candidate host cell lines were subjected to Cas-CLOVER-mediated gene editing, generating over one hundred potential GS knockout (GSKO) clones. A subset of the GSKO clones was subsequently validated using three orthogonal methods to confirm complete knockout of the GS gene in 98 clones. Randomly selected GSKO clones were utilized to produce standard monoclonal antibodies. The resulting pools demonstrated enhanced productivity, with up to a 14.5-fold increase in titer compared to their wild-type parental hosts. These findings highlight the potential of gene editing approaches to significantly improve recombinant protein production in CHO expression systems, offering valuable insights for biopharmaceutical manufacturing applications.

Keywords:  CHO cells; Cas‐CLOVER; biopharmaceutical production; gene editing; glutamine synthetase knockout (GSKO)

DOI:  https://doi.org/10.1002/btpr.70108
J Mass Spectrom. 2026 Mar;61(3): e70036

HPLC-MS/MS Method for Monitoring of L-Asparaginase Activity by Using Asparagine and Aspartic Acid Plasma Levels.

Cem Kaplan, İbrahim Daniş, Durişehvar Özer Ünal.

  The effectiveness of L-asparaginase and therefore the effectiveness of acute lymphoblastic leukemia treatment will be understood by determining the substrates of the enzyme, L-asparagine and L-glutamine. For this purpose, the high-performance liquid chromatography-tandem mass spectrometry method was developed and validated by analyzing the L-asparaginase substrates asparagine and glutamine and its products aspartic acid and glutamic acid from plasma. Acetonitrile and ammonium acetate were used at 0.4 mL/min in gradient mobile phase flow using a HILIC column for chromatographic separations. The linear amino acid range was found to be 500-5000 ng/mL for asparagine, aspartic acid, and glutamic acid, and 5-50 μg/mL for glutamine, respectively. Detection limit and quantitation limit were found to be 100-500 ng/mL for asparagine, aspartic acid, and glutamic acid, and 1-5 μg/mL for glutamine, respectively. The validated method has been successfully applied to plasma samples. The method was found to be selective and reproducible.

Keywords:  L‐asparaginase activity; acute lymphoblastic leukemia; amino acid analysis; mass spectrometry; therapeutic drug monitoring

DOI:  https://doi.org/10.1002/jms.70036
Adv Sci (Weinh). 2026 Feb 13. e13341

Single-Mitochondrion ATP Profiling Directs Discovery of Targetable OXPHOS Dependency in Cancers.

Xu Xiao, Cheng Lu, Hao Chen, Jing Zhou, Yunyun Hu, Haonan Di, Guoqiang Su, Xiaomei Yan.

  Mitochondrial adenosine triphosphate (mitoATP) serves as the primary bioenergetic currency for oxidative phosphorylation (OXPHOS)-driven malignancies, yet its precise organelle-level quantification remains challenging due to mitochondrial heterogeneity and cytosolic interference. Herein, we report MitoATP-nFCM, a nano-flow cytometry platform enabling single-mitochondrion ATP measurement via simultaneous fluorescence and side scatter detection. We uncover 1.7-1.9-fold higher ATP levels in isolated mitochondria from breast (MCF-7, MDA-MB-231) and colon (HCT-15, HCT-116) cancer cells than in their normal counterparts. Single-organelle analysis further reveals coordinated metabolic reprogramming in cancer mitochondria, featuring elevated membrane potential, increased ATP synthase expression, and reduced hexokinase 2 levels, demonstrating their OXPHOS-dominant bioenergetic phenotype that contrasts with classical Warburg-effect expectations. Furthermore, we establish a screening strategy to identify highly potent cancer-selective inhibitors targeting mitochondrial metabolism. We find that bedaquiline (ATP synthase inhibitor) outperforms oligomycin A in specificity, VLX600 (electron transport chain inhibitor) shows superior selectivity to rotenone/metformin, and CPI-613 (tricarboxylic acid cycle blocker) surpasses other glutaminase inhibitors. MitoATP-nFCM establishes a quantitative single-organelle platform that profiles elevated mitoATP levels in cancer cells and enables precision screening of OXPHOS-targeting inhibitors.

Keywords:  cancer vulnerability; mitochondrial ATP; mitochondrial metabolism; precision cancer therapy; single‐organelle analysis

DOI:  https://doi.org/10.1002/advs.202513341
Biotechnol Prog. 2026 Feb 10. e70111

Innovative methodology for flexible monitoring of various bioprocesses by using pre-existing Raman data coupled with automated transfer learning technique.

Adèle Schini, Hadi El Radi, Johan Cailletaud, Célia Sanchez, Nathan Gay, Bruno Ebel, Emmanuel Guedon, Laurent Jourdainne.

  This study introduces an innovative approach for the flexible monitoring of bioprocesses using Raman spectroscopy coupled with automated transfer learning. Traditional Raman spectroscopy requires extensive process-specific calibration, limiting its transferability across different conditions. To address this, we developed an automated method that utilizes the dynamic orthogonal projection (DOP) algorithm to use pre-existing chemometric models built from one process ("Input Process") to monitor a distinct process ("Target Process") which lacked its own Raman models. These new processes conditions varied in terms of culture mode, cell line, media, analyzer, and acquisition settings. This method used spectral data from Target Process to modify the existing spectral data from Input Process, aligning them with the new conditions. The approach was validated on Chinese Hamster Ovary cell cultures, targeting critical metabolic parameters such as glucose, lactate, glutamine, and viable cell density. The results showed that with only one batch used for the transfer, the average relative errors compared to offline values were around 10% for glucose and lactate but remained high for VCD and glutamine. After a second batch to perform the transfer on two batches, the relative errors were further reduced below 10% for most parameters. By effectively transferring models across different processes, this approach minimizes the need for extensive recalibrations, enhancing the efficiency and applicability of Raman spectroscopy in diverse bioprocess environments.

Keywords:  Raman spectroscopy; chemometric modeling; instrument calibration; process analytical technology (PAT); transfer learning; upstream CHO cell culture

DOI:  https://doi.org/10.1002/btpr.70111
J Nutr Biochem. 2026 Feb 05. pii: S0955-2863(26)00047-1. [Epub ahead of print] 110305

Transcriptomic profiling reveals T cell-mediated Glutamine immunomodulation via CD8A / LCK / LAT signaling in the liver model of piglets.

Guowei Liu, Yujie Cheng, Yiyu Zhang, Min Zhu.

  Glutamine (Gln) is the body's most abundant and versatile amino acid, playing a crucial role in immune responses. The liver, a highly vascularized and metabolically active organ, has a strong regenerative capacity and is vital for immune function, detoxification of xenobiotics, and maintaining metabolic balance. This study aimed to clarify the molecular mechanisms involved in Gln's regulation of liver functions. Dietary supplementation with 1% Gln for weaned Kele × Large White (Yorkshire) hybrid piglets (castrated male) was administered over a period of 28 days. Our findings indicate that Gln enhances liver development processes. Through mRNA sequencing, 444 differentially expressed genes (DEGs) were identified between the control group and the Gln group. Gene Ontology (GO) enrichment analysis of DEGs revealed that the top 2 enriched biological processes were the immune system and the immune response. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis highlighted several T cell-related immune pathways, including Th1 / Th2 cell differentiation, Th17 cell differentiation, and T cell receptor signaling pathway. Analysis of the KEGG pathway network and protein-protein interaction (PPI) network showed that DEGs encoding CD8 α-chain (CD8A), lymphocyte-specific protein tyrosine kinase (LCK), and linker for activation of T cells (LAT) occupy central hub positions, suggesting their critical role in immune regulation. Real-time quantitative PCR (RT-qPCR) results were consistent with the RNA sequencing data. Furthermore, Western blot analysis showed significantly increased protein expression of LCK and LAT in the Gln group, indicating the activation of the CD8A / LCK / LAT signaling axis. These results highlight Gln's immunomodulatory effects through hepatic T-cell signaling and establish a foundation for further investigation into Gln's impact on liver physiology.

Keywords:  Glutamine; Liver; T cell; Transcriptomic; immunomodulation

DOI:  https://doi.org/10.1016/j.jnutbio.2026.110305
J Clin Med. 2026 Feb 04. pii: 1208. [Epub ahead of print]15(3):

Neurochemical Changes Following Botulinum Toxin Type A in Chronic Migraine: An LC-MS/MS and HPLC Evaluation of Plasma and Urinary Biomarkers.

Seyma Dumur, Demet Aygun, Era Gorica, Hafize Boyaci, Bagnu Dundar, Dildar Konukoglu, Hafize Uzun.

  Background: Botulinum toxin type A (BoNT-A) is an established preventive therapy for chronic migraine (CM), yet the accompanying neurochemical changes remain incompletely characterized. Objective: To evaluate the effects of BoNT-A on plasma substance P (SP), γ-aminobutyric acid (GABA), glutamate, glutamine, and 5-hydroxytryptamine (5-HT), and on urinary 5-HT, and to explore relationships with clinical outcomes. Methods: In this prospective study, plasma neurotransmitters were analyzed in CM patients (n = 31) at baseline and one month after BoNT-A (155 U; PREEMPT protocol) and in healthy controls (n = 30). Plasma SP was measured using enzyme-linked immunosorbent assay (ELISA); plasma GABA, glutamate, and glutamine were quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS) with isotopically labeled internal standards; plasma and urinary 5-HT were determined by high-performance liquid chromatography (HPLC). Clinical outcomes included monthly headache frequency, Visual Analog Scale (VAS), and Migraine Disability Assessment (MIDAS). Statistical analyses applied appropriate parametric or non-parametric tests with p < 0.05 considered significant. Results: One month post-BoNT-A, headache frequency, MIDAS, and VAS were significantly reduced (all p < 0.001). SP levels were significantly higher after BoNT-A than at baseline and versus controls. Plasma 5-HT increased post-BoNT-A, while urinary 5-HT decreased. Plasma GABA was elevated in patients versus controls without statistical significance. Glutamine was significantly higher before treatment, whereas the Glu/Gln ratio increased after BoNT-A. Correlations revealed that higher GABA was associated with lower VAS and attack frequency post-treatment. Conclusions: BoNT-A provided short-term clinical improvement with distinct neurochemical changes, including increased plasma SP and 5-HT, decreased urinary 5-HT, reduced glutamine, and a higher Glu/Gln ratio. These biomarkers, particularly Glu/Gln, may serve as indicators of cortical excitability and therapeutic response in CM.

Keywords:  HPLC; LC–MS/MS; botulinum toxin A; migraine; neurotransmitters; substance P

DOI:  https://doi.org/10.3390/jcm15031208
Quant Biol. 2026 Jun;14(2): e70025

On why cancer cells require a great amount of glucose.

Xuechen Mu, Aoran Liu, Rui Shi, Long Xu, Zhenyu Huang, Ye Zhang, Ying Xu.

  The traditional thinking has been that cancer cells require a great amount of glucose to support their rapid growth, but the reality may be different. We have previously demonstrated that all cancer cells in The Cancer Genome Atlas harbor persistent Fenton reactions in their cytosol, which generate OH- and ultimately kill the cells by alkalosis if not neutralized timely. Here, we present data to show that (1) cancer cells uptake large amounts of glucose to produce sufficient levels of H+ ions to keep the cytosolic pH stable, hence keeping the cells viable; (2) de novo nucleotide biosynthesis represents the predominant acidifying pathway and gets on average the largest allocation of glucose metabolic flux among the 19 cancer types investigated; and (3) although the H+ ions produced by nucleotide biosynthesis and other acidifiers keep the cells alive, the synthesized nucleotides drive cancerous cell proliferation. Taken together, it is not that cancerous cell division requires high levels of glucose imports, instead it is the life-saving nucleotide syntheses that drive cell division. Understanding this causal relationship correctly is significant since it explains why cancers depend so heavily on glucose but not on other nutrients. More importantly, this realization may lead to fundamentally novel and more effective ways to treat cancer.

Keywords:  Fenton reaction; cancer metabolism; cancer proliferation; nucleotide biosynthesis; pH homeostasis

DOI:  https://doi.org/10.1002/qub2.70025
Clin Transl Oncol. 2026 Feb 11.

Genomic alterations and their correlation with metabolic-related genes in lung cancer.

Gauri Gaur, Niraj Kumar Jha, Lokesh Gambhir, Seema V Acharya, Dhruv Kumar.

  Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide, with 5-year survival rates below 21% primarily due to therapeutic resistance and metastatic progression. Genomic alterations in KRAS, EGFR, TP53, and MYC drive metabolic reprogramming that sustains tumor proliferation and therapy resistance. This review synthesizes evidence linking specific genomic alterations, including variant-specific KRAS alleles (G12C, G12D, and G12V) and TP53 gain- or loss-of-function mutations, to distinct metabolic phenotypes in NSCLC. It further examines the immunometabolic consequences of co-occurring mutations such as KRAS with TP53 or STK11/LKB1. The literature synthesis integrates genomic, metabolic, and immunologic profiling data to identify mutation-specific metabolic vulnerabilities and therapeutic targets. Genomic alterations establish distinct metabolic dependencies: KRAS-driven tumors exhibit enhanced glycolysis and glutaminolysis, EGFR-mutant tumors demonstrate increased lipogenesis, and TP53 loss promotes metabolic flexibility. Accumulation of lactate and depletion of glucose in the tumor microenvironment suppress CD8+ T-cell function, facilitating immune evasion. Rational combination strategies that pair genomic-targeted agents (sotorasib and adagrasib) with metabolic inhibitors (CB-839 and TVB-2640) show promise in overcoming adaptive resistance. Integrating genomic and metabolic profiling may enhance precision oncology approaches and improve clinical outcomes.

Keywords:  Genomic alterations; Glycolysis; Immunometabolism; Lung cancer; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12094-026-04229-4
Hepatology. 2026 Feb 10.

Statins halt polycystic liver disease by reprogramming metabolism and normalizing mitochondrial bioenergetics in cystic cholangiocytes.

Enara Markaide, Laura Izquierdo-Sanchez, Irene Olaizola, Josu Urretabizkaia-Garmendia, Mikel Ruiz de Gauna, Xabier Buqué, Irune Lasa-Elosegui, Ainhoa Lapitz, Thomas Bais, Beatriz Val, Pedro M Rodrigues, Rui E Castro, Maria J Perugorria, Luis Bujanda, Ron Gansevoort, Joost P H Drenth, Patricia Aspichueta, Jesus M Banales.

   BACKGROUND AIM: Polycystic liver disease (PLD) is a hereditary disorder characterized by the progressive development and enlargement of intrahepatic biliary cysts, which can lead to significant morbidity. Liver transplantation remains the only curative treatment. Mutations in endoplasmic reticulum (ER)-related genes contribute to ER stress in cystic cholangiocytes, promoting disease progression. Given the functional interplay between ER and mitochondria, we investigated mitochondrial dynamics and metabolism in cystic cholangiocytes from both PLD patients and Pkhd1mut rats to identify novel therapeutic targets.
APPROACH RESULTS: Cystic cholangiocytes exhibited increased mitochondrial mass, membrane potential, and superoxide levels, along with enhanced bioenergetic capacity and ATP production compared to normal cholangiocytes. These alterations were linked to the upregulation of electron transport chain protein complexes. Metabolic reprogramming involved enhanced oxidation of glucose, glutamine, and/or fatty acids, as well as increased de novo cholesterol synthesis and accumulation. Chronic treatment with pravastatin, a cholesterol synthesis inhibitor, significantly reduced hepatomegaly, cyst volume, and fibrosis in Pkhd1mut rats. It also normalized mitochondrial hyperactivity and reduced the proliferation of cystic cholangiocytes in culture, effects that were similarly observed with other statins such as atorvastatin and simvastatin. Importantly, a case-control study in PLD patients showed that statin use was associated with reduced liver growth, further supporting its potential therapeutic role.
CONCLUSION: Mitochondrial and metabolic dysregulation are central to the pathogenesis of PLD. Targeting cholesterol metabolism with statins represents a promising therapeutic strategy to slow disease progression and reduce cyst burden.

Keywords:  cholesterol; energy metabolism; liver cystogenesis; mitochondria; novel therapy

DOI:  https://doi.org/10.1097/HEP.0000000000001711