bims-glucam 2026-01-18 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–01–18
nine papers selected by
Sreeparna Banerjee, Middle East Technical University

Transport of the abundant intestinal amino acid glutamine by the enteric pathogen Campylobacter jejuni occurs via GutA (Cj0903), an AGCS family transporter.
PIK3CG deficiency promotes metabolic reprogramming in pancreatic Cancer by suppressing GLS2-driven glutamine metabolism.
GOT1 Inhibition Induces Extracellular Matrix Remodeling in Pancreatic Cancer.
Investigating the molecular mechanisms of glutamine metabolism and mitochondria-related biomarkers in Alzheimer's disease through transcriptomics and experimental validation.
Drug-tolerant persister cells reallocate carbon sources to fuel antioxidant metabolism for survival.
Comparative Analysis of Hypothalamic Responses to Stress and Glutamine Supplementation in Diet-Induced Obese Mice: A Study of Sex Differences.
Ampelopsin preserves glutamate homeostasis against cerebral ischemia.
Amino acid restriction sensitizes lung cancer cells to ferroptosis via GCN2-dependent activation of the integrated stress response.
The Demodifier: A tool for screening modification-induced alternate peptide taxonomy in palaeoproteomics.

Microbiology (Reading). 2026 Jan;172(1):

Transport of the abundant intestinal amino acid glutamine by the enteric pathogen Campylobacter jejuni occurs via GutA (Cj0903), an AGCS family transporter.

Ashley Griffin, Jack K Whitmore, Connor Sharp, Joseph P Webb, Daniel J Bennison, Rebecca M Corrigan, David J Kelly, Aidan J Taylor.

  Glutamine is the most abundant amino acid in the human body, playing a crucial role in numerous cellular processes. Notably for enteric bacteria, glutamine is abundant in the intestines where it helps to maintain gut health of the host, therefore presenting itself as an accessible nutrient. Campylobacter jejuni, a largely non-saccharolytic organism, favours just a few amino acids for growth, and glutamine is particularly efficient as a nitrogen source. Despite this, a glutamine transporter has not been conclusively identified in this important human pathogen. By measuring the global transcriptomic response of C. jejuni to replete glutamine conditions, we identified several candidate transporters, ultimately characterising Cj0903, here named glutamine uptake transporter A, as the major glutamine transporter belonging to the alanine or glycine:cation symporter family. We show that this transporter is ubiquitous in thermotolerant Campylobacter, demonstrating a conserved ability to utilise exogenous glutamine. In contrast, the ammonium transporter Amt was only present in a subset of C. jejuni, and we confirmed that amt negative isolates do not effectively utilise ammonium as a nitrogen source.

Keywords:  Campylobacter; alanine or glycine:cation symporter (AGCS); ammonium; glutamine; transcriptomics; transporters

DOI:  https://doi.org/10.1099/mic.0.001649
Int Immunopharmacol. 2026 Jan 14. pii: S1567-5769(25)02095-8. [Epub ahead of print]172 116106

PIK3CG deficiency promotes metabolic reprogramming in pancreatic Cancer by suppressing GLS2-driven glutamine metabolism.

Lu Han, Die Zhang, Weidong Xiao, Chunyan Zeng, Youxiang Chen.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) undergoes profound metabolic reprogramming. This study aims to elucidate how PIK3CG deficiency drives glutamine (Gln) metabolic reprogramming in PDAC.
METHODS: We first identified PIK3CG as a key differentially expressed gene in PDAC and confirmed that its expression level correlates with patient survival. We established both in vitro and in vivo PIK3CG-knockdown (PIK3CG-KD) models. Using these models, we assessed its regulatory effects on the Gln metabolic pathway, mitochondrial reactive oxygen species (mtROS) accumulation, mitochondrial membrane potential, and tumor cell pyroptosis. Moreover, we delineated the specific molecular mechanism linking PIK3CG to downstream signaling. This mechanism crucially involves GLS2, a key enzyme in glutamine metabolism.
RESULTS: PIK3CG deficiency suppresses the mechanistic target of rapamycin complex 1 (mTORC1) pathway, leading to enhanced phosphorylation of S6K2. This disrupts the interaction between nuclear S6K2 (Glu163) and P53 (Arg273), ultimately inhibiting GLS2 transcription. Consequently, a series of metabolic disturbances ensue: glutamate (Glu) accumulates substantially, Gln catabolism is blocked, and its influx into the TCA cycle is restricted, resulting in reduced α-ketoglutarate (α-KG) levels. The deficiency in α-KG triggers a significant accumulation of mtROS. Notably, despite elevated ROS levels, pyroptosis is suppressed and accompanied by exacerbated inflammation. Conversely, GLS2 overexpression rescues all the aforementioned phenotypes induced by PIK3CG-KD-including tumor growth, elevated mtROS, suppression of pyroptosis, and inflammatory response-while restoring Gln metabolic homeostasis.
CONCLUSION: Our study reveals a novel mechanism by which PIK3CG-KD regulates Gln metabolism and mitochondrial function via the S6K2/P53/GLS2 axis, providing a rationale for metabolic intervention and precision therapy in PIK3CG-deficient PDAC.

Keywords:  GLS2; Glutamine metabolism; PIK3CG; Pancreatic ductal adenocarcinoma; Pyroptosis

DOI:  https://doi.org/10.1016/j.intimp.2025.116106
Adv Sci (Weinh). 2026 Jan 12. e16578

GOT1 Inhibition Induces Extracellular Matrix Remodeling in Pancreatic Cancer.

Rodrigo Curvello, Sandra Hauser, Michael Seifert, Christopher K Barlow, Joel R Steele, Emma Salisbury, Daniel Croagh, Kathryn S Stok, Anna V Taubenberger, Ralf B Schittenhelm, Daniela Loessner.

  Pancreatic cancer cells rely on glutamine to sustain their survival in the stiff and poorly vascularized tumor microenvironment (TME). Inhibiting glutamic-oxaloacetic transaminase 1 (GOT1) is a strategy to target glutamine metabolism and impair cancer cell functions. However, it remains unclear how cellular and extracellular elements of the TME respond to GOT1 inhibition. We engineered a pancreatic TME model 'on a dish' and recreated the metabolic interactions. Stromal cells remodeled the extracellular matrix and upregulated metabolic programs, including glutamine metabolism, oxidative phosphorylation, and central carbon metabolism. Cell responses to GOT1 inhibition were modulated by TME elements, with reductions in cell viability and proliferation occurring only under tissue-like conditions. GOT1 inhibition altered matrix organization by upregulating different matrix-related proteins, while it did not enhance cell responses to cytotoxic drugs. Our findings uncover the metabolic crosstalk within the TME and show that metabolism-targeting treatments directly impact stromal elements of pancreatic cancer.

Keywords:  extracellular matrix; metabolism; pancreatic cancer; stromal cells; tissue engineering

DOI:  https://doi.org/10.1002/advs.202516578
Eur J Med Res. 2026 Jan 15.

Investigating the molecular mechanisms of glutamine metabolism and mitochondria-related biomarkers in Alzheimer's disease through transcriptomics and experimental validation.

Xiaying Si, Shihan Tian, Yudong Chen, Xin Li, Guode Wu, Yuan Yao, Manxia Wang.

   BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder. This study aims to identify biomarkers associated with glutamine metabolism-related genes (GRGs) and mitochondria-related genes (MRGs) in AD through bioinformatics analysis, offering insights for prevention and treatment strategies.
METHODS: Candidate genes were first picked out through differential gene expression profiling, construction of weighted gene co-expression network analysis (WGCNA), and interaction network analysis. Biomarkers were then filtered using machine learning algorithms. For these biomarkers, expression verification and receiver operating characteristic (ROC) curve analysis were carried out. These biomarkers underwent GeneMANIA analysis, subcellular and chromosomal localization, enrichment analysis, along with immune infiltration assessment, establishment of a multi-layered molecular regulatory network, and prediction of potential therapeutic agents by leveraging drug-gene interaction databases. Finally, the consistency was validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR).
RESULTS: Initially, 10 candidate genes were identified through bioinformatics analysis. Machine learning, expression validation, and ROC analysis pinpointed SNCA and PPP2R1A as biomarkers (AUC > 0.7). These biomarkers were associated with 20 functionally similar genes and were active in the nucleus and cytoplasm. SNCA was located on chromosome 4, and PPP2R1A on chromosome 19. Enrichment analysis unveiled their involvement in pathways such as olfactory transduction. Additionally, these biomarkers influenced immune cells; for instance, there was a positive correlation between PPP2R1A and type 2 T helper cells (cor = 0.66, P = 1.03 × 10-5). A molecular regulatory network demonstrated that these biomarkers were regulated by 134 miRNAs, and 72 potential drugs targeting these biomarkers were identified. RT-qPCR confirmed the expression consistency with bioinformatics results.
CONCLUSION: This study ultimately identified SNCA and PPP2R1A as biomarkers for AD, providing a theoretical foundation and potential targets for the diagnosis and treatment of AD.

Keywords:  Alzheimer’s disease; Glutamine metabolism; Immune infiltration analysis; Mitochondria; Molecular regulatory network

DOI:  https://doi.org/10.1186/s40001-025-03747-1
bioRxiv. 2026 Jan 06. pii: 2026.01.05.697775. [Epub ahead of print]

Drug-tolerant persister cells reallocate carbon sources to fuel antioxidant metabolism for survival.

Melvin Li, Bradley Priem, Luke V Loftus, Michael J Betenbaugh, Kenneth J Pienta, Sarah R Amend.

Therapy resistance is the leading cause of cancer-related deaths. Drug-tolerant persister cells (DTPs) represent a major barrier to cancer cure, mediating resistance through adaptive cell state transitions and driving tumor progression. Here, we investigate metabolic differences between DTPs and drug-sensitive cancer cells using integrated fluxomics. Proteomic profiling and extracellular flux analyses revealed that DTPs upregulate glycolysis and gluconeogenesis while reducing oxidative phosphorylation, indicating a shift in central carbon metabolism. Isotope tracing and metabolic modeling demonstrate that DTPs utilize glucose to fuel the pentose phosphate pathway (PPP) to generate NADPH and metabolize glutamine to provide carbons for the PPP via gluconeogenesis. Integrating our multi-omic datasets into a genome-scale model identified that DTPs sustain antioxidant metabolism by decreasing fluxes of other NADPH-consuming reactions upon in silico PPP knockout. These findings reveal a systems-level shift in DTP metabolism that maintains antioxidant activity for cell survival, highlighting potential new targets and treatment paradigms to overcome therapy resistance.

DOI: https://doi.org/10.64898/2026.01.05.697775
Inflammation. 2026 Jan 10.

Comparative Analysis of Hypothalamic Responses to Stress and Glutamine Supplementation in Diet-Induced Obese Mice: A Study of Sex Differences.

Virginie Dreux, Candice Lefebvre, Charles-Edward Breemeersch, Adam Tiffay, Pierre Déchelotte, Alexis Goichon, Ludovic Langlois, Moïse Coëffier.

  Hypothalamic inflammation plays a key pathophysiological mechanism linking chronic consumption of a high fat diet (HFD) to the development of obesity and associated metabolic complications. Pilot studies report that oral glutamine (Gln) supplementation might reduce waist circumference and improve metabolic and inflammatory status in obesity patients. Although Gln metabolism plays a key role in intercellular communication in the central nervous system, its potential beneficial effects remain unexplored in these contexts. Here, we aimed to evaluate how stress and glutamine supplementation can modulate the hypothalamic response to HFD in mice using a chronic-restraint stress (CRS) model, which mimics IBS symptoms. From week 12 to week 14, mice received or not Gln diluted in drinking water (2 g/kg/day) and were placed in restraint tubes (2 h/day) for the last four consecutive days of protocol. Male and female obese mice showed a difference in vulnerability to CRS-induced effects. Moreover, mice responded to Gln supplementation in a sex-dependent manner, especially in stress conditions. Hypothalamic pathways regulating energy homeostasis were more impacted in male mice, whereas factors involved in neuroinflammation were more affected in female mice. Gln supplementation led to an increase in Mc4r and Bdnf mRNA levels and GFAP expression in male mice, while upregulated Iba1 and Il6 mRNA levels as well as signs of microgliosis were observed in stressed females. In conclusion, mice with obesity showed sex-specific hypothalamic response to glutamine supplementation and stress. Further investigations should be done to decipher underlying mechanisms.

Keywords:  Glial cells; Glutamine; High fat diet; Hypothalamus; Neuroinflammation; Obesity; Stress

DOI:  https://doi.org/10.1007/s10753-025-02428-9
Biomed Pharmacother. 2026 Jan 12. pii: S0753-3322(26)00034-X. [Epub ahead of print]195 119002

Ampelopsin preserves glutamate homeostasis against cerebral ischemia.

Zhen Li, Fang Li, Wang Song, Chun-Mei Long, Xin Zeng, Wen-Kai Guo, Bin Chen, Tai-Xin Jia, Li Lu.

  The glutamate (Glu)-glutamine (Gln) cycle between astrocytes and neurons plays a crucial role in maintaining extracellular Glu levels during excitatory neurotoxicity, with glutamine synthetase (GS) and glutaminase (GLS) serving as the key enzymes. Ampelopsin (Amp) exhibits diverse biological and pharmacological activities, including antioxidant, anti-inflammatory, and antitumor effects. Notably, Amp regulates GLS, which is also the established target of CB-839, a potent and specific inhibitor known to suppress tumorigenesis. However, the influence of this effect on neuroprotective effects and Glu homeostasis remains unclear. This study aimed to construct a middle cerebral artery occlusion/reperfusion (MCAO/R) model to assess the effects of Amp and CB-839 on Glu-induced ischemic injury in vivo. Herein, Glu and Gln levels within the Glu-Gln metabolic cycle, and protein levels of GLS, GS, glutamate transporter-1 (GLT-1), and N-methyl-D-aspartate receptor (NMDAR) were analyzed. Immunofluorescence staining was performed to determine the distribution of GLS and GS in brain astrocytes and neurons. Notably, both Amp and CB-839 exerted neuroprotective effects in MCAO/R mice by reducing cerebral infarction area, alleviating brain edema, and improving neurological function. Furthermore, they attenuated neuronal necrosis and mitigated the ischemia-induced damage to neurons and Nissl bodies. In addition, both Amp and CB-839 enhanced GS-mediated Glu-to-Gln conversion in astrocytes by increasing GS activity in the ischemic brain and reducing Glu accumulation through GLT-1 upregulation, which facilitated Glu uptake. In neurons, both Amp and CB-839 inhibited GLS-mediated Gln hydrolysis to Glu by downregulating GLS expression, leading to elevated Gln and decreased Glu levels during cerebral ischemia. Simultaneously, NMDAR expression was reduced, preventing excitatory neurotoxicity driven by excessive glutamatergic signaling. Overall, this study highlights the potential of Amp in providing neuroprotection in mice subjected to transient focal cerebral ischemia by promoting the dynamic Glu homeostasis.

Keywords:  Ampelopsin (Amp); CB-839; Cerebral ischemia; Glutamate-glutamine cycle

DOI:  https://doi.org/10.1016/j.biopha.2026.119002
Redox Biol. 2025 Dec 24. pii: S2213-2317(25)00501-4. [Epub ahead of print]90 103988

Amino acid restriction sensitizes lung cancer cells to ferroptosis via GCN2-dependent activation of the integrated stress response.

Viktor Antonsson Garellick, Nadia Gul, Parvin Horrieh, Dyar Mustafa, Angana A H Patel, Martin Dankis, Samantha W Alvarez, Johanna Berndtson, Saeed Mahdavi, Maria Schwarz, Andreas Persson, Fikret Zahirovic, Clotilde Wiel, Volkan I Sayin, Per Lindahl.

  Lung cancer cells are vulnerable to iron-dependent oxidation of phospholipids leading to ferroptosis, a process countered by glutathione peroxidase-4 that converts lipid hydroperoxides to lipid alcohols using glutathione as reducing agent. Since ferroptosis-inducing agents are in clinical development, identifying modifiers of ferroptosis susceptibility is warranted. Here, we investigate the impact of amino acids on susceptibility to buthionine sulfoximine (BSO), a glutamate-cysteine ligase inhibitor that blocks biosynthesis of glutathione. We found that reduced amounts of amino acids other than cysteine increased the sensitivity to BSO and other ferroptosis-inducing agents, in a panel of mouse and human lung cancer cells, without affecting glutathione production. Activation of the amino acid sensor protein GCN2 and the integrated stress response lowered the threshold for lipid peroxidation by promoting ATF4-dependent mitochondrial respiration and reactive oxygen species leakage from the electron transport chain under glutathione depletion. The finding provides new insights into lung cancer metabolism and raises the possibility of using amino acid restricted diets in combination with ferroptosis-inducing agents as cancer therapies.

Keywords:  Amino acids; Ferroptosis; Glutathione; Integrated stress response; Lung cancer; Mitochondrial respiration

DOI:  https://doi.org/10.1016/j.redox.2025.103988
PLoS One. 2026 ;21(1): e0339465

The Demodifier: A tool for screening modification-induced alternate peptide taxonomy in palaeoproteomics.

Miranda Evans.

In palaeoproteomic research, the accuracy of taxonomic matches is crucial, as research questions frequently hinge on which species were utilised by ancient people. However, protein modifications including deamidation of glutamine and asparagine, and conversion of glutamine or glutamic acid to pyroglutamic acid, can change the sequence of peptides, leading to spurious taxonomic detections and potentially inaccurate archaeological interpretations. While a handful of examples of this phenomenon have been reported in the literature, the issue is potentially much wider reaching than currently realised. In reality, any time a peptide containing a deamidated glutamine or asparagine residue, an unmodified glutamic acid or aspartic acid residue, or a pyroglutamic acid modification is detected by proteomic search software, the sequence, and therefore potentially its taxonomy, may be incorrect, which could potentially lead to unsound archaeological interpretations. The Demodifier is a fast, open source tool which solves this issue by screening for modification-induced alternate peptide taxonomy, enabling archaeologists to make informed interpretations of the taxonomies of peptides detected in ancient samples. To assess its utility, The Demodifier is tested against an archaeological dataset containing all unique peptides reported in palaeoproteomic studies of dental calculus and vessels. The results reveal that modification-induced alternate peptide taxonomies are severely under-reported, occurring almost ten times more frequently than previously understood. Modifications were found to produce three different types of inaccurate taxonomic matches: those which yielded completely different taxonomic lowest common ancestors to the input peptide, those which were more taxonomically specific than the input peptide, and those which were less taxonomically specific than the input peptide. The Demodifier therefore enables the rapid detection of potentially inaccurate peptide taxonomies, avoiding spurious archaeological interpretations in future studies.

DOI: https://doi.org/10.1371/journal.pone.0339465