bims-glucam 2026-04-05 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–04–05
eleven papers selected by
Sreeparna Banerjee, Middle East Technical University

CD90 Promotes Gastric Cancer Progression by Regulating SLC1A5-Mediated Glutamine Metabolism Through YY1.
Inhibition of ERN1 suppresses the expression of phosphoenolpyruvate carboxykinase 2 in U87MG glioblastoma cells and increases its sensitivity to glucose and glutamine deprivation.
Metabolic engineering of SLC38A2 reprograms glutamine utilization and enhances CAR-macrophage antitumor function in solid tumors.
ERN1-dependent regulation of BAG cochaperone 1 expression and the sensitivity to glutamine deprivation in U87MG glioblastoma cells.
Metabolic reprogramming-a breakthrough point in overcoming resistance to BRAF mutant melanoma targeted therapy (Review).
Advances in Metabolic Reprogramming and Immune Regulatory Mechanisms in Lung Cancer.
DXM, CYP2D6-inhibiting antidepressants, piracetam, and glutamine: proposing a ketamine-class antidepressant regimen with existing drugs.
Untargeted metabolomic profiling reveals mTORC1-dependent regulation of amino acid utilization in lymphatic endothelial cells.
SARS-CoV-2 envelope protein mitochondrial localization reveals host metabolic disruption.
Ameliorative effects of mulberry fruit anthocyanin extract on gut microbiota and liver metabolites in high-fat and high-cholesterol diet-fed ApoE-/- mice.
TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation.

Cancer Sci. 2026 Mar 31.

CD90 Promotes Gastric Cancer Progression by Regulating SLC1A5-Mediated Glutamine Metabolism Through YY1.

Zihua Zhou, Siyi Liu, Chenyu Zhang, Jun Deng, Lin Liang, Yanhong Zhou.

  CD90 (THY1) is a cell surface glycoprotein that plays a crucial role in the occurrence and development of various malignant tumors. It affects tumor cell proliferation, metastasis, angiogenesis, stem cell characteristics, and energy metabolism. CD90 is an important biomarker for many malignant tumors and is closely related to tumor prognosis. However, the role and specific mechanisms of CD90 in glutamine metabolism in gastric cancer (GC) cells remain incompletely understood. In this study, we report that CD90 affects glutamine metabolism in GC cells through SLC1A5, ultimately promoting GC progression. Mechanistically, CD90 promotes the binding of YY1 to the SLC1A5 promoter, enhances the transcriptional activity of the SLC1A5 promoter, and increases its transcriptional level. This, in turn, affects SLC1A5-mediated glutamine metabolism and ferroptosis in GC cells, ultimately facilitating GC progression. Our results suggest that CD90 plays an important role in regulating glutamine metabolism in GC cells, providing important experimental evidence for elucidating the pathogenesis of GC.

Keywords:  CD90; SLC1A5; gastric cancer; glutamine metabolism

DOI:  https://doi.org/10.1111/cas.70377
Endocr Regul. 2026 Jan 01. 60(1): 61-71

Inhibition of ERN1 suppresses the expression of phosphoenolpyruvate carboxykinase 2 in U87MG glioblastoma cells and increases its sensitivity to glucose and glutamine deprivation.

Yuliia M Viletska, Oleksandr H Minchenko, Olena O Khita, Myroslava Y Sliusar, Oleh V Halkin, Halyna E Kozynkevych, Dmytro O Minchenko.

  Objective. Phosphoenolpyruvate carboxykinase (PCK) catalyzes the conversion of oxaloacetate to phosphoenolpyruvate and regulates pyruvate metabolism and gluconeogenesis in response to glucocorticoid and insulin stimuli. Mitochondrial isoform of this enzyme (PCK2) is overexpressed in glioblastoma cells and participates in metabolic reprogramming and cell proliferation. This study aims to examine the impact of ERN1 (endoplasmic reticulum to nucleus signaling 1) inhibition on PCK2 expression and sensitivity to glucose and glutamine deprivation to determine the role of ERN1 signaling in the regulating its expression in glioblastoma cells. Methods. The glioblastoma cell line U87MG and two genetically modified variants of these cells were used. These were glioblastoma cell sublines with suppressed endoribonuclease and protein kinase activities of ERN1 (dnERN1) or only ERN1 endoribonuclease (dnrERN1), and control cells transfected with an empty vector. The suppression of ERN1 function by silencing of ERN1 and XBP1 mRNAs was also used. Hypoxia was generated using the HIF1A prolyl hydroxylase inhibitor dimethyloxalylglycine. For glucose and glutamine deprivation, DMEM medium without glucose or glutamine was used. The expression level of the PCK2 mRNA was analyzed by real-time qPCR and normalized to the beta-actin mRNA. Results. It has been demonstrated that PCK2 mRNA expression is significantly decreased in dnERN1 glioblastoma cells. Similar suppression of this mRNA expression was also observed in cells with only the endoribonuclease activity of ERN1 inhibited, indicating that this enzymatic activity is involved in the regulation of PCK2 expression. The silencing of ERN1 and XBP1 mRNAs also induced similar changes in PCK2 mRNA expression, possibly mediated by XBP1s. The expression of PCK2 was enhanced under glutamine deprivation in control glioblastoma cells, but inhibition of ERN1 activity strongly increased this effect. Upregulated PCK2 expression was also observed in control glioblastoma cells under glucose deprivation. However, the inhibition of ERN1 activity strongly increased the sensitivity of this gene expression to glucose deprivation. Furthermore, PCK2 mRNA expression was resistant to hypoxic conditions in cells with native ERN1. At the same time, in glioblastoma cells with inhibited ERN1 activity, a strong induction of PCK2 expression was observed. Conclusion. The results of this study demonstrated that ERN1 inhibition reduces PCK2 mRNA expression through the ERN1 endoribonuclease activity. This mRNA expression is upregulated under glutamine and glucose deprivation. Moreover, ERN1 inhibition strongly enhanced the sensitivity of PCK2 mRNA expression to glucose and glutamine deprivation as well as to hypoxia.

Keywords:  ERN1 endoribonuclease; ERN1 inhibition; PCK2; gene expression; glioblastoma cells; glutamine and glucose deprivation; hypoxia

DOI:  https://doi.org/10.2478/enr-2026-0008
Cancer Biol Med. 2026 Apr 01. pii: j.issn.2095-3941.2025.0775. [Epub ahead of print]

Metabolic engineering of SLC38A2 reprograms glutamine utilization and enhances CAR-macrophage antitumor function in solid tumors.

Mingzhu Liu, Qingxi Chen, Luoling Zhang, Yunxuan Zhou, Ning Wen, Jin Jin, Junchao Cai, Shicheng Su, Jiang Li, Qiyi Zhao.

   OBJECTIVE: This study was aimed at investigating metabolic dysregulation in tumor-associated macrophages (TAMs) in breast cancer and developing a metabolically enhanced chimeric antigen receptor macrophage (CAR-M) strategy to boost antitumor potency in solid tumors.
METHODS: Integrated scRNA-seq and metabolomic analyses were performed to characterize metabolic alterations in macrophages within the breast cancer tumor microenvironment (TME). According to the identified metabolic vulnerabilities, SLC38A2-overexpressing anti-HER2 CAR-Ms were engineered. Glutamine uptake and phagocytic activity were assessed to evaluate functional enhancement.
RESULTS: TAMs in breast cancer exhibited substantial metabolic dysregulation, particularly impaired glutamine metabolism accompanied by decreased expression of the glutamine transporter SLC38A2. Overexpression of SLC38A2 in anti-HER2 CAR-Ms, compared with conventional anti-HER2 CAR-Ms, enhanced glutamine uptake and markedly augmented phagocytosis of HER2+ breast cancer cells.
CONCLUSIONS: Metabolic engineering via SLC38A2 restored glutamine fitness and enhanced the antitumor activity of HER2-targeted CAR-Ms, thus providing a promising strategy to boost CAR-M-mediated tumor suppression in solid tumors.

Keywords:  CAR-macrophage; SLC38A2; glutamine metabolism; metabolic engineering

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0775
Endocr Regul. 2026 Jan 01. 60(1): 37-47

ERN1-dependent regulation of BAG cochaperone 1 expression and the sensitivity to glutamine deprivation in U87MG glioblastoma cells.

Yuliia M Viletska, Oleksandr H Minchenko, Olena O Khita, Daria O Tsymbal, Myroslava Y Sliusar, Oleh V Halkin, Halyna E Kozynkevych, Dmytro O Minchenko.

  Objective. The BAG cochaperone 1 (BAG1) binds to oncogene BCL2 and markedly enhances its anti-apoptotic effects. This cochaperone represents a link between growth factor receptors and anti-apoptotic mechanisms mediated by endoplasmic reticulum stress. BAG1 interacts with the glucocorticoid receptor and modulates its transcription activity. As a cochaperone for several HSP70 proteins, it participates in control of protein folding. The present study aims to investigate the regulation of the BAG1 mRNA expression in U87MG glioblastoma cells by hypoxia and glucose or glutamine deprivation, depending on the inhibition of ERN1 (endoplasmic reticulum to nucleus signaling 1) with the intent to reveal the role of ERN1 signaling in the regulation of this gene expression and function in oncogenesis. Methods. The U87MG glioblastoma cells (transfected by an empty vector; control) and cells with inhibited ERN1 endoribonuclease and protein kinase (dnERN1) or only ERN1 endoribonuclease (dnrERN1) were used. Silencing of ERN1 and XBP1 mRNAs for suppression of ERN1 function was also used. A hypoxic condition was created by dimethyloxalylglycine (4 h). DMEM medium without glucose or glutamine was used for glucose and glutamine deprivation (16 h). The expression level of the BAG1 mRNA was studied by real-time qPCR and normalized to the beta-actin mRNA. Results. Inhibition of the endoribonuclease activity of ERN1 significantly decreased BAG1 mRNA expression. However, a lesser suppression of this mRNA expression was observed in dnERN1 cells (with inhibited ERN1 endoribonuclease and protein kinase) indicating the involvement of protein kinase in controlling BAG1 expression. The silencing of ERN1 and XBP1 mRNAs also reduced the expression of BAG1 mRNA demonstrating the involvement of XBP1s in this regulation. The expression of the BAG1 gene was resistant to glutamine deprivation and upregulated in response to glucose deprivation in control glioblastoma cells. However, the inhibition of ERN1 increased the sensitivity of BAG1 gene expression to both glucose and glutamine deprivation. Furthermore, the expression of the BAG1 gene was increased under hypoxia in control U87MG cells; however, a greater induction was observed in dnERN1 cells. Conclusion. The results of this study demonstrated that ERN1 inhibition reduces BAG1 mRNA expression through the endoribonuclease activity of ERN1 and that protein kinase activity counteracts endoribonuclease in regulating the expression of BAG1 mRNA. Moreover, ERN1 inhibition also enhances the sensitivity of BAG1 mRNA expression to nutrient supply and hypoxia resulting in reduced resistance of glioblastoma cells.

Keywords:  BAG1; ERN1 and XBP1 silencing; ERN1 endoribonuclease; ERN1 inhibition; ERN1 protein kinase; gene expression; glioblastoma cells; glutamine and glucose deprivation; hypoxia

DOI:  https://doi.org/10.2478/enr-2026-0005
Oncol Lett. 2026 May;31(5): 184

Metabolic reprogramming-a breakthrough point in overcoming resistance to BRAF mutant melanoma targeted therapy (Review).

Xueting Zhao, Fang Chen, Huibin Li.

  Targeted therapy for BRAF-mutant melanoma induces metabolic reprogramming, which drives the development of drug resistance. Studies indicate that following treatment with BRAF inhibitors and/or MEK inhibitors, melanoma cells alter metabolic pathways by modifying various regulatory factors. These adaptations include increased lactate accumulation, enhanced oxidative phosphorylation, elevated glutamine utilization via the tricarboxylic acid cycle, activation of the kynurenine pathway and increased fatty acid synthesis. Collectively, these alterations reshape the tumor microenvironment, suppress ferroptosis and activate alternative signaling pathways, thereby conferring resistance to targeted therapy. This paper systematically reviews the mechanisms underlying therapy-induced metabolic reprogramming in BRAF-mutant melanoma and explores potential combinatorial strategies that target these metabolic vulnerabilities alongside established melanoma therapies. Key metabolic targets with promising therapeutic potential identified include lysine-specific demethylase 1, oxidative phosphorylation components, phosphoglycerate dehydrogenase, indoleamine 2,3-dioxygenase 1 and lipid metabolism enzymes such as fatty acid synthase and 3-hydroxy-3-methylglutaryl-coenzyme a reductase.

Keywords:  BRAF-mutant melanoma; drug resistance; metabolic reprogramming; targeted metabolism; targeted therapy

DOI:  https://doi.org/10.3892/ol.2026.15539
Oncol Res. 2026 ;34(4): 11

Advances in Metabolic Reprogramming and Immune Regulatory Mechanisms in Lung Cancer.

Xiaomeng Li, Xuejiao Li, Hongbo Wu, Rui Li.

  Lung cancer remains the leading cause of cancer-related mortality worldwide, primarily driven by metabolic reprogramming and immune evasion mechanisms within tumor cells. To adapt to the nutrient-deprived tumor microenvironment (TME), lung cancer cells undergo profound metabolic reprogramming, characterized by enhanced glycolysis (the Warburg effect), increased glutamine dependency (mediated by GLS1), and accelerated lipid synthesis (involving enzymes such as FASN). These metabolic alterations not only remodel the TME but also dampen antitumor immune responses by promoting immunosuppressive cell populations (e.g., Tregs and M2 macrophages) and inhibiting effector functions of CD8+ T cells and natural killer (NK) cells. Critically, a bidirectional crosstalk operates between tumor cell metabolism and the immunosuppressive TME: metabolic reprogramming drives immune suppression through metabolite accumulation, whereas the immunosuppressive TME, in turn, promotes tumor cell adaptability-thus forming a positive feedback loop that reinforces immune evasion and therapy resistance. This review elucidates key molecular pathways governing metabolic reprogramming in lung cancer-spanning glucose, amino acid, and lipid metabolism-and their dynamic crosstalk with immune regulation, including epigenetic modifications and non-coding RNA-mediated mechanisms. Additionally, it evaluates emerging therapeutic strategies targeting the metabolic-immune axis, such as inhibitors of HK2 or GLS1 combined with anti-PD-1/PD-L1 agents, which aim to reverse immunosuppression and improve clinical outcomes. By synthesizing recent advances, this work provides a theoretical framework for precision oncology interventions, highlighting the potential of metabolic immunotherapies and future directions integrating AI and multi-omics data to overcome resistance in lung cancer.

Keywords:  Lung cancer; immune evasion; metabolic reprogramming; metabolic-immune axis; tumor microenvironment

DOI:  https://doi.org/10.32604/or.2026.076176
Front Psychiatry. 2026 ;17 1751605

DXM, CYP2D6-inhibiting antidepressants, piracetam, and glutamine: proposing a ketamine-class antidepressant regimen with existing drugs.

Ngo Cheung.

  Rapid-acting antidepressants show that mood can lift within hours when glutamatergic circuits shift from an "NMDA-dominant" to an "AMPA-dominant" state. Intravenous ketamine achieves this flip but is hampered by dissociation and logistics, while dextromethorphan + bupropion (Auvelity®) primarily supplies the initial NMDA blockade and yields slower, less durable benefit. We hypothesize that a fully oral, low-cost, four-component regimen may be able to approximate ketamine's full plasticity cascade (1) dextromethorphan (DXM) for NMDA antagonism; (2) a potent CYP2D6 inhibitor (fluoxetine, paroxetine, or high-dose duloxetine) to prolong DXM exposure; (3) piracetam as an AMPA positive allosteric modulator; and (4) micronized L-glutamine to restore presynaptic glutamate pools and buffer against excitotoxicity. Preclinical evidence supports mechanistic synergy along the same axis, but the full combination remains untested in humans. This hypothesis warrants formal preclinical and clinical evaluation.

Keywords:  CYP2D6-inhibiting antidepressants; DXM; depression; glutamatergic; glutamine; ketamine; piracetam

DOI:  https://doi.org/10.3389/fpsyt.2026.1751605
Vascul Pharmacol. 2026 Apr 01. pii: S1537-1891(26)00029-7. [Epub ahead of print] 107609

Untargeted metabolomic profiling reveals mTORC1-dependent regulation of amino acid utilization in lymphatic endothelial cells.

Jie Zhu, Felix Darko, Fei Han, Summer Simeroth, Lingjun Li, Haiwei Gu, Pengchun Yu.

  The lymphatic vascular system plays essential roles in tissue fluid drainage, dietary fat absorption and transport, and immune cell trafficking. To support these physiological functions, the lymphatic vasculature forms an extensive and highly organized network throughout the body. We recently discovered that the mechanistic target of rapamycin complex 1 (mTORC1), with RAPTOR as an indispensable component, directs glycolysis and glutaminolysis in lymphatic endothelial cells (LECs) to promote lymphatic vessel formation. However, the role of mTORC1 in regulating LEC metabolism remains incompletely understood. Here, by conducting untargeted metabolomic profiling of control and RAPTOR-deficient LECs, we uncover a global impact of mTORC1 inhibition on amino acid utilization. Specifically, RAPTOR deficiency impairs the conversion of glutamine to glutamic acid, resulting in decreased levels of glutamic acid and aspartic acid, as well as reduced abundance of N-acetyl-glutamic acid and N-acetyl-aspartic acid-two metabolites unexpectedly detected in LECs. Integrated metabolomic and transcriptomic analyses further reveal that impaired glutaminolysis in RAPTOR-depleted LECs is accompanied by increased intracellular asparagine, arginine, and metabolites associated with arginine catabolism, potentially driven by upregulation of their respective transporters. In addition, RAPTOR depletion results in abnormal accumulation of branched-chain amino acids (BCAAs) and other essential amino acids primarily involved in protein synthesis. Mechanistically, our data suggest that defective BCAA catabolism and impaired translational control contribute to these metabolic alterations. Collectively, these findings reveal an important role of mTORC1 signaling in coordinating amino acid utilization and suggest that this regulation is critical for lymphatic vessel formation.

Keywords:  Amino acid catabolism; Amino acid transporters; Essential amino acids; Lymphatic endothelial cells; Nonessential amino acids; RAPTOR; mTORC1

DOI:  https://doi.org/10.1016/j.vph.2026.107609
J Biol Chem. 2026 Mar 31. pii: S0021-9258(26)00289-9. [Epub ahead of print] 111419

SARS-CoV-2 envelope protein mitochondrial localization reveals host metabolic disruption.

Emily A David, Elijah J Bass, Hannah M Woods, Daniel Stephenson, Kellyann Román-Cruz, Charles E Chalfant, Robert V Stahelin.

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped virus that encodes four structural proteins, including the small transmembrane envelope (E) protein. While E is known to function in viral assembly and egress, it contributes to host cell dysfunction and disease severity. We demonstrate that SARS-CoV-2 E localizes to host cell mitochondria and alters mitochondrial structure, metabolism, and redox homeostasis. Using fluorescence microscopy, we observed that E forms tubular cytoplasmic structures that colocalize with mitochondria and ceramide-rich domains. Lipidomic analysis revealed that E expression leads to reductions in cardiolipin, phosphatidylcholine, and lysophospholipids. Mitochondrial membrane potential was decreased in E-expressing cells, consistent with disrupted electron transport chain (ETC) activity, which was further supported by mitochondria stress testing via Seahorse. Despite increased mitochondrial reactive oxygen species (ROS), E did not trigger apoptosis, suggesting containment of oxidative stress within the organelle. Metabolomic profiling revealed decreased levels of key glycolytic and tricarboxylic acid (TCA) cycle intermediates, along with altered glutathione and sulfur metabolism. Notably, glutamine levels increased, potentially to compensate for reduced 2-oxoglutarate. Together, these findings suggest that E protein localizes to the mitochondria, perturbs lipid and metabolic homeostasis, and promotes ROS retention without inducing cell death. This mitochondrial dysfunction may support a shift toward aerobic glycolysis, facilitating viral replication. Our study highlights an underappreciated role for E in modulating host metabolism.

Keywords:  SARS-CoV-2; cellular localization; envelope protein; membrane potential; metabolism; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1016/j.jbc.2026.111419
Front Nutr. 2026 ;13 1780996

Ameliorative effects of mulberry fruit anthocyanin extract on gut microbiota and liver metabolites in high-fat and high-cholesterol diet-fed ApoE-/- mice.

Tala Shi, Xinyuan Li, Shuo Wen, Wei Wang, Shuai Hou, Wenqing Jiang, Wei Mi, Zhiyong Hu, Wu Lian, Sha Liu, Peng Lu.

   Aim: This study aims to investigate the effects of mulberry anthocyanin (MA) in high-fat and high-cholesterol (HFHC) diet-fed ApoE-/- mice.
Methods: ApoE-/- mice were randomly divided into control (ACON), mulberry fruit anthocyanin extract (MFAE), cyanidin-3-glucoside (C3G) group 1 (C3GT), and C3G group 2 (C3GP). After 7 weeks of HFHC diet feeding and following 2-3 weeks of treatment, samples were collected and analyzed.
Results: The C3GT group significantly decreased low-density lipoprotein (7.3 ± 1.5 mmol/L) and interleukin-1β (355.4 ± 41.7 pg./mL) levels. Moreover, the MFAE (636.3 ± 90.7 pg./mL), C3GT (611.5 ± 65.4 pg./mL), and C3GP (757.5 ± 47.6 pg./mL) significantly increased glutathione peroxidase (GSH-PX) levels compared with those in the ACON group. The MA treatments significantly increased the number of Anaerotruncus, Tyzzerella, and Butyricicoccus, while decreasing the abundance of Sphingomonas, Odoribacter, and Rikenella. The MA intervention not only decreased the adenosine-5'-triphosphate (ATP) and indole-3-butyric acid but also upregulated the Pg36:3 and glutamine.
Conclusion: MA treatment may attenuate AS-associated risk factors by decreasing inflammatory factor-related gut microbial genera. The mechanism may be related to regulating liver glutamine, ATP, and related metabolic pathways.

Keywords:  cyanidin-3-O-glucoside; gut microbial; high fat and high cholesterol diet; liver metabolites; mulberry fruit anthocyanin extract

DOI:  https://doi.org/10.3389/fnut.2026.1780996
Nat Commun. 2026 Apr 01.

TNF alpha unmasks enteric malate aspartate shuttle dysfunction bridging Parkinson disease and intestinal inflammation.

Bruno Ghirotto, Luís Eduardo Gonçalves, Vivien Ruder, Christina James, Elizaveta Gerasimova, Tania Rizo, Holger Wend, Michaela Farrell, Juan Atilio Gerez, Natalia Cecilia Prymaczok, Merel Kuijs, Maiia Shulman, Anne Hartebrodt, Iryna Prots, Arne Gessner, Michael Vieth, Friederike Zunke, Jürgen Winkler, David B Blumenthal, Fabian J Theis, Roland Riek, Claudia Günther, Markus Neurath, Pooja Gupta, Beate Winner.

Gastrointestinal dysfunction often precedes motor symptoms in Parkinson's disease (PD), suggesting the enteric nervous system (ENS) is central to early pathogenesis. How α-synuclein contributes to ENS dysfunction, and how inflammation modulates this, remains unclear. Here we show that Tumor Necrosis Factor alpha enhances α-synuclein accumulation in induced pluripotent stem cell-derived enteric neurons and glia, and impairs the malate-aspartate shuttle, a key pathway for mitochondrial energy production. This drives a metabolic shift toward glutamine oxidation in patient cells. This metabolic impairment reduces overall mitochondrial function, which is partially rescued by the neuroprotective compound Chicago-Sky-Blue 6B. Furthermore, transcriptomic and histological analyses of human gut tissue from inflammatory bowel disease patients reveal that inflammation-associated metabolic suppression and α-synuclein upregulation occur beyond PD, representing general hallmarks of intestinal inflammation. These findings highlight a conserved metabolic vulnerability in the ENS and establish patient-derived enteric lineages as a robust platform to model inflammatory ENS pathology.

DOI: https://doi.org/10.1038/s41467-026-71317-y