bims-glucam 2025-07-13 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–07–13
ten papers selected by
Sreeparna Banerjee, Middle East Technical University

Beyond the tumor: Enhancing pancreatic cancer therapy through glutamine metabolism and innovative drug delivery.
Metabolic reprogramming in osteosarcoma.
Glutamine: A misunderstood amino acid with therapeutic potential.
Advances of SIRT4 in cancer metabolism and therapy.
Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity.
Interleukin-35 regulates the differentiation of regulatory T cells through the JAK-STAT pathway and influences glutamine metabolism in ARDS.
Natural products targeting the metabolism of amino acids: from discovery to synthetic development.
CPF Induces GC2spd Cell Injury via ROS/AKT/Efcab6 Pathway.
NF-κB-mediated cytokine secretion and glutamate metabolic reprogramming converge in breast cancer brain tropism.
Targeting Cystine Metabolism in the Lung Cancer Environment Enhances the Efficacy of Immune Checkpoint Inhibition.

J Cell Commun Signal. 2025 Sep;19(3): e70033

Beyond the tumor: Enhancing pancreatic cancer therapy through glutamine metabolism and innovative drug delivery.

Min Su, Huan Qin, Jie Shen, Hao An, Yu Cao.

  Pancreatic ductal adenocarcinoma (PDAC) depends a lot on how it uses glutamine to grow quickly and stay alive. Oncogenic drivers such as KRAS, c-Myc, and HIF-1α increase how much glutamine gets taken up and broken down. Meanwhile, the bacteria in the gut and tumor itself also affect how much glutamine is available throughout the body and near the tumor. This impacts both how the tumor grows and how the immune system can detect and respond to it. Multiple strategies have emerged to disrupt this dependence: glutamine antagonists (DON and its prodrugs DRP-104, JHU-083), small-molecule glutaminase inhibitors (CB-839), antibody-drug conjugates targeting the ASCT2 transporter, and combination regimens pairing glutamine blockade with immune checkpoint inhibitors. Nanoparticle formulations-including pH-sensitive and PEGylated liposomes co-delivering DON and gemcitabine-enable targeted delivery and reduce off-target toxicity. Single-agent treatments do not work so well because the cells can adapt. They boost enzymes such as asparagine synthetase and increase how they burn fatty acids to make up for the lack of glutamine. To overcome these escape routes, future interventions must concurrently target compensatory pathways and integrate biomarker-driven patient selection. Combining glutamine-targeted agents with inhibitors of asparagine synthesis or lipid oxidation, guided by multi-omics profiling, promises a more durable therapeutic benefit and lays the groundwork for personalized treatment of PDAC.

Keywords:  DON; drug delivery systems; glutamine metabolism; pancreatic cancer; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.1002/ccs3.70033
Pediatr Discov. 2023 Sep;1(2): e18

Metabolic reprogramming in osteosarcoma.

Yulu Shi, Xiaohan Yue, Qing Luo.

  Tumor cells undergo metabolic reprogramming to meet their energy and anabolic demands to maintain their malignant phenotype. Activation of oncogenes and deletion of tumor suppressors promotes metabolic reprogramming in cancer by directly or indirectly regulating enzymatic activities associated with metabolic pathways. Metabolic reprogramming in tumor cells mainly involves the glycolytic pathway, pentose phosphate pathway, serine synthesis pathway, enhanced glutamine metabolism or fatty acid anabolism, and abnormal mitochondrial oxidative phosphorylation (OXPHOS). The tricarboxylic acid (TCA) cycle is the central pathway of mitochondrial OXPHOS, and glucose, amino acid and fatty acid metabolism are associated with the TCA cycle. Metabolic abnormalities and rewiring of metabolic pathways are also present in Osteosarcoma (OS). The abnormal metabolic pattern in OS is associated with cell proliferation, migration, invasion and drug resistance. This review summarizes the current studies on glycolysis, amino acid metabolism, lipid synthesis and the TCA cycle related to OS.

Keywords:  OXPHOS; amino acid; fatty acid; glycolytic; metabolism; osteosarcoma

DOI:  https://doi.org/10.1002/pdi3.18
Nutr Health. 2025 Jul 10. 2601060251356147

Glutamine: A misunderstood amino acid with therapeutic potential.

Michael K McMullen.

  Background: Glutamine is an amino acid with trophic activity in the small intestine. The small intestine derives exogenous glutamine from foods and endogenous glutamine from arterial blood. Glutamine is vital for the rapidly proliferating enterocytes lining the intestinal mucosa and promotes the expression of proteins in the tight junctions, strengthening the barrier function and reducing gut permeability. With excessive physical activity, malnutrition, acute and chronic illnesses, sarcopenia or prolonged fasting, plasma levels drop. When glutamine is depleted, the small intestine atrophies causing increased gut permeability and bacterial dislocation. The use of intravenous glutamine is well established in critical medicine, by increasing depressed glutamine plasma levels intestinal atrophy is averted. Therefore, glutamine is classified as a conditionally essential amino acid. Aim: To calculate the amounts of glutamine derived from both food and endogenous processes and to establish a suitable dosage for oral supplementation. Methods: The contribution of dietary amino acids and endogenous glutamine was assessed and compared. The pharmacokinetics of glutamine supplementation was reviewed. Results: Approximately 88% of the glutamine metabolised daily is endogenously produced. Almost half of this comes from muscle protein breakdown. Studies with supplemental free-form glutamine for treating intestinal permeability, at doses based on dietary intake, have not yielded positive results, whereas doses of 30 g glutamine, similar to daily amount metabolised by the enterocytes yielded positive results. Discussion: Clinical doses of free-form glutamine for intestinal disorders should be akin to the daily amount of glutamine metabolised by the small intestine rather than the daily dietary intake.

Keywords:  Glutamine; enterocyte; gut permeability; leaky gut; small intestine

DOI:  https://doi.org/10.1177/02601060251356147
Pediatr Discov. 2023 Sep;1(2): e17

Advances of SIRT4 in cancer metabolism and therapy.

Xiaohan Yue, Yulu Shi, Qing Luo.

  The Sirtuins family consists of SIRT1-SIRT7, which belong to class III of the histone deacetylases, a family of highly conserved NAD (nicotinamide adenine dinucleotide)-dependent enzymes expressed in the nucleus, cytoplasm, and mitochondria. In addition to having ADP-ribosyltransferase, NAD+-dependent deacetylase, lipoamide, and long-chain deacetylase activities, it can also regulate the function of substrate proteins through ADP-ribosylation, diacylation, and long-chain deacylation. These enzyme activities also confer many critical biological functions on SIRT4, making SIRT4 involved in many mitochondrial energy metabolic processes, such as promoting insulin secretion, participating in the glycolytic process in concert with glycolysis inhibitors, inhibiting glutamate dehydrogenase from regulating glutamine metabolism, and participating in reactions such as DNA damage. Because SIRT4 has such diverse functions, it plays a role in the metabolism and treatment of tumors. Here, we review the progress of SIRT4 research in tumor metabolism and therapy.

Keywords:  SIRT4; cancer; cancer metabolism; cancer therapy

DOI:  https://doi.org/10.1002/pdi3.17
bioRxiv. 2025 Jul 06. pii: 2025.07.04.663231. [Epub ahead of print]

Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity.

Eric Greene, Richard Muniz, Hiroki Yamamura, Samuel E Hoff, Priyanka Bajaj, D John Lee, Erin M Thompson, Angelika Arada, Gyun Min Lee, Massimiliano Bonomi, Justin M Kollman, James S Fraser.

To maintain metabolic homeostasis, enzymes must adapt to fluctuating nutrient levels through mechanisms beyond gene expression. Here, we demonstrate that human glutamine synthetase (GS) can reversibly polymerize into filaments aided by a composite binding site formed at the filament interface by the product, glutamine. Time-resolved cryo-electron microscopy (cryo-EM) confirms that glutamine binding stabilizes these filaments, which in turn exhibit reduced catalytic specificity for ammonia at physiological concentrations. This inhibition appears induced by a conformational change that remodulates the active site loop ensemble gating substrate entry. Metadynamics ensemble refinement revealed >10 Å conformational range for the active site loop and that the loop is stabilized by transient contacts. This disorder is significant, as we show that the transient contacts which stabilize this loop in a closed conformation are essential for catalysis both in vitro and in cells. We propose that GS filament formation constitutes a negative-feedback mechanism, directly linking product concentration to the structural and functional remodeling of the enzyme.

DOI: https://doi.org/10.1101/2025.07.04.663231
Int Immunol. 2025 Jul 11. pii: dxaf041. [Epub ahead of print]

Interleukin-35 regulates the differentiation of regulatory T cells through the JAK-STAT pathway and influences glutamine metabolism in ARDS.

Qiao-Zhi Peng, Mu Zhang, Ai-Ping Zhang, Min-Kang Guo, Ren-Jie Luo, Ling Zeng, Chang Chen, Shi-Hui Lin, Fang Xu, Ke Xie.

  The aim of this study was to elucidate the effect of IL-35 on T cell differentiation and its mechanism. We evaluated the therapeutic effect of IL-35 on acute respiratory distress syndrome (ARDS) using clinical samples and mouse cecum ligation and puncture (CLP) model. The effects of IL-35 on Regulatory T cells (Treg) were verified by flow cytometry, immunohistochemistry (IHC) and qRT-PCR. Liquid chromatography-mass spectrometry (LC-MS) was used to detect the effects of IL-35 on changes in glutamin metabolites and TCA circulation. Western blot was used to detect changes in forkhead box protein 3 (Foxp3), key enzymes and STAT phosphorylation subgroup proteins in the presence of cerdulatinib. Finally, A549 cells were treated with EL-4 cell supernatant to explore the effect of cerdulatinib on the therapeutic effect of IL-35 injury. Inflammatory factors decreased and Foxp3 increased in response to IL-35. In addition, Foxp3 was upregulated in a glutamine-deficient environment, and notably, glutamine-related metabolism and TCA cycle-related substances were altered with the involvement of IL-35. IL-35 upregulated phosphorylation of STAT isoforms, and cerdulatinib reversed it. Finally, the effects of IL-35 on Foxp3, key enzymes and glutamine metabolite changes were all reversed by cerdulatinib. Our study shows that IL-35 reduces lung inflammation and promotes Treg differentiation. IL-35 affects the glutamine metabolism and the TCA cycle. In addition, we demonstrated that the relevant functions of IL-35 may be mediated by STAT isoform phosphorylation.

Keywords:  IL-35; Treg

DOI:  https://doi.org/10.1093/intimm/dxaf041
Nat Prod Rep. 2025 Jul 11.

Natural products targeting the metabolism of amino acids: from discovery to synthetic development.

Hyun Su Kim, Ahmed H E Hassan, Kyuho Moon, Jaehoon Sim.

Covering: up to 2025Amino acids constitute the essential components of biological systems. Over the recent years, there has been a growing interest in exploring amino acid metabolism as a source of novel druggable targets for intractable diseases such as cancer, metabolic disorders, and degenerative diseases. Culminating research has unveiled novel therapeutic targets associated with amino acid metabolism, including glutamine, cysteine, arginine, and tryptophan metabolism. The pursuit of therapeutic drug targets has resulted in the discovery of potential modulators showing promise for the development of new drug candidates. Many of these modulators have been derived from natural products, employing diverse methods such as traditional medical knowledge, high-throughput screening, and bioinformatics approaches. Based on these discoveries, a variety of synthetic analogues have been developed to improve pharmacological profiles, target selectivity, and drug-like properties. Structural optimization of natural product scaffolds, including derivatization, bioisostere incorporation, and prodrug strategies, has enabled the rational design of potent inhibitors targeting amino acid metabolism. These efforts have expanded the utility of naturally occurring inhibitors, offering enhanced efficacy and therapeutic potential. In this review, we systematically categorize natural products that target enzymes involved in amino acid metabolism, highlighting the recent advances in their development as medicinal agents. This work aims to provide a valuable resource for researchers by outlining the therapeutic potential of natural products and identifying opportunities for future investigation.

DOI: https://doi.org/10.1039/d5np00039d
Cells. 2025 Jun 20. pii: 940. [Epub ahead of print]14(13):

CPF Induces GC2spd Cell Injury via ROS/AKT/Efcab6 Pathway.

Xuelian Zhang, Mengyang Zhang, Chunzhi Wang, Qingchuan Song, Haiyan Yang, Qi Tang, Qiaoling Zhao, Jing Wang, Chuanying Pan.

  Chlorpyrifos (CPF) has been extensively utilized in recent decades due to its highly efficient insecticidal properties. However, the widespread use of pesticides has posed new challenges to male reproduction. This study aims to explore the potential molecular mechanisms of male reproductive decline induced by CPF. We employ flow cytometry, qRT-PCR, Western blot, RNA sequencing, and bioinformatics analysis to investigate the potential molecular mechanisms involved in CPF-induced male reproductive damage in GC2spd cells. Our results revealed that after 24 h of CPF treatment, the cell viability, cell cycle, apoptosis, and reactive oxygen species (ROS) accumulation of GC2spd cells were significantly affected in vitro. RNA sequencing analysis data indicated that a total of 626 genes were differentially expressed compared to the DMSO group, especially for Efcab6, Nox3, and Cmpk2. These differential genes were mainly enriched in signaling pathways such as PI3K-AKT and glutamine metabolism. In addition, further validation through qRT-PCR, Western blot, and experiments involving the inhibition of intracellular ROS generation with N-acetylcysteine collectively confirmed that CPF induces male reproductive damage through the ROS/AKT/Efcab6 pathway. These studies elucidate potential targets and molecular mechanisms underlying CPF-induced male infertility, providing a theoretical basis for the prevention of male reproductive damage caused by pesticide residues.

Keywords:  Chlorpyrifos; Efcab6; PI3K-AKT; RNA-Sequencing; male infertility

DOI:  https://doi.org/10.3390/cells14130940
Cancer Lett. 2025 Jul 08. pii: S0304-3835(25)00475-6. [Epub ahead of print] 217907

NF-κB-mediated cytokine secretion and glutamate metabolic reprogramming converge in breast cancer brain tropism.

Sara Di Russo, Giulia Elizabeth Borsatti, Amani Bouzidi, Francesca Romana Liberati, Agnese Riva, Farida Tripodi, Lucrezia Romana Rolfi, Sharon Spizzichino, Antonella Tramutola, Marzia Perluigi, Daniela Trisciuoglio, Giorgio Giardina, Alessandro Paiardini, Paola Coccetti, Serena Rinaldo, Francesca Cutruzzolà, Alessio Paone.

  Brain metastases are an increasingly common and life-threatening complication of breast cancer. Here, we report that breast cancer cells with a propensity for cerebral colonization (BrM cells) display a distinct imbalance in the NF-κB pathway characterized by elevated IKKβ and reduced IKKα levels. This imbalance reduces the levels of the downstream NF-κB modulators IκBα and TAX1BP1, fostering a chronically active pro-inflammatory program. Such BrM cells secrete high concentrations of IL-8 and GRO chemokines, enhancing blood-brain barrier permeability in vitro and triggering astrocyte activation in vivo. In parallel, we observed that the altered NF-κB signaling increases the expression of glutamate transporters EAAT1 and EAAT2, which allows BrM cells to uptake and utilize glutamate, a neurotransmitter readily available in the brain, as a key energy source. Analysis of energy metabolism confirms a pronounced reliance on glutamate for both oxidative phosphorylation and glycolysis, which correlates with an increased migratory and invasive capacity. Importantly, pharmacological inhibition of glutamate import curtails in vitro migratory ability and reduces the formation of brain lesions in a murine model. Our study thus highlights a dual strategy employed by BrM cells, whereby they orchestrate a pro-inflammatory milieu to breach the BBB and simultaneously exploit glutamate metabolism to sustain invasiveness. These findings highlight the inflammatory-metabolic axis as a promising target for therapeutic or preventive strategies against breast cancer progression to the brain.

Keywords:  Breast cancer; NF-κB signaling; blood-brain barrier; brain metastasis; glutamate; inflammation

DOI:  https://doi.org/10.1016/j.canlet.2025.217907
Adv Sci (Weinh). 2025 Jul 10. e13084

Targeting Cystine Metabolism in the Lung Cancer Environment Enhances the Efficacy of Immune Checkpoint Inhibition.

Yun Xu, Shumin Li, Jiaji Wu, Shumin Xu, Mo Shen, Chenyang Wang, Lundqvist Andreas, Jianghao Yu, Zhiyong Xu, Yueli Shi, Nana Liu, Yunke Yang, Jiangnan Zhao, Ying Yang, Pingli Wang, Peng Yi, Jin Cheng, Junhui Sun, Mengshu Li, Peng Xiao, Kai Wang.

  Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has shown promising therapeutic effects in the treatment of lung cancer, the overall efficacy of PD-1/PD-L1 inhibitors is only 20%-30%. Thus, more effective combination therapies are needed. This study finds that cystine and cysteine levels in tumor tissues of lung cancer patients are significantly higher than adjacent non-tumor tissues. Cystine deficiency polarizes macrophages toward an M1 phenotype, secreting more TNF-α, CXCL9, and CXCL10. However, using a cystine-free diet marginally reduces the development of lung cancer in vivo. A cystine-free diet slightly reduces lung cancer progression in vivo. Further studies show that cystine deprivation or erastin-mediated transport inhibition increased PD-L1 expression in macrophages both in vitro and in vivo. Combining a cystine-free diet or IKE injection with PD-L1 antibody treatment significantly inhibited subcutaneous tumor growth in mice. Mechanistic studies indicat that cystine deficiency-induced GSH depletion activates NF-κB in macrophages by reducing its glutathionylation. This effect can be reversed by replenishing GSH or using an NF-κB inhibitor. At the same time, lung cancer patients with better responses to immunotherapy are found to have lower serum GSH levels. These findings suggest that targeting cystine metabolism combined with PD-L1 inhibition is a promising therapeutic strategy.

Keywords:  PD‐L1; cystine; immunotherapy; lung cancer; macrophage polarization; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202413084