bims-glucam 2025-07-06 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–07–06
eleven papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting glutamine metabolism as a potential target for cancer treatment.
Non-canonical nuclear function of glutaminase cooperates with Wnt signaling to drive EMT during neural crest development.
Cathepsin K Aggravates Pulmonary Fibrosis Through Promoting Fibroblast Glutamine Metabolism and Collagen Synthesis.
Ghrelin attenuates metabolic dysfunction-associated steatotic liver disease by activating glutamine metabolism via inhibition of the IRE1α-XBP-1 pathway.
Systemic metabolic changes in acute and chronic lymphocytic choriomeningitis virus infection.
A novel glutamine metabolism-related risk model for prognostic prediction of liver hepatocellular carcinoma.
L-arginine vs. L-glutamine oral suspensions for radiation-induced oral mucositis: a triple-blind randomized trial.
Targeting CAF-specific metabolic pathways in breast cancer.
SIRT5 inhibition impairs mitochondrial metabolism and enhances venetoclax-induced elimination of acute myeloid leukemia cells.
Involvement of KEAP1/NRF2 pathway in non-BRAF mutated squamous cell carcinoma of the thyroid.
[Metabolic insights into cellular senescence and in therapeutic approaches].

J Exp Clin Cancer Res. 2025 Jul 01. 44(1): 180

Targeting glutamine metabolism as a potential target for cancer treatment.

Wenxuan Zou, Zitao Han, Zihan Wang, Qian Liu.

  Metabolic reprogramming is a hallmark of cancer cells, and the advent of "glutamine addiction" in numerous tumors signifies a pivotal advancement for precision-targeted therapy. This review demonstrates that glutamine metabolism is a pivotal factor in the development of malignant phenotypes in tumors by modulating multifaceted regulatory networks (Hippo/YAP, mTORC1 signaling pathway, and non-coding RNAs). These networks play a crucial role in the reprogramming of glutamine metabolism, which in turn affects various hallmarks of cancer, including cancer cell proliferation, ROS-mediated inhibition of apoptosis, and EMT-associated invasive metastasis. With respect to targeted therapeutic strategies, the focus on key transporters and metabolizing enzymes (ASCT2/GLS1) provides a theoretical foundation for the development of multi-targeted combination therapeutic regimens based on the inhibition of glutamine metabolism. A body of research has demonstrated that the metabolic processes of glutamine regulate a variety of immune system functions, including T cell depletion/activation, the polarization of TAMs, and the function of NK cells. This regulatory relationship, termed the metabolic-immune axis, is a crucial factor in the development of immune escape mechanisms by tumors. The study further suggests that a combination of targeted intervention strategies, involving the modulation of glutamine metabolism, has the potential to reshape the immune microenvironment and enhance the efficacy of CAR-T cell therapy. It is important to note that glutamine metabolism also affects tumor stroma formation by remodeling cancer-associated fibroblasts (CAFs). In response to therapeutic resistance mechanisms, tumor cells form adaptive escapes through ASNS and GAD metabolic branch activation, glucose/lipid metabolic compensation, and ATF4 transcriptional stress networks. This review systematically integrates the critical role of glutamine metabolism in tumor development and therapeutic resistance, providing new perspectives and translational pathways for the development of precision therapeutic strategy selection based on metabolic plasticity modulation.

Keywords:  Anticancer targets; Drug resistance; Glutamine metabolism; Immune evasion; Malignant progression of tumors

DOI:  https://doi.org/10.1186/s13046-025-03430-7
Nat Commun. 2025 Jul 01. 16(1): 5554

Non-canonical nuclear function of glutaminase cooperates with Wnt signaling to drive EMT during neural crest development.

Nioosha Nekooie Marnany, Alwyn Dady, Isabelle Duband-Goulet, Frédéric Relaix, Roberto Motterlini, Roberta Foresti, Sylvie Dufour, Jean-Loup Duband.

Metabolic reprograming has been linked to epithelial-to-mesenchymal transition (EMT) in cancer cells, but how it influences EMT in normal cells remains largely unknown. Here we explored how metabolism impacts delamination and migration of avian trunk neural crest cells, an important progenitor cell population of the vertebrate embryo. We report that delamination exhibits a quiescent metabolic phenotype whereas migration is characterized by OXPHOS-driven metabolism coupled to distinct expression of metabolic, EMT and developmental genes. While glucose and glutamine are required for delamination and migration, we uncover a specific role for glutamine and its catabolizing enzyme glutaminase in the unfolding of NCC delamination. Namely, glutamine is required for nuclear accumulation of glutaminase, which interacts and cooperates with Wnt signaling to regulate EMT gene expression and cell cycle during delamination. Our data indicate that similarly to cancer cells, embryonic cells engage metabolic enzymes for non-canonical signaling functions to connect metabolism with EMT.

DOI: https://doi.org/10.1038/s41467-025-58573-0
Adv Sci (Weinh). 2025 Jul 03. e13017

Cathepsin K Aggravates Pulmonary Fibrosis Through Promoting Fibroblast Glutamine Metabolism and Collagen Synthesis.

Mengting Chen, Xiaoxiao Meng, Yong Zhu, Dapeng Wang, Mengmeng Wang, Ziyuan Wang, Xue Tian, Jiaxiang Zhang, Zhiying Yue, Zhengfeng Yang, Ruilan Wang.

  Fibroblast collagen synthesis is a hallmark of the pathogenesis and progression of pulmonary fibrosis (PF). However, the factors that trigger the abnormal activation of fibroblasts in PF are still not well understood. Using proteomics and single-cell sequencing dataset screening, extra accumulation of Cathepsin K (CTSK) is detected in the periphery as well as in fibroblasts in the lungs of PF mouse models. Addition of recombinant CTSK (rCTSK) aggravates collagen accumulation and PF progression in bleomycin-induced PF mice. Mechanically, CTSK underwent endocytosis through interaction with sorting nexin 9 (SNX9), which is engaged in TGF-β1 induced SMAD3 activation for downstream glutaminase 1 (GLS1) upregulation and glutamine enrichment. In turn, extra glutamine increases collagen synthesis in fibroblasts. More significantly, serum CTSK levels positively correlated with glutamine levels and poor prognosis in patients with PF. Thus, the results identify CTSK as a novel regulator of fibroblast activation that remodels glutamine metabolism and promotes collagen synthesis during PF pathogenesis. The correlation between peripheral CTSK and glutamine levels implies its future feasibility in the prediction and prevention of PF progression.

Keywords:  CTSK; SNX9; collagen synthesis; glutamine metabolism; pulmonary fibrosis

DOI:  https://doi.org/10.1002/advs.202413017
Biochem Pharmacol. 2025 Jun 26. pii: S0006-2952(25)00354-5. [Epub ahead of print]240 117089

Ghrelin attenuates metabolic dysfunction-associated steatotic liver disease by activating glutamine metabolism via inhibition of the IRE1α-XBP-1 pathway.

Qian Zhao, Jun Xu, Ziqiang Xia, Xiangyin Lv, Yaling Lou, Nan Ye, Dandan Zhu, Yixiao Wang, Yuan Zeng, Xiangting Zhang, Weimin Cai, Huiya Ying, Ruoru Zhou, Tianhao Weng, Fujun Yu.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a complex interplay of metabolic and cellular stress pathways. Disruptions in several metabolic processes, including endoplasmic reticulum (ER) stress, glutamine metabolism, and ferroptosis, are key in the initiation and progression of MASLD. Although ghrelin confers protective effects against MASLD, its mechanism of action remains unclear. This study aimed to investigate the role of ghrelin in MASLD management and lipid reduction. Male C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to establish a chronic MASLD model. From weeks 7 to 12, the mice received intraperitoneal ghrelin (10 µg/kg) twice a week. Liver and serum samples were obtained for histological and biochemical analyses. In vitro analysis was performed using HepG2 cells. The findings revealed that ghrelin protected liver cells from oxidative stress and ferroptosis by stimulating stearoyl-CoA desaturase-1 (SCD1)-mediated lipogenesis and the ASCT2/glutaminase-1 (GLS1)/mTORC1 signaling pathway, mitigating HFD-induced hepatic injury. Notably, these protective effects of ghrelin against SCD1-mediated ferroptosis were inhibited by the GLS1-specific inhibitor, BPTES. Additionally, ghrelin exerted protective effects on liver cells in HFD-fed mice by suppressing IRE1α-XBP-1-mediated ER stress signaling. Conversely, the IRE1/XBP1s activator IXA4 diminished the protective effects of ghrelin on glutamine metabolism and ferroptosis. SCD1 deficiency resulted in mTORC1 activation, exacerbating ER stress. SCD1 modulates cellular metabolism and stress responses by regulating mTORC1 activity, forming an interactive closed-loop system. Collectively, ghrelin enhances ASCT2/mTORC1/SCD1 signaling to confer resistance to ferroptosis by inhibiting ER stress-mediated IRE1α-XBP-1 signaling, alleviating ferroptosis and lipid accumulation in the context of MASLD.

Keywords:  ASCT2/mTORC1/SCD1 signaling; Endoplasmic reticulum stress; Ferroptosis; Ghrelin; Metabolic dysfunction-associated steatotic liver disease

DOI:  https://doi.org/10.1016/j.bcp.2025.117089
Mol Metab. 2025 Jun 26. pii: S2212-8778(25)00101-2. [Epub ahead of print] 102194

Systemic metabolic changes in acute and chronic lymphocytic choriomeningitis virus infection.

Caroline Bartman, Shengqi Hou, Fabian Correa, Yihui Shen, Victoria da Silva-Diz, Maya Aleksandrova, Daniel Herranz, Joshua D Rabinowitz, Andrew Intlekofer.

  Viral infection of cells leads to metabolic changes, but how viral infection changes whole-body and tissue metabolism in vivo has not been comprehensively studied. In particular, it is unknown how metabolism might be differentially affected by an acute infection that the immune system can successfully clear compared to a chronic persistent infection. Here we used metabolomics and isotope tracing to identify metabolic changes in mice infected with acute or chronic forms of lymphocytic choriomeningitis virus (LCMV) for three or eight days. Both types of infection alter metabolite levels in blood and tissues, including itaconate and thymidine. However, we observed more dramatic metabolite changes in the blood and tissues of mice with persisting LCMV infection compared to those infected with the acute viral strain. Isotope tracing revealed that the contribution of both glucose and glutamine to the tricarboxylic acid (TCA) cycle increase in the spleen, liver, and kidneys of mice infected with chronic LCMV, while acute LCMV only increases the contribution of glutamine to the TCA cycle in the spleen. We found that whole-body turnover of both glutamine and thymidine increase during acute and chronic infection, whereas whole-body glucose turnover was surprisingly unchanged. Activated T cells in vitro produce thymidine and virus-specific T cells ex vivo have increased thymidine levels, nominating T lymphocytes as the source of thymidine in LCMV infection. In sum, we provide comprehensive measurements of whole-body and tissue metabolism in acute and chronic viral infection, and identify altered thymidine metabolism as a marker of viral infection.

Keywords:  Immunometabolism; Isotope tracing; Metabolomics; Tissue metabolism; Whole-body metabolism

DOI:  https://doi.org/10.1016/j.molmet.2025.102194
Oncol Lett. 2025 Sep;30(3): 403

A novel glutamine metabolism-related risk model for prognostic prediction of liver hepatocellular carcinoma.

Xia He, Rui Wang, Yonghua Zhu, Xi Chen, Yu Zhang, Min Sun.

  Glutamine has emerged as a focus of cancer metabolism research, although its role in liver hepatocellular carcinoma (LIHC) has yet to be fully elucidated. To determine the role of glutamine metabolism in the development of LIHC, the gene expression profiles and the clinical data of patients with LIHC were obtained from The Cancer Genome Atlas database and the International Cancer Genome Consortium website. Consensus clustering was used to identify distinct molecular clusters. Functional en 10.3892/ol.2025.15149 richment analysis between clusters was performed using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases, and gene set variation analysis was performed. Least absolute shrinkage and selection operator and multivariate Cox regression analyses were then performed to generate a novel prognostic model. The prognostic, immune, mutational and drug-sensitive characteristics of the model were subsequently evaluated. The clinical proteomic tumor analysis consortium and reverse transcription-quantitative PCR analysis were then used to assess the protein and mRNA expression levels of the modeled genes. In addition, western blot analysis and Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, Transwell and wound healing assays were performed to further evaluate the role of glutamate-oxaloacetate transaminase 2 (GOT2) in the pathogenesis of LIHC. Data from multiple LIHC cohorts were utilized to identify two distinct clusters of LIHC, each characterized by unique clinical and immunological features associated with different levels of glutamine metabolism-related genes. Numerous functional pathway differences were identified between these clusters, and these were demonstrated to be crucial for the onset and progression of LIHC. For modeling of glutamine metabolism-related features, patients with LIHC were divided into two groups, namely a high- and a low-risk group. Different clusters of patients with LIHC exhibited distinct characteristics in terms of their clinicopathological features, drug-sensitivity and mutations. For example, the high-risk group had a higher mutational load and was associated with a poorer prognosis compared to the low-risk group. Finally, GOT2 protein and mRNA expression levels were significantly lower in LIHC tissues compared to paracancerous tissues, and GOT2 knockdown promoted the malignant phenotype of LIHC. In conclusion, the results of the present study indicate that glutamine metabolism exerts a crucial role in the tumorigenesis and progression of LIHC, and that this is positively associated with poor prognosis. The identified glutamine metabolism-related signature was revealed to have notable accuracy in predicting the prognosis and immune characteristics of patients with LIHC. Moreover, the expression level of GOT2 was downregulated in LIHC, and a low expression of GOT2 was indicative of a poor prognosis for patients with LIHC, suggesting that the expression of GOT2 may be used as a potential therapeutic target.

Keywords:  glutamine metabolism; liver hepatocellular carcinoma; prediction model

DOI:  https://doi.org/10.3892/ol.2025.15149
J Cancer Res Clin Oncol. 2025 Jul 03. 151(7): 198

L-arginine vs. L-glutamine oral suspensions for radiation-induced oral mucositis: a triple-blind randomized trial.

Fatma E A Hassanein, Christine Mikhail, Sarah Elkot, Asmaa Abou-Bakr.

   PURPOSE: Radiation-induced oral mucositis (RIOM) severely impacts patients with head and neck cancer (HNC) undergoing radiotherapy, often leading to pain and malnutrition. L-arginine and glutamine are immune-enhancing amino acids with potential benefits in wound healing and inflammation control. This study evaluated the efficacy of L-arginine versus L-glutamine oral suspensions in managing RIOM.
METHODS: In this triple-blind, randomized controlled trial, 69 HNC patients with RIOM were allocated to three groups (n = 23 each): Group I (L-arginine 5 g + maltodextrin 5 g), Group II (glutamine 5 g + maltodextrin 5 g), or Group III (maltodextrin 10 g). Outcomes, assessed at weeks 2, 5, and 7 of radiotherapy, included the WHO oral mucositis scale, Pain Visual Analogue Scale (Pain-VAS), body mass index (BMI), and Oral Health Impact Profile (OHIP-14) questionnaire.
RESULTS: By week 5, WHO scale scores differed significantly among groups (p < 0.001), with arginine and glutamine groups exhibiting lower mucositis severity than the maltodextrin group. Pain-VAS scores at weeks 5 and 7 were significantly lower in the arginine and glutamine groups compared to maltodextrin (p = 0.004 and p < 0.001, respectively). By 7th week of radiotherapy, BMI was significantly decreased in the maltodextrin group than in either the arginine (p = 0.028) or glutamine (p = 0.001) groups, indicative of treatment-mediated weight loss. In contrast, the BMI over time in the arginine (p = 0.87) and glutamine (p = 0.170) groups were almost constant. This indicates that compared to maltodextrin alone, both amino acid supplements prevented a decline in BMI during radiotherapy. OHIP-14 scores improved significantly in the arginine and glutamine groups at weeks 5 and 7 (p < 0.001), indicating better quality of life.
CONCLUSIONS: Both L-arginine and glutamine significantly reduced RIOM severity, pain, and weight loss compared to maltodextrin, while improving quality of life in patients with head and neck cancer. Although no statistically significant difference was found between the two, a higher proportion of patients receiving L-arginine achieved complete healing by week 7, suggesting a potential late advantage. These findings support the use of both amino acids as viable options for symptom management during radiotherapy.
TRIAL REGISTRATION: ClinicalTrials.gov (NCT06764420), registered 08/01/2024.

Keywords:  Head and neck cancer; L-arginine; L-glutamine; Oral mucositis; Radiotherapy

DOI:  https://doi.org/10.1007/s00432-025-06213-x
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jul 01.

Targeting CAF-specific metabolic pathways in breast cancer.

Alaa Khalaf Bediwi, Ahmed Hjazi, Mundher Kedhem, Ali G Alkhathami, RenukaJyothi S, Priya Priyadarshini Nayak, Amrita Pargaien, Udaybir Singh, Fathi Jihad Hammady, Salah Abdulhadi Salih.

  Breast cancer (BC) cells are distinguished by their capacity to reconfigure metabolism to support rapid growth and survive in hypoxic, nutrient-deficient environments. In the breast tumor microenvironment (TME), metabolic changes-including the Warburg effect, modifications in Krebs cycle intermediates, and adjusted oxidative phosphorylation-are closely associated with the dynamic signaling between tumor cells and stromal elements. Cancer-associated fibroblasts (CAFs), a diverse and adaptable group inside the stroma, significantly influence metabolic pathways, including those regulating glucose, amino acid, and lipid metabolism. Recent research underscores that the metabolic interaction between BC cells and CAFs not only promotes tumor growth and invasion but also facilitates treatment resistance. This review is aimed at consolidating the existing data on the metabolic interactions between BC cells and CAFs, highlighting molecular mechanisms and pathways that could represent potential targets for future therapies.

Keywords:  Breast cancer; Cancer-associated fibroblasts; Metabolic pathways; Targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00210-025-04390-7
Leukemia. 2025 Jun 30.

SIRT5 inhibition impairs mitochondrial metabolism and enhances venetoclax-induced elimination of acute myeloid leukemia cells.

Moran Wang, Ruiqi Zhu, Donald Small, Lan Lin, Li Li, Shengling Ma, Linghui Xia, Shanshan Luo, Wenjuan He, Jianming Yu, Junying Li, Ruowen Wei, Ao Zhang, Wei Shi, Yu Hu.

Metabolic reprogramming is a key focus of targeted therapies in acute myeloid leukemia (AML). The mitochondrial sirtuin SIRT5 removes succinyl groups from specific lysines and impacts cell metabolism, but its role in AML tumorigenesis has not been extensively explored. A recent study highlighted that SIRT5 regulates AML cell activity by modulating glutamine metabolism, but its molecular targets in AML remain unclear. This study aims to identify the substrates of SIRT5 in AML. It was found that a total of 83 proteins with 121 lysine (K) residues showed increased succinylation after SIRT5 knockdown, as determined by succinylome analysis of MOLM-13 cells. SIRT5 was validated to interact with HADHA, a key molecule in the fatty acid oxidation pathway. Knockdown of SIRT5 resulted in hypersuccinylation and reduced enzymatic activity of HADHA. Mimetic mutations of lysine indicated that SIRT5 desuccinylates HADHA at K644. Inhibiting SIRT5 or HADHA increased sensitivity to venetoclax (VEN) in both VEN-sensitive and VEN-resistant cell lines. SIRT5 knockdown enhanced VEN-mediated suppression of mitochondrial metabolism and improved the survival of AML-transplanted NSG mice when combined with VEN. This study reveals the role of SIRT5 in AML metabolic regulation and provides valuable insights for developing SIRT5-targeted drugs and combination therapies with metabolic inhibitors.

DOI: https://doi.org/10.1038/s41375-025-02673-9
J Pathol. 2025 Jul 02.

Involvement of KEAP1/NRF2 pathway in non-BRAF mutated squamous cell carcinoma of the thyroid.

Elin Schoultz, Jakob Dahlberg, Lisa M Nilsson, Jozefina J Dzanan, Therese Carlsson, Niklas Dahr, Ellinor Andersson, Ghayeb Muhammad, Andreas Muth, Erik Elias, Henrik Fagman, Volkan I Sayin, Jonas A Nilsson, Mikael Nilsson.

  Squamous cell carcinoma (SCC) of the thyroid is a rare tumor that is classified as an anaplastic thyroid cancer (ATC) due to its similar unresponsiveness to chemoradiotherapy and an outstandingly poor prognosis. Due to its rarity, current knowledge about this tumor is mostly based on single-case reports. The tumor-cell-origin and molecular pathogenesis remain unclear, although the presence of BRAF mutations in some cases suggest it may evolve from papillary thyroid carcinoma (PTC). Here we provide direct evidence of derivation of SCC of the thyroid from PTC, based on a unique combination of likely pathogenic mutations in KEAP1, STK11 (LKB1), and RB1 found in both tumor components, along with loss of one copy of chromosome 11 and additional somatic mutations in the SCC tumor. Transdifferentiation from PTC to SCC was also evident by immunohistochemistry. Out of eight attempted patient-derived xenografts (PDX) from advanced thyroid cancers, only one derived from thyroid SCC successfully engrafted in immunodeficient NOG mice. Untreated PDXs showed high Ki67 indices but did not reproduce the conspicuous stromal invasion of CDH1low/SNAI2+/CDH2+ cells that characterized the primary tumor. Based on the mutation profile (NFE2L2, PIK3CA, CDKN2A, and TP53), experiments were designed to evaluate targeted drug therapy using third-passage PDX transplants. The combination of TRK and PI3K inhibitors, cabozantinib and GDC-0326, additively reduced PDX growth by nearly 90%. Remarkably, CB-839 (telaglenastat), a glutaminase inhibitor targeting metabolic rewiring downstream of NRF2 activation, was equally effective. Both combined treatment with cabozantinib + GDC-0326 and CB-839 monotherapy diminished the expression of NQO1, an NRF2 transcriptional target, in tumor cells. Glutaminase inhibition further promoted squamous differentiation in engrafted tumors. Both investigated SCC tumors were negative for BRAFV600E or any other common driver mutation of thyroid cancer. Collectively, these findings indicate that aberrant activation of the KEAP1/NRF2 pathway due to somatic mutations is a previously unrecognized feature of thyroid SCC and suggest that glutaminase inhibition may serve as a potential therapeutic option for this subgroup of ATC patients. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords:  ATC; KEAP1; NFE2L2; NQO1; NRF2; PDX; PTC; SCC; glutaminase inhibition; squamous

DOI:  https://doi.org/10.1002/path.6444
Nihon Yakurigaku Zasshi. 2025 ;160(4): 256-260

[Metabolic insights into cellular senescence and in therapeutic approaches].

Ryota Kobori, Yasuhiro Nakano, Soichiro Kumamoto, Yoshikazu Johmura.

Aging serves as a risk factor for various age-associated disorders, such as cancer and type 2 diabetes. The study of aging is linked with metabolic research, due to the metabolic changes associated with aging. For example, chronic inflammation and the accumulation of DNA damages associated with aging lead to a decrease in NAD+ levels and mitochondrial dysfunction, resulting in cells becoming irreversibly cell cycle arrested, known as senescent cells. Senescent cells exhibit metabolic changes distinct from normal cells, along with distinct phenotypic characteristics, such as the senescence-associated secretory phenotypes (SASP), characterized by the excessive secretion of bioactive molecules such as inflammatory cytokines and chemokines. The accumulation of senescent cells has been observed in the pathology of age-related diseases, and their characteristics are thought to contribute to disease progression. Recent research has focused on the characteristics of senescent cells, such as their resistance to apoptosis, and aims to eliminate these cells from the body through pharmacological inhibition. Indeed, experimental evidence has demonstrated improvements in age-related phenotypes following the removal of senescent cells. Here, we review how age-related changes in cell metabolism induce cellular senescence, what are the metabolic characteristics of senescent cells, and how they affect the organism. Additionally, we also review our recent findings on the elimination of senescent cells by pharmacological inhibition of glutaminolysis rate-limiting enzyme GLS1, and outline the prospects for drug discovery targeting senescent cells.

DOI: https://doi.org/10.1254/fpj.24066