bims-glucam 2025-09-07 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–09–07
ten papers selected by
Sreeparna Banerjee, Middle East Technical University

LINC00114 promotes colorectal cancer metastasis by targeting HNRNPA1 to regulate glutamine metabolism reprogramming and angiogenesis.
Metabolic Inhibitor Loaded Metal-Phenolic Nanocapsules Enable Synergistic Cancer Therapy through Cuproptosis and Immunometabolic Reprogramming.
Glutaminase inhibition confers antitumor effects in vitro and in vivo on tyrosine kinase inhibitors-resistant renal cell carcinoma cells by affecting vascular endothelial growth factor signaling.
Melatonin-induced ferroptosis in pancreatic cancer cells by stimulating endoplasmic reticulum stress and inhibiting alanine-serine-cysteine transporter 2-driven glutamine metabolism.
Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.
Photochemical Generation of Peroxynitrite: Concurrent Inhibition of Glycolysis and Glutamine Metabolism for Enhanced Metabolic Therapy.
Identification of sepsis biomarkers through glutamine metabolism-mediated immune regulation: a comprehensive analysis employing mendelian randomization, multi-omics integration, and machine learning.
Developing a prognostic model of glutamine metabolism-related genes associated with clinical features and immune status in melanoma.
Unexplored gene PHKA1 interplays between glucose metabolism and breast cancer.
Sirtuins regulate macrophage polarization in heart failure: Metabolic reprogramming, epigenetic regulation, and immune cell interactions.

Acta Biochim Biophys Sin (Shanghai). 2025 Sep 02.

LINC00114 promotes colorectal cancer metastasis by targeting HNRNPA1 to regulate glutamine metabolism reprogramming and angiogenesis.

Shiyu Tang, Meng Liu, Yangyang Zhu, Lifa Li, Chen Qing, Yuehua Guan, Tong Zhou, Xuegui Tang.

  Colorectal cancer (CRC) is a common type of gastrointestinal malignancy, and it has a close connection with long noncoding RNAs (lncRNAs). This study aims to examine the involvement of long noncoding RNA LINC00114, which targets heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) in regulating glutamine metabolism and angiogenesis in the metastasis of colorectal cancer (CRC). LINC00114 and HNRNPA1 levels are measured in CRC tissues and cells to determine their expression levels. Then, siRNA targeting LINC00114 (si-LINC00114) is used to transfect CRC cells, and cell proliferation and metastasis are detected. The influence of exogenous glucose and glutamine supplementation on angiogenesis induced by LINC00114 in CRC is investigated in HUVECs. Glutamine metabolism in CRC cells is also detected. Furthermore, the role of LINC00114 in CRC xenograft tumors is studied in vivo. LINC00114 and HNRNPA1 are highly expressed in CRC and positively correlate with CD31. si-LINC00114 significantly inhibits proliferation, metastasis and HNRNPA1 expression in CRC cells. An RNA-binding-protein immunoprecipitation (RIP) assay confirms that LINC00114 can bind to HNRNPA1 and positively regulate its expression. Further experiments confirm that si-LINC00114 significantly inhibits cell proliferation and tubule formation in HUVECs. Exogenous glucose and glutamine supplementation significantly promotes the levels of LINC00114 and HNRNPA1 in CRC cells and promotes tubule formation in HUVECs. In addition, transfection of CRC cells with si-LINC00114 and/or oe-HNRNPA1 regulates glutamine metabolism in CRC cells. Animal studies confirm that intervention with LINC00114 represses the progression and vascular normalization of CRC and regulates glutamine metabolism. In conclusion, LINC00114 promotes CRC metastasis by targeting HNRNPA1 to regulate glutamine metabolic reprogramming and angiogenesis.

Keywords:  HNRNPA1; LINC00114; angiogenesis; colorectal cancer; metabolic reprogramming; metastasis

DOI:  https://doi.org/10.3724/abbs.2025141
ACS Appl Mater Interfaces. 2025 Sep 04.

Metabolic Inhibitor Loaded Metal-Phenolic Nanocapsules Enable Synergistic Cancer Therapy through Cuproptosis and Immunometabolic Reprogramming.

Bin Li, Houyang Hu, Songyan Li, Xuechun Wang, Zilin Ma, Wen Zhao, Yunxuan Song, Jianwei Jiao, Fenglei Xu, Xiuying Duan, Guiqiang Zhang.

  Abnormal glycolysis and glutamine metabolism not only sustain tumor growth but also reprogram the tumor microenvironment (TME). However, due to compensatory mechanisms and low tumor immunogenicity, targeting a single metabolic pathway is often insufficient for effective cancer therapy. We here developed dual-starvation therapeutic metal-phenolic nanocapsules (CG@Cap) by encapsulating a glutamine metabolism inhibitor with a zeolitic imidazolate framework-8 and adsorbing glucose oxidase on the surface, followed by coordination-driven assembly with tannic acid and copper ions. After preferential accumulation at tumor sites and internalization by tumor cells, the nanocapsules release their cargo, simultaneously suppressing glycolysis and glutamine metabolism. This dual inhibition disrupts tumor energy supply and remodels the immunosuppressive TME. Furthermore, the resulting redox imbalance enhances copper-induced cuproptosis, eliciting a strong antitumor immune response. In tumor-bearing mice, CG@Cap demonstrated potent therapeutic efficacy, highlighting the promise of integrating immunometabolic reprogramming with cuproptosis induction for cancer therapy.

Keywords:  Cuproptosis; Glutamine Metabolism; Glycolysis; Immunotherapy; Metal−Phenolic nanocapsules

DOI:  https://doi.org/10.1021/acsami.5c10711
Biomed Pharmacother. 2025 Aug 29. pii: S0753-3322(25)00686-9. [Epub ahead of print]191 118492

Glutaminase inhibition confers antitumor effects in vitro and in vivo on tyrosine kinase inhibitors-resistant renal cell carcinoma cells by affecting vascular endothelial growth factor signaling.

Kento Morozumi, Yoshihide Kawasaki, Izumi Sakamoto, Tomonori Sato, Masamitsu Maekawa, Shinya Takasaki, Shinichi Yamashita, Nariyasu Mano, Akihiro Ito.

  Tyrosine kinase inhibitors (TKIs) are key drugs in advanced renal cell carcinoma. Their prolonged efficacy is expected to translate directly into improved prognosis for patients with advanced renal cell carcinoma. In our previous studies, we identified important metabolic pathways related to sunitinib resistance. In this study, we examined whether TKI resistance could be overcome by controlling the glutamine metabolic pathway involved in sunitinib resistance. We established multiple renal cancer cell lines resistant to sunitinib and cabozantinib. We analyzed changes in the glutamine metabolic pathway associated with drug resistance. Furthermore, we inhibited the glutamine metabolic pathway using a glutaminase inhibitor (GLSi) and examined the antitumor effects of these TKIs on resistant renal cancer cells in vitro and in vivo. We also analyzed the mechanism of the antitumor effect of GLSi. In all established TKI-resistant cell lines, TKI resistance was associated with increased glutamine metabolism. GLSi showed significant antitumor effects on proliferation, invasion, and migration in all resistant cell lines. Immunostaining of resected TKI-resistant tumors demonstrated that GLSi-resistant TKIs exhibited sufficient antiangiogenic effects. VEGFR signal analysis suggested that the reduction of glutamate by GLSi activated PETN, which reduced VEGFR expression and its signaling, resulting in antitumor effects. GLSi has the potential to resensitize TKIs in TKI-resistant renal cancer cells. Therefore, controlling glutamine metabolism may extend the efficacy of existing TKIs and further improve the prognosis of patients with advanced renal cancer.

Keywords:  PTEN; TKI resistance; VEGFR; glutaminase; glutamine metabolism; renal cell carcinoma

DOI:  https://doi.org/10.1016/j.biopha.2025.118492
World J Gastroenterol. 2025 Aug 28. 31(32): 108654

Melatonin-induced ferroptosis in pancreatic cancer cells by stimulating endoplasmic reticulum stress and inhibiting alanine-serine-cysteine transporter 2-driven glutamine metabolism.

Qian Zhao, Hui Zhang, Huang-Min Wu, Qun-Ying Yang, Hong Zhao, Le Kang, Xiang-Yin Lv.

   BACKGROUND: Pancreatic cancer, characterized by aggressive proliferation and metastasis, is a lethal malignancy. The nightly hormone melatonin serves as a rhythm-regulating hormone, and is used to treat different cancers including pancreatic cancer.
AIM: To investigate how melatonin acts against human pancreatic cancer cell lines and analyze the biological processes that cause the observed effects.
METHODS: Panc-1 and AsPC-1 cells were treated with melatonin. Cell viability was measured using the cell counting kit-8 assay. Western blotting and immunofluorescence were used to analyze protein expression levels. Ferroptosis was measured by analyzing lipid reactive oxygen species and malondialdehyde levels; apoptosis was assessed using flow cytometry.
RESULTS: Melatonin significantly inhibited the viability, colony formation, migration, and invasion of Panc-1 and AsPC-1 cells. Additionally, melatonin activated the endoplasmic reticulum (ER) stress pathway (protein kinase R-like ER kinase-eukaryotic initiation factor 2α-activating transcription factor 4), inhibited glutamine metabolism (alanine-serine-cysteine transporter 2-glutaminase 1-glutathione peroxidase 4, alanine-serine-cysteine transporter 2-glutathione peroxidase 4), and promoted ferroptosis in pancreatic cancer cells. Co-treatment with a high melatonin concentration and protein kinase R-like ER kinase agonist (CCT020312) enhanced melatonin-induced ferroptosis in pancreatic cancer cells. Melatonin demonstrated a variety of anticancer effects by inhibiting autophagy. This was achieved through the increased expression of sequestosome-1 and decreased expression of light chain 3. Additionally, melatonin facilitated the promotion of apoptosis.
CONCLUSION: Melatonin induces ferroptosis in pancreatic cancer cells by activating transcription factor 4-dependent ER stress and inhibiting glutamine metabolism, promotes apoptosis in pancreatic cancer cells, and inhibits autophagy, leading to synergistic anticancer effects.

Keywords:  Activating transcription factor 4; Alanine-serine-cysteine transporter 2; Ferroptosis; Melatonin; Pancreatic cancer

DOI:  https://doi.org/10.3748/wjg.v31.i32.108654
Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2502483122

Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.

Haowen Jiang, Sarah Jane Tiche, Clifford Jiajun He, Junyan Liu, Fuyun Bian, Mohamed Jedoui, Balint Forgo, Md Tauhidul Islam, Meng Zhao, Pamela Emengo, Bo He, Yang Li, Albert M Li, Anh T Truong, Jestine Ho, Cathyrin Simmermaker, Yanan Yang, Meng-Ning Zhou, Zhen Hu, Katrin J Svensson, Daniel J Cuthbertson, Florette K Hazard, Lei Xing, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye.

  Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the tricarboxylic acid cycle and switching substrate preference from glutamine to glucose. These effects were abolished by electron transport chain (ETC) inhibitors or in ρ0 cells lacking mitochondrial DNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing of xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, potentially improving patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.

Keywords:  differentiation; mitochondria; neuroblastoma; retinoic acid; uncoupler

DOI:  https://doi.org/10.1073/pnas.2502483122
J Am Chem Soc. 2025 Sep 01.

Photochemical Generation of Peroxynitrite: Concurrent Inhibition of Glycolysis and Glutamine Metabolism for Enhanced Metabolic Therapy.

Lizhen Yuan, Liang Yang, Wen Song, Haoyang Song, Jing-Jing Hu, Xiaoding Lou, Fan Xia, Juyoung Yoon.

Disrupting homeostasis within tumor cells by interfering with their diverse metabolic pathways is an attractive tumor treatment method. However, current methods generally focus on one pathway within tumor cells, such as glycolysis or the glutamine (Gln) metabolic pathway, overlooking potential strong correlations between different cellular pathways and preventing a comprehensive blockade of the tumor energy supply, thereby compromising therapeutic efficacy. Herein, a photochemistry-activated peroxynitrite (ONOO-) nanogenerator, capable of simultaneously inhibiting glycolysis and Gln metabolism in tumor cells, is proposed to achieve enhanced metabolic therapy. Specifically, the ONOO- nanogenerator is constructed by loading the thermally sensitive nitric oxide (NO) donor BNN-6 onto dual-function Prussian blue (PB) nanocubes through electrostatic interaction, followed by coating with tumor cell membranes to achieve homologous targeting. Under near-infrared light irradiation, PB decomposes hydrogen peroxide (H2O2) to produce oxygen, while the converted heat induces BNN-6 decomposition to generate NO. Subsequently, NO reacts with oxygen to form nitrite, and then with H2O2 to yield ONOO- under acidic conditions. ONOO- achieves simultaneous inhibition of glycolysis and Gln metabolism through the nitration of key proteins. More importantly, the former effectively reduces lactate levels, and the latter increases Gln levels, which both, in turn, remodel the tumor microenvironment and stimulate a strong immune response. The in vitro and in vivo data demonstrated that these changes significantly inhibited the growth and spread of primary and distant metastatic tumors in a mouse model. This approach takes advantage of tumor-specific physicochemical properties to enable localized and highly efficient ONOO- synthesis, offering promise for enhanced metabolic therapy.

DOI: https://doi.org/10.1021/jacs.5c07860
Front Immunol. 2025 ;16 1640425

Identification of sepsis biomarkers through glutamine metabolism-mediated immune regulation: a comprehensive analysis employing mendelian randomization, multi-omics integration, and machine learning.

Zhuang'e Shi, Fuping Wang, Lishun Yang, Couwen Li, Bing Gong, Ruanxian Dai, Guobing Chen.

   Background: Sepsis is a global health challenge associated with high morbidity and mortality rates. Early diagnosis and treatment are challenging because of the limited understanding of its underlying mechanisms. This study aimed to identify biomarkers of sepsis through an integrated multi-method approach.
Methods: Mendelian randomization (MR) analysis was performed using data on 1400 plasma metabolites, 731 immune cell phenotypes, and sepsis genome-wide association studies. Single-cell RNA sequencing (scRNA-seq) data GSE167363 was used for cell annotation, differential expression analysis, Gene Set Enrichment Analysis (GSEA), transcription factor activity prediction, and cellular pseudotime analysis. The hub genes were identified via least absolute shrinkage and selection operator regression using GSE236713. The predictive models were constructed using the CatBoost, XGBoost, and NGBoost algorithms based on the data from GSE236713 and GSE28750. SHapley Additive ex Planations (SHAP) was used to filter the key molecules, and their expressions were confirmed via RT-qPCR of the peripheral blood mononuclear cells of the patients with sepsis and healthy controls.
Results: Two-step MR revealed that glutamine degradant mediated the causal relationship between SSC-A on HLA-DR + NK and sepsis. ScRNA-seq analysis revealed distinct variations in the composition of immune cell phenotypes in the control and sepsis groups. NK cells were associated with glutamine metabolism. GSEA illustrated the top 10 pathways positively and negatively correlated in NK cells with high vs. low glutamine metabolism. Transcription factor prediction revealed opposing transcription factor profiles for these NK cells subsets. NK cell cellular pseudotime plot and immune cell infiltration analysis results were displayed. The predictive models achieved AUCs of 0.95 (CatBoost), 0.80 (XGBoost), and 0.62 (NGBoost). SHAP analysis identified SRSF7, E2F2, RAB13, and S100A8 as key molecular of the model. RT-qPCR revealed decreased SRSF7 expression and increased RAB13, E2F2, and S100A8 expression in sepsis.
Conclusion: SSC-A on HLA-DR + NK cells reduced the risk of sepsis by decreasing glutamine degradation. SRSF7, E2F2, RAB13, and S100A8 were identified as potential pathogenic biomarkers of sepsis.

Keywords:  ScRNA-seq; biomarkers; machine learning; mendelian randomization; sepsis

DOI:  https://doi.org/10.3389/fimmu.2025.1640425
Front Oncol. 2025 ;15 1485006

Developing a prognostic model of glutamine metabolism-related genes associated with clinical features and immune status in melanoma.

Hongyan Hu, Jing Yang, Jin Miao, Chen Li, Cao Wang, Fengming Ran, Jie Zou, Yi Zhang, Liufang Zhao, Wentao Zhao, Conghui Ai.

   Introduction: Melanoma exhibited a poor prognosis due to its aggression and heterogeneity. The effect of glutamate metabolism promoting tumor progression on cutaneous melanoma remains unknown. Herein, glutamine metabolism-related genes (GRGs) were identified followed by constructing a prognostic model for melanoma via bioinformatics analysis.
Methods: Patient data were collected from ,Gene Expression Omnibus (GEO) and The Cancer Genome Atlas-Skin Cutaneous Melanoma (TCGA-SKCM). In addition, GRGs were extracted from the MSigDB database, and the R package "Seurat" was used for scRNA-seq data processing.
Results: eight key genes (CHMP4A, IFFO1, ANKRD10, ZDHHC11, CLPB, ANKMY1, TCAP and POLG2) were identified to construct a risk model. Based on univariate and multivariate Cox regression analyses, clinical characteristics including Clark stage and ulcer status were identified as independent prognostic factors, and a nomogram was successfully constructed. Survival analysis demonstrated that the overall survival rates of the high-risk group were lower than those of the low-risk group. The gene set enrichment analysis (GSEA) results showed that only ANKRD10, ANKMY1 and TCAP were enriched in the "glycolysis gluconeogenesis" pathway. The high-risk and low-risk groups displayed significant differences in immune cell infiltration and immune checkpoint expression. Analysis on drug sensitivity revealed that the high-risk group was highly sensitive to rapamycin. Additionally, it was verified that IFFO1, ANKRD10 and POLG2 were markedly upregulated and CHMP4A was also markedly downregulated in A375 cells by RT-PCR, which was consistent with the partial results of biological analysis.
Discussion: Overall, it would provide valuable information about the GRGs of prognosis and immune status in melanoma.

Keywords:  bioinformatics; glutamine metabolism; immune microenvironment; melanoma; prognosis

DOI:  https://doi.org/10.3389/fonc.2025.1485006
Biochim Biophys Acta Mol Cell Res. 2025 Aug 27. pii: S0167-4889(25)00157-0. [Epub ahead of print]1872(8): 120052

Unexplored gene PHKA1 interplays between glucose metabolism and breast cancer.

Sweta H Makwana, Jyoti Poswal, Pooja Yadav, Shailendra P Singh, Chandi C Mandal.

  Cancer cells often undergo metabolic reprogramming, typically increasing their uptake and utilization of energy sources like glucose, fatty acids, lactate, glutamine, and pyruvate, while maintaining redox balance. Rather than relying on oxidative phosphorylation, cancer cells preferentially engage glycolysis to convert pyruvate into lactate. This metabolic reprogramming correlates with altered glucose metabolism and dysregulated insulin signalling. Diabetes is associated with increased risk of certain cancer types. Cancer database analysis of genes involved in glucose metabolism, insulin signalling and diabetes, identified an unexplored differentially expressed PHKA1 gene associated with poor patient survivability in breast cancer. Expression of the PHKA1 gene was found to be upregulated under an environment of high glucose and insulin in cancer cells. Silencing PHKA1 via siRNA led to marked decrease in proliferative, invasion, migratory, and stem-like properties of MDA-MB-231 and MCF-7 breast cancer cells. Experimental findings demonstrated reduced expression of mesenchymal markers (e.g., Vimentin, Zeb-1/2), cell cycle markers (e.g., CDK-2/4), and proliferative markers (e.g., Bcl-2 and Bcl-xl), while expression of epithelial markers (e.g., E-cadherin and Keratin-19) were enhanced in PHKA1 knockdown cells when compared to control. Performance of glycolysis stress and mito stress assay further demonstrated that siPHKA1 cells had diminished glycolytic activity alongside suppressed mitochondrial function. These findings highlight intricate relationship between metabolic dysregulation observed in diabetes, contributing to the progression of cancer. Collectively, these observations highlight PHKA1 as an oncogenic candidate with potential role in breast cancer. Comprehensive understanding of such metabolic alterations is critical to designing targeted therapeutic strategies aimed at mitigating breast cancer progression.

Keywords:  Breast cancer; Diabetes; Glucose metabolism; Glycolysis; Phosphorylase Kinase Regulatory Subunit Alpha 1 (PHKA1); siRNA-mediated knock-down

DOI:  https://doi.org/10.1016/j.bbamcr.2025.120052
Pharmacol Res. 2025 Aug 30. pii: S1043-6618(25)00361-5. [Epub ahead of print]220 107936

Sirtuins regulate macrophage polarization in heart failure: Metabolic reprogramming, epigenetic regulation, and immune cell interactions.

Ruifang Lin, Yun Zhu, Yongjun Liu, Zhihua Guo, Jiaming Wei, Ya Li, Yunfeng Yu.

  Heart failure (HF) is an end-stage cardiovascular syndrome caused by structural or functional cardiac abnormalities. Its high morbidity and mortality underscore the urgent need for novel therapeutic strategies. In recent years, the dynamic regulatory mechanisms underlying macrophage polarization in the onset and progression of HF have attracted widespread attention. The Sirtuin family, as NAD+ -dependent deacetylases, has emerged as a key regulatory factor in reshaping the macrophage polarization phenotype by integrating metabolic reprogramming, epigenetic regulation, and immune cell interactions. This paper systematically elaborates the molecular mechanisms by which Sirtuins (SIRT1-SIRT7) regulate metabolic reprogramming (e.g., glucose metabolism, lipid metabolism, and glutamine metabolism), coordinate epigenetic modifications (e.g., DNA methylation, histone modifications, and non-coding RNA regulation), and mediate interactions between immune cells to dynamically balance macrophage polarization. Furthermore, this review summarizes recent advances in the active components of phytomedicines, such as resveratrol, pterostilbene, astragaloside IV, quercetin, dihydromyricetin, berberine, honokiol, ginsenoside Rc, ginsenoside Rg1, and ginsenoside Rg3, in targeting the Sirtuin-macrophage polarization axis for the prevention and treatment of HF. This review aims to provide a theoretical framework and translational guidance for developing HF-targeted therapeutic strategies based on Sirtuin-mediated macrophage polarization, as well as for the research and development of related natural products.

Keywords:  Epigenetic regulation; Heart failure; Immune cell interaction; Macrophage polarization; Metabolic reprogramming; Sirtuins

DOI:  https://doi.org/10.1016/j.phrs.2025.107936