bims-glucam 2025-04-13 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–04–13
twenty-two papers selected by
Sreeparna Banerjee, Middle East Technical University

Complementary approaches define the metabolic features that accompany Richter syndrome transformation.
O-GlcNAcylation of glutaminase isoform KGA inhibits ferroptosis through activation of glutaminolysis in hepatoblastoma.
Amino acids in cancer: Understanding metabolic plasticity and divergence for better therapeutic approaches.
The perspective of targeting cancer cell metabolism: combination therapy approaches.
Impact of exogenous glutamine on growth-related gene expression and metabolic pathways in Trachinotus blochii.
Diversity of metabolic features and relevance to clinical subtypes of gliomas.
Rethinking corticosteroids use in oncology.
G-protein coupled receptors in metabolic reprogramming and cancer.
Radiation induces M2 polarization of glioma-associated macrophages via upregulation of glutamine synthetases.
NMR Metabolomic Profiling of Differentiated SH-SY5Y Neuronal Cells: Amyloid-β Toxicity and Protective Effects of Galantamine and Lycorine.
GCLC desuccinylation regulated by oxidative stress protects human cancer cells from ferroptosis.
TNF- α disrupts the malate-aspartate shuttle, driving metabolic rewiring in iPSC-derived enteric neural lineages from Parkinson's Disease patients.
Stable isotope tracing reveals glucose metabolism characteristics of drug-resistant B-cell acute lymphoblastic leukemia.
Nanotherapeutics induced redox resetting of oxidative and nitrosative stress: targeting glutathione-depletion in cancer.
Optimized Long-TE 1H sLASER MR Spectroscopic Imaging at 3T for Separate Quantification of Glutamate and Glutamine in Glioma.
Exploring Diagnostic Markers and Therapeutic Targets in Parkinson's Disease: A Comprehensive 1H-NMR Metabolomic Analysis - Systematic Review.
Unraveling the nexus: Genomic instability and metabolism in cancer.
Mitochondrial, metabolic and bioenergetic adaptations drive plasticity of colorectal cancer cells and shape their chemosensitivity.
The glutathione system maintains the thiol redox balance in the mitochondria of fission yeast.
Glutathione Metabolism in Ferroptosis and Cancer Therapy.
Dysregulated glutathione metabolism impairs natural killer cell function in patients with acute leukemia.
GLS2 inhibition synergizes with copper to reprogram TCA cycle for cuproptosis-driven radiosensitization in esophageal cancer.

Cell Mol Life Sci. 2025 Apr 09. 82(1): 152

Complementary approaches define the metabolic features that accompany Richter syndrome transformation.

Giulia Omezzolli, Andrea Iannello, Francesco E Vallone, Lorenzo Brandimarte, Matilde Micillo, Nadia Bertola, Chiara Lavarello, Nicole Grinovero, Giulio Ferrero, Kevin Mellert, Peter Möller, Silvia Bruno, Richard R Furman, John N Allan, Andrea Petretto, Silvia Deaglio, Silvia Ravera, Tiziana Vaisitti.

  Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into a high-grade lymphoma with previously unknown metabolic features. Transcriptomic data from primary CLL and RS samples, as well as RS-patient-derived xenografts, highlighted cellular metabolism as one of the most significant differentially expressed processes. Activity assays of key enzymes confirmed the intense metabolic rewiring of RS cells, which is characterized by an elevated rate of Krebs cycle, oxidative phosphorylation, and glutamine metabolism. These pathways were sustained by increased uptake of glucose and glutamine, two critical substrates for these cells. Moreover, RS cells showed activation of anabolic processes that resulted in the synthesis of nucleotides and lipids necessary to support their high proliferation. Exposure to drugs targeting PI3K and NF-kB, two master regulators of cellular metabolism, resulted in the shutdown of ATP production and glycolysis. Overall, these data suggest that metabolic rewiring characterizes the transformation of CLL into RS, presenting new translational opportunities.

Keywords:  Building blocks; Chronic lymphocytic leukemia; Metabolic dependencies; Metabolic rewiring; Metabolic targeting; Richter transformation

DOI:  https://doi.org/10.1007/s00018-025-05670-4
Cell Death Discov. 2025 Apr 09. 11(1): 160

O-GlcNAcylation of glutaminase isoform KGA inhibits ferroptosis through activation of glutaminolysis in hepatoblastoma.

Sijia Fang, Guoqing Zhu, Yi Xie, Miao Ding, Ni Zhen, Jiabei Zhu, Siwei Mao, Xiaochen Tang, Han Wu, Qi Zhang, Aijia Zhang, Xin Ni, Qiuhui Pan, Ji Ma.

Hepatoblastoma (HB), the most common pediatric hepatic malignancy, exhibits an increasing incidence. Metabolism reprogramming represents a pivotal hallmark in the oncogenic transformation process, with glutamine emerging as a critical energy source for neoplastic cells, rivaling glucose. However, the mechanism by which glutamine is involved in the development of HB remains unclear. Our study identified glutamine metabolism as a crucial factor in the development of HB. The key enzyme of glutamine metabolism, kidney-type glutaminase (GLS1), is activated in HB and regulates cell proliferation. Mechanistically, the GLS1 subtype KGA, utilizing glutamate derived from glutaminolysis, enhances glutathione (GSH) synthesis, which in turn inhibits ferroptosis in HB cells. Importantly, the Thr563 residue of KGA undergoes O-GlcNAcylation, enhancing enzyme activity and stability, accelerating glutaminolysis, and promoting the proliferation of HB. This study demonstrated that enhanced glutaminolysis, driven by GLS1, is crucial for the development of HB by inhibiting ferroptosis. The O-GlcNAcylation of KGA isoform ensures its stability and glutaminase function in HB cells, which can serve as a promising therapeutic target for KGA-mediated glutaminolysis in HB.

DOI: https://doi.org/10.1038/s41420-025-02464-2
Cell Rep. 2025 Apr 05. pii: S2211-1247(25)00300-6. [Epub ahead of print]44(4): 115529

Amino acids in cancer: Understanding metabolic plasticity and divergence for better therapeutic approaches.

Linda K Do, Hyun Min Lee, Yun-Sok Ha, Chan-Hyeong Lee, Jiyeon Kim.

  Metabolic reprogramming is a hallmark of malignant transformation. While initial studies in the field of cancer metabolism focused on central carbon metabolism, the field has expanded to metabolism beyond glucose and glutamine and uncovered the important role of amino acids in tumorigenesis and tumor immunity as energy sources, signaling molecules, and precursors for (epi)genetic modification. As a result of the development and application of new technologies, a multifaceted picture has emerged, showing that context-dependent heterogeneity in amino acid metabolism exists between tumors and even within distinct regions of solid tumors. Understanding the complexity and flexibility of amino acid metabolism in cancer is critical because it can influence therapeutic responses and predict clinical outcomes. This overview discusses the current findings on the heterogeneity in amino acid metabolism in cancer and how understanding the metabolic diversity of amino acids can be translated into more clinically relevant therapeutic interventions.

Keywords:  CP: Cancer; CP: Metabolism; amino acids; cancer metabolism; metabolic heterogeneity

DOI:  https://doi.org/10.1016/j.celrep.2025.115529
Mol Biol Rep. 2025 Apr 09. 52(1): 375

The perspective of targeting cancer cell metabolism: combination therapy approaches.

Arezu Karimpur-Zahmatkesh, Mohammad Khalaj-Kondori.

  Cancer cells are considered the most adaptable for their metabolic status, which supports growth, survival, rapid proliferation, invasiveness, and metastasis in a nutrient-deficient microenvironment. Since the discovery of altered glucose metabolism (aerobic glycolysis), which is generally known as a part of metabolic reprogramming and an innate trait of cancer cells, in 1930 via Dr. Otto Warburg, numerous studies have endeavored to recognize various aspects of cancer cell metabolism and find new methods for efficiently eradicating described cells by targeting their energy metabolism. In this way, the outcomes have mainly been promising. Accordingly, outlining the related results will indeed assist us in making a definitive path for developing targeted therapy strategies based on cancer cell-altered metabolism. The present study reviews the key features of cancer cell metabolism and treatment strategies based on them. It emphasizes the importance of targeting cancer cell dysregulated metabolic pathways that influence the cell energy supply and manage cancer cell growth and survival. This trial also introduces a multimodal therapeutic strategy hypothesis, a potential next-generation combination therapy approach, and suggests interdisciplinary research to recognize the complexities of cancer metabolism and exploit them for designing more efficacious cancer therapeutic strategies.

Keywords:  Cancer; Combination therapy; Metabolic pathway; Multimodal approach; Targeted therapy

DOI:  https://doi.org/10.1007/s11033-025-10472-9
Comp Biochem Physiol Part D Genomics Proteomics. 2025 Apr 09. pii: S1744-117X(25)00095-4. [Epub ahead of print]55 101507

Impact of exogenous glutamine on growth-related gene expression and metabolic pathways in Trachinotus blochii.

Shukui Sun, Lei Wang, Huapeng Chen, Da Zheng, Xinxin Wang, Haoran Yu, Yesong Liang, Junlong Sun, Jian Luo, Feibiao Song.

  In recent years, the scale of Trachinotus blochii aquaculture has been expanding. Our previous research identified glutamine metabolism related genes as key regulators of T. blochii growth. Recently, fish essential amino acids have been developed as nutritional additives in aquaculture feed. To explore the effects of glutamine on growth related genes in T. blochii, we formulated T. blochii feed and conducted a feeding trial. No exogenous glutamine was added to the control group, alongside four experimental groups supplemented with 0.3 %, 0.6 %, 0.9 %, and 1.2 % exogenous glutamine, respectively. After eight weeks feeding, liver enzyme activity analysis indicated that adding 0.3 % and 0.6 % exogenous glutamine reduced MDA levels. Similarly, T-AOC and T-SOD activities were higher in the livers of T. blochii supplemented with 0.3 % glutamine. Liver samples were also collected for transcriptome sequencing. The results showed that the oxidative phosphorylation pathway was activated, and the fat digestion system pathway was significantly enriched following the addition of exogenous glutamine. Co-mRNA network analysis showed enrichment in a large number of genes related to the ubiquinone oxidoreductase family. However, significant differences were observed in disease related genes when glutamine was added at 0.9 % and 1.2 %. In summary, supplementing 0.3 % to 0.6 % glutamine in T. blochii feed can enhance amino acid metabolism and fat utilization. It can also activate pathways related to oxidative phosphorylation and fat digestion and absorption, thereby making more energy available to influence other physiological factors. These results provide an important reference for the optimization of the feed formula for T. blochii.

Keywords:  Glutamine; Liver; RNA-seq; Trachinotus blochii

DOI:  https://doi.org/10.1016/j.cbd.2025.101507
Semin Cancer Biol. 2025 Apr 05. pii: S1044-579X(25)00055-0. [Epub ahead of print]112 126-134

Diversity of metabolic features and relevance to clinical subtypes of gliomas.

Pushan Dasgupta, Vinay K Puduvalli.

  Gliomas carry a dismal prognosis and have proven difficult to treat. Current treatments and efforts to target individual signaling pathways have failed. This is thought to be due to genetic and epigenetic heterogeneity and resistance. Therefore, interest has grown in developing a deeper understanding of the metabolic alterations that represent drivers and dependencies in gliomas. Therapies that target glioma-specific metabolic dependencies overcome the challenges of disease heterogeneity. Here, we present the diverse metabolic features of each current clinical subtype of glioma. We believe that this approach will enable the development of novel strategies to specifically target the various clinical and molecular subtypes of glioma using these metabolic features.

Keywords:  Cancer metabolism; Glioma; Glioma metabolome; Glioma subtypes; Metabolic targets

DOI:  https://doi.org/10.1016/j.semcancer.2025.03.008
Front Pharmacol. 2025 ;16 1551111

Rethinking corticosteroids use in oncology.

Pierrick Martinez, Jean-Marc Sabatier.

  Corticosteroids (CSs), widely used in oncology for their anti-inflammatory and immunosuppressive properties, help manage cancer-related symptoms and side effects. However, their long-term use may negatively affect patient survival and exacerbate tumor progression. Elevated glucose and glutamine metabolism, disruption of vitamin D levels, and alterations in the microbiome are some of the key factors contributing to these adverse outcomes. Approaches such as ketogenic diets, fasting, sartans, and vitamin D supplementation have shown promise in providing similar benefits to CSs while mitigating the risks associated with the mechanisms identified as contributing to tumor progression. This perspective underscores the necessity for a reevaluation of CSs use in cancer care and advocates for further research into safer, more effective therapeutic strategies.

Keywords:  corticosteroids; glucocorticoids; glutaminolysis; glycolysis; microbiome; renin-angiotensin system; vitamin D

DOI:  https://doi.org/10.3389/fphar.2025.1551111
Pharmacol Ther. 2025 Apr 07. pii: S0163-7258(25)00061-0. [Epub ahead of print] 108849

G-protein coupled receptors in metabolic reprogramming and cancer.

Songyeon Ahn, Benny Abraham Kaipparettu.

  G-protein coupled receptors (GPCR) are one of the frequently investigated drug targets. GPCRs are involved in many human pathophysiologies that lead to various disease conditions, such as cancer, diabetes, and obesity. GPCR receptor activates multiple signaling pathways depending on the ligand and tissue type. However, this review will be limited to the GPCR-mediated metabolic modulations and the activation of relevant signaling pathways in cancer therapy. Cancer cells often have reprogrammed cell metabolism to support tumor growth and metastatic plasticity. Many aggressive cancer cells maintain a hybrid metabolic status, using both glycolysis and mitochondrial metabolism for better metabolic plasticity. In addition to glucose and glutamine pathways, fatty acid is a key mitochondrial energy source in some cancer subtypes. Recently, targeting alternative energy pathways like fatty acid beta-oxidation (FAO) has attracted great interest in cancer therapy. Several in vitro and in vivo experiments in different cancer models reported encouraging responses to FAO inhibitors. However, due to the potential liver toxicity of FAO inhibitors in clinical trials, new approaches to indirectly target metabolic reprogramming are necessary for in vivo targeting of cancer cells. This review specifically focused on free fatty acid receptors (FFAR) and β-adrenergic receptors (β-AR) because of their reported significance in mitochondrial metabolism and cancer. Further understanding the pharmacology of GPCRs and their role in cancer metabolism will help repurpose GPCR-targeting drugs for cancer therapy and develop novel drug discovery strategies to combine them with standard cancer therapy to increase anticancer potential and overcome drug resistance.

Keywords:  Free fatty acid receptors; Mitochondria metabolism; cancer; Β-Adrenergic receptors

DOI:  https://doi.org/10.1016/j.pharmthera.2025.108849
Int Immunopharmacol. 2025 Apr 03. pii: S1567-5769(25)00585-5. [Epub ahead of print]154 114595

Radiation induces M2 polarization of glioma-associated macrophages via upregulation of glutamine synthetases.

Yijun Lu, Chen Zhou, Jie Li, Lingling Liu, Xinyu Liu, Lichen Shen, Xin Lai, Hongcang Gu, Zhi Zhang, Junchao Qian.

  Radiation-induced alterations in the tumor microenvironment (TME) may cause the shift of a few immune cells to immunosuppressive phenotypes, resulting in tumor radiotherapy resistance. The current study is aimed at investigating the impact of radiation on the polarization of glioma-associated macrophages (GAMs) and elucidating the underlying mechanisms. Through the irradiation (IR) of macrophages co-cultured with glioma cells and murine gliomas, we observed that IR promoted the polarization of GAMs towards a pro-tumorigenic M2 phenotype by modulating STAT5 to upregulate and activate glutamine synthetase (GS), consequently fostering glioma cells proliferation, migration, and invasion. Conversely, inhibition of GS activity with L-Methionine Sulfoximine (MSO) could shift macrophages towards the anti-tumor M1 phenotype. Moreover, in murine orthotopic glioma models, the combined treatment of MSO and radiation therapy exhibited a significant inhibitory effect on glioma growth. The combination also led to the suppression of tumor vasculature, increased infiltration of CD8+ T cells, and enhanced tumor cells apoptosis. In summary, our findings suggested that radiation combined with GS inhibition might potentially be a novel therapeutic strategy for glioma by modulating macrophage polarization and further promoting anti-tumor immunity.

Keywords:  Glioma; Glutamine synthetase; Macrophage; Radiotherapy; STAT5

DOI:  https://doi.org/10.1016/j.intimp.2025.114595
Cells. 2025 Apr 01. pii: 525. [Epub ahead of print]14(7):

NMR Metabolomic Profiling of Differentiated SH-SY5Y Neuronal Cells: Amyloid-β Toxicity and Protective Effects of Galantamine and Lycorine.

Arian Kola, Filippo Costanti, Jordan Kahfi, Abdul-Hamid Emwas, Mariusz Jaremko, Daniela Valensin.

  Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by metabolic dysregulation, oxidative stress, amyloid-β (Aβ) aggregation, metal dyshomeostasis, and mitochondrial dysfunction. Current treatments provide only symptomatic relief, highlighting the need for novel therapeutic strategies. This study investigates the metabolic effects of the alkaloids galantamine (GAL) and lycorine (LYC) in differentiated SH-SY5Y neuroblastoma cells, an established in vitro model for AD, which acquire a neuronal phenotype upon differentiation. Using untargeted and targeted NMR-based metabolomics combined with multivariate statistical analysis, we analyzed extracellular metabolic profiles under basal conditions and following Aβ42 exposure, both in the presence and absence of GAL and LYC. Our findings reveal distinct metabolic responses to Aβ toxicity, with significant alterations in pyruvate and glutamine metabolism. Both GAL and LYC contributed to the restoration of glutamine and lysine homeostasis, but LYC had a more pronounced effect, better sustaining cellular energy balance and mitochondrial function. Unlike LYC, GAL treatment was associated with pyruvate accumulation, highlighting a distinct metabolic response between the two compounds. These variations may reflect distinct mechanisms of action, potentially influencing their therapeutic roles in counteracting Aβ-induced toxicity. This study highlights the value of metabolic profiling for assessing neuroprotective agents and reinforces the potential of natural alkaloids in this context.

Keywords:  Alzheimer’s disease; SH-SY5Y; alkaloids; amyloid-β; galantamine; glutamate–glutamine cycle; lycorine; metabolomics; oxidative stress; pyruvate

DOI:  https://doi.org/10.3390/cells14070525
Cell Death Differ. 2025 Apr 05.

GCLC desuccinylation regulated by oxidative stress protects human cancer cells from ferroptosis.

Zixiang Chen, Kaifeng Niu, Mengge Li, Yuchun Deng, Ji Zhang, Di Wei, Jiaqi Wang, Yongliang Zhao.

Tumor cells evolve strong antioxidant capacities to counteract the abnormal high level of reactive oxygen species (ROS) in the tumor microenvironment. Glutamate-cysteine ligase catalyzing subunit (GCLC) for synthesis of antioxidant glutathione (GSH) represents the key enzyme to maintain redox homeostasis of tumor cells, however, whether its activity is regulated by posttranslational modifications, such as succinylation, remains to be clarified. Here, we demonstrate the existence of succinylation modification on GCLC by in vitro and in vivo assays. NAD-dependent deacetylase Sirtuin-2 (SIRT2) serves as the desuccinylase and catalyzes GCLC desuccinylation at sites of K38, K126, and K326. Specifically, GCLC directly interacts with SIRT2, which can be substantially enhanced upon ROS treatment. This strengthened association results in GCLC desuccinylation and activation, consequently promoting GSH synthesis and rendering cancer cells resistant to ferroptosis induction. Depletion of SIRT2 decreases total GSH level and meanwhile increases the cellular susceptibility to ferroptosis, which can mostly be rescued by introducing wild-type GCLC, but not its 3K-E mutant. We further demonstrated that histone acetyltransferase P300 serves as the succinyltransferase of GCLC, and their association is remarkably decreased after ROS treatment. Thus, SIRT2-regulated GCLC succinylation represents an essential signaling axis for cancer cells to maintain their redox balance in coping with oxidative stress-induced ferroptosis.

DOI: https://doi.org/10.1038/s41418-025-01505-8
bioRxiv. 2025 Mar 26. pii: 2025.03.25.644826. [Epub ahead of print]

TNF- α disrupts the malate-aspartate shuttle, driving metabolic rewiring in iPSC-derived enteric neural lineages from Parkinson's Disease patients.

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, Friederike Zunke, Jürgen Winkler, David B Blumenthal, Fabian J Theis, Roland Riek, Claudia Günther, Markus Neurath, Pooja Gupta, Beate Winner.

Gastrointestinal (GI) dysfunction emerges years before motor symptoms in Parkinson's disease (PD), implicating the enteric nervous system (ENS) in early disease progression. However, the mechanisms linking the PD hallmark protein, α-synuclein (α-syn), to ENS dysfunction - and whether these mechanisms are influenced by inflammation - remains elusive. Using iPSC-derived enteric neural lineages from patients with α-syn triplications, we reveal that TNF-α increases mitochondrial-α-syn interactions, disrupts the malate-aspartate shuttle, and forces a metabolic shift toward glutamine oxidation. These alterations drive mitochondrial dysfunction, characterizing metabolic impairment under cytokine stress. Interestingly, targeting glutamate metabolism with Chicago Sky Blue 6B restores mitochondrial function, reversing TNF-α-driven metabolic disruption. Our findings position the ENS as a central player in PD pathogenesis, establishing a direct link between cytokines, α-syn accumulation, metabolic stress and mitochondrial dysfunction. By uncovering a previously unrecognized metabolic vulnerability in the ENS, we highlight its potential as a therapeutic target for early PD intervention.

DOI: https://doi.org/10.1101/2025.03.25.644826
Anal Chim Acta. 2025 May 22. pii: S0003-2670(25)00278-8. [Epub ahead of print]1352 343884

Stable isotope tracing reveals glucose metabolism characteristics of drug-resistant B-cell acute lymphoblastic leukemia.

Rong Hu, Zhengwei Duan, Mengyao Wang, Mengting Liu, Yaoxin Zhang, Yanxi Lu, Yuhan Qian, Enjie Wei, Jianghua Feng, Pengfei Guo, Yang Chen.

   BACKGROUND: Adult B-cell acute lymphocytic leukemia (B-ALL) is a malignant hematologic tumor characterized by the uncontrolled proliferation of B-cell lymphoblasts in the bone marrow. Despite advances in treatment, including chemotherapy and consolidation therapy, many B-ALL patients experience unfavorable prognoses due to the development of drug resistance. The precise mechanisms governing chemotherapy resistance, particularly those related to metabolic reprogramming within tumors, remain inadequately elucidated.
RESULTS: Nalm6/DOX cells exhibited significantly elevated levels of glucose, pyruvate, alanine, glutamine, and glycine compared to Nalm6 cells. Conversely, reduced levels of citrate, acetate, and leucine were observed in Nalm6/DOX cells. Upon exposure to the culture medium supplemented with tracer 13C6-glucose, the Nalm6/DOX cells showed an increase in the abundance of 13C-alanine and a decrease in the levels of 13C-lactate, indicating impaired utilization of 13C-pyruvate. Combining β-chloro-alanine (ALTi) with DOX could decrease the drug resistance phenotype of Nalm6/DOX cells. The results demonstrated that glycolysis and tricarboxylic acid cycle were suppressed in Nalm6/DOX cells, while metabolic flux through the alanine and glutamine pathways was increased. Therefore, inhibition of alanine biosynthesis in Nalm6/DOX exhibits the potential to reverse drug resistance.
SIGNIFICANCE: A new insight into the impact of metabolism on chemotherapy resistance in B-ALL has been gained through the use of stable isotope resolved metabolomics based on nuclear magnetic resonance and ultra-performance liquid chromatography/tandem mass spectrometry. This provides promising ways for the development of innovative therapeutic strategies to alleviate drug resistance and relapse in affected patients.

Keywords:  Alanine; Doxorubicin; NMR; Stable isotope resolved metabolomics; TCA cycle; UPLC-MS/MS

DOI:  https://doi.org/10.1016/j.aca.2025.343884
Nanomedicine (Lond). 2025 Apr 07. 1-11

Nanotherapeutics induced redox resetting of oxidative and nitrosative stress: targeting glutathione-depletion in cancer.

Kapil Dangi, Vijay Kumar, Disha Mittal, Pooja Yadav, Mansi Malik, Anita Kamra Verma.

  Cancer cells display a distinctive defense mechanism against any exogenous moieties that renders all treatments inefficient. Glutathione, a thiol tripeptide plays a paradoxical role in cancer as intracellular glutathione (GSH) are voracious scavengers of free radicals produced by chemotherapy, generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Cancer cells show Warburg effect, wherein the intracellular GSH levels are exceptionally enhanced to overcome the oxidative stress created by ROS/RNS production or by the other free radicals generated as side products of intracellular redox reactions. Therefore, redox resetting is essential to maintain the redox homeostasis for cell survival and their proliferation and trigger escalation of GSH levels. Nanotherapeutics have facilitated the targeted delivery of GSH-depleting agents in combination with radiotherapy, chemotherapy, and novel therapeutic interventions including chemodynamic therapy (CDT), photodynamic therapy (PDT), ferroptosis induction, sonodynamic therapy (SDT), and immunotherapy are being explored. This review aims to compile the strategic role of GSH in cancer cells, the importance of nanotherapeutics for GSH depletion in cancer to target numerous forms of programmed cell death (PCD), including apoptosis, ferroptosis, necroptosis, and autophagy.

Keywords:  Cancer; Ferroptosis; GSH depletion; Nanotherapeutics; PDT; Redox-resetting

DOI:  https://doi.org/10.1080/17435889.2025.2489918
J Magn Reson Imaging. 2025 Apr 08.

Optimized Long-TE 1H sLASER MR Spectroscopic Imaging at 3T for Separate Quantification of Glutamate and Glutamine in Glioma.

Seyma Alcicek, Michael W Ronellenfitsch, Joachim P Steinbach, Andrei Manzhurtsev, Dennis C Thomas, Katharina J Weber, Vincent Prinz, Marie-Thérèse Forster, Elke Hattingen, Ulrich Pilatus, Katharina J Wenger.

   BACKGROUND: Glutamate and glutamine are critical metabolites in gliomas, each serving distinct roles in tumor biology. Separate quantification of these metabolites using in vivo MR spectroscopy (MRS) at clinical field strengths (≤ 3T) is hindered by their molecular similarity, resulting in overlapping, hence indistinguishable, spectral peaks.
PURPOSE: To develop an MRS imaging (MRSI) protocol to map glutamate and glutamine separately at 3T within clinically feasible time, using J-modulation to enhance spectral differentiation, demonstrate its reliability/reproducibility, and quantify the metabolites in glioma subregions.
STUDY TYPE: Prospective.
POPULATION: Phantoms, 5 healthy subjects, and 30 patients with suspected glioma. IDH wild-type glioblastoma cases were evaluated to establish a uniform group.
FIELD STRENGTH/SEQUENCE: 3T, Research protocol: 2D 1H sLASER MRSI (40 and 120 ms TE) with water reference, 3D T1-weighted and 2D T2-weighted. Trial-screening process: T1-weighted, T1-weighted contrast-enhanced, T2-weighted, FLAIR.
ASSESSMENT: Spectral simulations and phantom measurements were performed to design and validate the protocol. Spectral quality/fitting parameters for scan-rescan measurements were obtained using LCModel. The proposed long-TE data were compared with short-TE data. BraTS Toolkit was employed for fully automated tumor segmentation.
STATISTICAL TESTS: Scan-rescan comparison was performed using Bland-Altman analysis. LCModel coefficient of modeling covariance (CMC) between glutamate and glutamine was mapped to evaluate their model interactions for each spectral fitting. Metabolite levels in tumor subregions were compared using one-way ANOVA and Kruskal-Wallis. A p value < 0.05 was considered statistically significant.
RESULTS: Spectral quality/fitting parameters and metabolite levels were highly consistent between scan-rescan measurements. A negative association between glutamate and glutamine models at short TE (CMC = -0.16 ± 0.06) was eliminated at long TE (0.01 ± 0.05). Low glutamate in tumor subregions (non-enhancing-tumor-core: 5.35 ± 4.45 mM, surrounding-non-enhancing-FLAIR-hyperintensity: 7.39 ± 2.62 mM, and enhancing-tumor: 7.60 ± 4.16 mM) was found compared to contralateral (10.84 ± 2.94 mM), whereas glutamine was higher in surrounding-non-enhancing-FLAIR-hyperintensity (9.17 ± 6.84 mM) and enhancing-tumor (7.20 ± 4.42 mM), but not in non-enhancing-tumor-core (4.92 ± 3.38 mM, p = 0.18) compared to contralateral (2.94 ± 1.35 mM).
DATA CONCLUSION: The proposed MRSI protocol (~12 min) enables separate mapping of glutamate and glutamine reliably along with other MRS-detectable standard metabolites in glioma subregions at 3T.
EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.

Keywords:  1H sLASER long‐TE; MR spectroscopy; brain tumor; glutamate; glutamine; reproducibility

DOI:  https://doi.org/10.1002/jmri.29787
Arch Immunol Ther Exp (Warsz). 2025 Jan 01. 73(1):

Exploring Diagnostic Markers and Therapeutic Targets in Parkinson's Disease: A Comprehensive 1H-NMR Metabolomic Analysis - Systematic Review.

Andrzej Wasilewski, Eliza Wasilewska, Agata Serrafi.

  Parkinson's disease (PD) affects millions of people globally. Accurate early diagnosis remains a challenge due to the lack of specific biomarkers. This systematic review explores the potential of 1H-NMR metabolomics in identifying diagnostic markers and therapeutic targets for PD. A comprehensive analysis was conducted across databases such as Scopus, Web of Science, PubMed, and Embase, focusing on studies that utilized 1H-NMR spectroscopy to profile metabolites associated with PD progression. The review identifies key metabolites-glutamate, taurine, myo-inositol, glutamine, and creatine-that play critical roles in the pathophysiology of PD. Glutamate, linked to excitotoxicity and neuronal degeneration, emerges as a prominent target for therapeutic intervention, while taurine is associated with oxidative stress. Myo-inositol, a key regulator of autophagy, underscores the biochemical dysregulation associated with PD, similar to glutamine and glutamate. Creatine's role in neuronal energy metabolism suggests potential avenues for treatment focused on energy supplementation. The reproducibility of metabolite findings varied, indicating the complexity of PD's metabolomic landscape. Despite challenges in consistency, these metabolites hold promise as biomarkers for diagnosing PD and tracking disease progression. The review underscores the need for further validation of these markers and their integration with other omics technologies to enhance PD management. By identifying key metabolic pathways, this study opens new directions for personalized medicine, offering potential therapeutic targets to slow disease progression and improve patient outcomes.

Keywords:  1H-NMR spectroscopy; Metabolite profiling; Metabolomic; Oxidative stress; Parkinson’s disease; Therapeutic targets

DOI:  https://doi.org/10.2478/aite-2025-0011
Cell Rep. 2025 Apr 08. pii: S2211-1247(25)00311-0. [Epub ahead of print]44(4): 115540

Unraveling the nexus: Genomic instability and metabolism in cancer.

Vaibhavi Gujar, Haojian Li, Tanya T Paull, Carola A Neumann, Urbain Weyemi.

  The DNA-damage response (DDR) is a signaling network that enables cells to detect and repair genomic damage. Over the past three decades, inhibiting DDR has proven to be an effective cancer therapeutic strategy. Although cancer drugs targeting DDR have received approval for treating various cancers, tumor cells often develop resistance to these therapies, owing to their ability to undergo energetic metabolic reprogramming. Metabolic intermediates also influence tumor cells' ability to sense oxidative stress, leading to impaired redox metabolism, thus creating redox vulnerabilities. In this review, we summarize recent advances in understanding the crosstalk between DDR and metabolism. We discuss combination therapies that target DDR, metabolism, and redox vulnerabilities in cancer. We also outline potential obstacles in targeting metabolism and propose strategies to overcome these challenges.

Keywords:  CP: Cancer; DNA damage response; DNA repair; cancer therapy; metabolism; redox metabolism; therapy resistance

DOI:  https://doi.org/10.1016/j.celrep.2025.115540
Cell Death Dis. 2025 Apr 05. 16(1): 253

Mitochondrial, metabolic and bioenergetic adaptations drive plasticity of colorectal cancer cells and shape their chemosensitivity.

Nikita Markov, Sirina Sabirova, Gulnaz Sharapova, Marina Gomzikova, Anna Brichkina, Nick A Barlev, Marcel Egger, Albert Rizvanov, Hans-Uwe Simon.

The extent of mitochondrial heterogeneity and the presence of mitochondrial archetypes in cancer remain unknown. Mitochondria play a central role in the metabolic reprogramming that occurs in cancer cells. This process adjusts the activity of metabolic pathways to support growth, proliferation, and survival of cancer cells. Using a panel of colorectal cancer (CRC) cell lines, we revealed extensive differences in their mitochondrial composition, suggesting functional specialisation of these organelles. We differentiated bioenergetic and mitochondrial phenotypes, which point to different strategies used by CRC cells to maintain their sustainability. Moreover, the efficacy of various treatments targeting metabolic pathways was dependent on the respiration and glycolysis levels of cancer cells. Furthermore, we identified metabolites associated with both bioenergetic profiles and cell responses to treatments. The levels of these molecules can be used to predict the therapeutic efficacy of anti-cancer drugs and identify metabolic vulnerabilities of CRC. Our study indicates that the efficacy of CRC therapies is closely linked to mitochondrial status and cellular bioenergetics.

DOI: https://doi.org/10.1038/s41419-025-07596-y
Free Radic Biol Med. 2025 Apr 09. pii: S0891-5849(25)00222-9. [Epub ahead of print]

The glutathione system maintains the thiol redox balance in the mitochondria of fission yeast.

Laura de Cubas, Susanna Boronat, Montserrat Vega, Alba Domènech, Ferran Gómez-Armengol, Alexey Artemov, Olga Lyublinskaya, José Ayté, Elena Hidalgo.

  The thioredoxin and glutathione (GSH)-glutaredoxin electron donor pathways provide a reducing environment to the cell and maintain homeostasis of numerous redox reactions. The abundant tripeptide GSH has multiple roles, including redox buffering, detoxification, peroxide scavenging and iron-sulfur cluster assembly. Glutathione reductase, Pgr1 in fission yeast, maintains glutathione reduced, and it is essential in most organisms. Cells lacking Pgr1 exhibit severe pleiotropic defects. We used multiple approaches to unravel the compartment-specific roles of Pgr1. Our findings confirmed that Pgr1 had dual cytosolic and mitochondrial localization. Mitochondrial homeostasis was severely impaired in Δpgr1 cells and most of these defects were restored by expression of an exclusively mitochondrial Pgr1 isoform. As expected, the cytosol of Δpgr1 cells showed low ratio of reduced-to-oxidized glutathione. However, this did not significantly affect peroxiredoxin-dependent hydrogen peroxide scavenging, suggesting a minimal role, if any, of GSH in cytosolic thiol reduction. The transcriptome of Δpgr1 cells revealed signatures of oxidative stress and iron deprivation, suggesting that the GSH-containing sensor of iron starvation, the glutaredoxin Grx4, is also a sensor of GSH oxidation. In the mitochondria, Pgr1 not only provided the GSH electron donor for the glutaredoxin-based pathway but also recycled mitochondrial Trx2, thereby contributing to thiol redox homeostasis in the matrix. In conclusion, glutathione reductase is essential for maintaining a balanced redox environment in the mitochondria by recycling Trx2, Grx2 and the GSH-containing Grx5, and therefore contributes to the processes of iron-sulfur cluster assembly and respiration, while controlling Grx4 dynamics in the cytosol.

Keywords:  GSH; glutathione reductase; iron-sulfur cluster assembly; mitochondria; redox balance

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.012
Cancer Lett. 2025 Apr 04. pii: S0304-3835(25)00263-0. [Epub ahead of print] 217697

Glutathione Metabolism in Ferroptosis and Cancer Therapy.

Xiangfei Xue, Manyuan Wang, Jiangtao Cui, Minying Yang, Lifang Ma, Rui Kang, Daolin Tang, Jiayi Wang.

Glutathione (GSH), a non-enzymatic antioxidant in mammalian cells, plays an essential role in maintaining redox balance, mitigating oxidative stress, and preserving cellular homeostasis. Beyond its well-established function in detoxifying reactive oxygen species (ROS), GSH serves as a critical regulator of ferroptosis-an iron-dependent form of cell death marked by excessive lipid peroxidation. Serving as a cofactor for glutathione peroxidase 4 (GPX4), GSH catalyzes the conversion of lipid peroxides into non-toxic lipid alcohols, thereby preventing the accumulation of deleterious lipid oxidation products and halting the spread of oxidative damage. In cancer cells, upregulated GSH synthesis and GPX4 activity contribute to an enhanced antioxidant defense, countering oxidative stress provoked by increased metabolic demands and exposure to therapeutic agents such as chemotherapy, radiotherapy, and immunotherapy. This ability of cancer cells to modulate their ferroptosis susceptibility through GSH metabolism underscores its potential as a therapeutic target. Additionally, GSH influences several key oncogenic and tumor-suppressive signaling pathways, including NFE2L2/NRF2, TP53/p53, NF-κB, Hippo, and mTOR, which collectively regulate responses to oxidative stress, affect metabolic processes, and modulate sensitivity to ferroptosis in cancer cells. This review explores recent advancements in understanding GSH's multifaceted role in ferroptosis, emphasizing its implications for cancer biology and therapeutic interventions.

DOI: https://doi.org/10.1016/j.canlet.2025.217697
Int Immunopharmacol. 2025 Apr 03. pii: S1567-5769(25)00556-9. [Epub ahead of print]154 114566

Dysregulated glutathione metabolism impairs natural killer cell function in patients with acute leukemia.

Yue Zhao, Yan Wang, Tingting Liang, Xian Song, Yingqiao Zhu, Xinru Liu, Mengya Lv, Changcheng Zheng, Fang Ni.

  Natural killer (NK) cell function is markedly impaired in patients with acute leukemia, weakening their anti-tumor immune response. However, the mechanisms underlying NK cell dysfunction are not fully understood. Here, we reveal that NK cells from patients with acute leukemia (AL-NK) exhibit significantly reduced intracellular glutathione (GSH) levels, accompanied by disrupted redox homeostasis and increased levels of mitochondrial reactive oxygen species. Flow cytometry and transcriptomic analyses indicate that dysregulated GSH metabolism leads to mitochondrial dysfunction in NK cells, thereby impairing their antileukemic cytotoxicity and proliferative capacity. Notably, supplementation with glutathione reduced ethyl ester (GSHEE)-a GSH precursor-effectively restores GSH levels in AL-NK cells, enhancing mitochondrial activity, oxidative phosphorylation, ATP production, and NK cell-mediated cytotoxicity. Moreover, GSHEE treatment activates the mTOR signaling pathway in NK cells, further promoting their function and proliferation. Overall, our study identifies dysregulated GSH metabolism as a key driver of NK cell dysfunction in acute leukemia and suggests that GSH-based interventions may provide a promising strategy to enhance NK cell-mediated immunotherapies.

Keywords:  Acute leukemia; Cytotoxicity; Glutathione; Mitochondria; Natural killer cells; RNA-sequencing

DOI:  https://doi.org/10.1016/j.intimp.2025.114566
Exp Hematol Oncol. 2025 Apr 10. 14(1): 55

GLS2 inhibition synergizes with copper to reprogram TCA cycle for cuproptosis-driven radiosensitization in esophageal cancer.

Wang Jing, Wenhao Wang, Yi Ding, Renya Zeng, Hui Zhu, Zhichao Kang, Alei Feng, Zhe Yang.

  Esophageal squamous cell carcinoma (ESCC) is notorious for its poor prognosis. In the present study, the role of glutaminase 2 (GLS2) and copper (Cu) in the radiosensitivity of ESCC was explored. Both in vitro and in vivo experiments were conducted, and the results demonstrated that the knockdown of GLS2 could suppress cell proliferation and augment the sensitivity to radiotherapy (RT). The addition of Cu influenced cell viability and radiosensitivity. Notably, under normal GLS2 expression status, exogenous Cu augmented RT sensitivity without triggering cuproptosis. Mechanistically, the suppression of GLS2 interacted with Cu to downregulate lipoic acid synthase and dihydrolipoamide S-succinyltransferase, resulting in the reduction of the activity of α-ketoglutarate dehydrogenase complex and the obstruction of the tricarboxylic acid cycle, ultimately leading to the enhancement of RT sensitivity. These findings emphasize the significance of cuproptosis in ESCC radiotherapy and provide potential directions for therapeutic strategies.

Keywords:  Cancer metabolism; Cuproptosis; Esophageal cancer; GLS2; Radiotherapy

DOI:  https://doi.org/10.1186/s40164-025-00653-4