bims-glucam 2025-02-02 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–02–02
twenty papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine and cancer: metabolism, immune microenvironment, and therapeutic targets.
BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer.
Infectious Spleen and Kidney Necrosis Virus ORF093R and ORF102R Regulate Glutamate Metabolic Reprogramming to Support Virus Proliferation by Interacting with c-Myc.
Inhibition of Glutamine Metabolism Suppresses Tumor Progression through Remodeling of the Macrophage Immune Microenvironment.
Identification of glutamine as a potential therapeutic target in dry eye disease.
The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives.
Targeting pancreatic cancer glutamine dependency confers vulnerability to GPX4-dependent ferroptosis.
Micropeptide hSPAR regulates glutamine levels and suppresses mammary tumor growth via a TRIM21-P27KIP1-mTOR axis.
Alzheimer's disease: an integrative bioinformatics and machine learning analysis reveals glutamine metabolism-associated gene biomarkers.
A mitochondria-targeted iridium(III) complex-based sensor for endogenous GSH detection in living cells.
Cellular Signaling of Amino Acid Metabolism in Prostate Cancer.
Metabolic Reprogramming at the Edge of Redox: Connections Between Metabolic Reprogramming and Cancer Redox State.
Metabolic reprogramming of neutrophils in the tumor microenvironment: Emerging therapeutic targets.
Adaptation mechanisms in cancer: Lipid metabolism under hypoxia and nutrient deprivation as a target for novel therapeutic strategies (Review).
The Impact of Metabolic Rewiring in Glioblastoma: The Immune Landscape and Therapeutic Strategies.
Emerging insights into the impact of systemic metabolic changes on tumor-immune interactions.
Nrf2 Regulates Basal Glutathione Production in Astrocytes.
Multi-signal fluorescent probe for simultaneous differentiation and imaging of Hg2+, Cys, Hcy, and GSH in living cells and zebrafish.
IDH1 mutation inhibits differentiation of astrocytes and glioma cells with low oxoglutarate dehydrogenase expression by disturbing α-ketoglutarate-related metabolism and epigenetic modification.
Predictive role of SLC1A5 in neuroblastoma prognosis and immunotherapy.

Cell Commun Signal. 2025 Jan 24. 23(1): 45

Glutamine and cancer: metabolism, immune microenvironment, and therapeutic targets.

Ding Nan, Weiping Yao, Luanluan Huang, Ruiqi Liu, Xiaoyan Chen, Wenjie Xia, Hailong Sheng, Haibo Zhang, Xiaodong Liang, Yanwei Lu.

  Glutamine is the most abundant amino acid in human serum, and it can provide carbon and nitrogen for biosynthesis, which is crucial for proliferating cells. Moreover, it is widely known that glutamine metabolism is reprogrammed in cancer cells. Many cancer cells undergo metabolic reprogramming targeting glutamine, increasing its uptake to meet their rapid proliferation demands. An increasing amount of study is being done on the particular glutamine metabolic pathways in cancer cells.Further investigation into the function of glutamine in immune cells is warranted given the critical role these cells play in the fight against cancer. Immune cells use glutamine for a variety of biological purposes, including the growth, differentiation, and destruction of cancer cells. With the encouraging results of cancer immunotherapy in recent years, more investigation into the impact of glutamine metabolism on immune cell function in the cancer microenvironment could lead to the discovery of new targets and therapeutic approaches.Oral supplementation with glutamine also enhances the immune capabilities of cancer patients, improves the sensitivity to chemotherapy and radiotherapy, and improves prognosis. The unique metabolism of glutamine in cancer cells, its function in various immune cells, the impact of inhibitors of glutamine metabolism, and the therapeutic use of glutamine supplements are all covered in detail in this article.

Keywords:  Cancer; Glutaminase inhibitors; Glutamine antimetabolites; Glutamine metabolism; Immune cells

DOI:  https://doi.org/10.1186/s12964-024-02018-6
Life Metab. 2024 Aug;3(4): loae016

BET inhibition induces GDH1-dependent glutamine metabolic remodeling and vulnerability in liver cancer.

Wen Mi, Jianwei You, Liucheng Li, Lingzhi Zhu, Xinyi Xia, Li Yang, Fei Li, Yi Xu, Junfeng Bi, Pingyu Liu, Li Chen, Fuming Li.

  Bromodomain and extra-terminal domain (BET) proteins, which function partly through MYC proto-oncogene (MYC), are critical epigenetic readers and emerging therapeutic targets in cancer. Whether and how BET inhibition simultaneously induces metabolic remodeling in cancer cells remains unclear. Here we find that even transient BET inhibition by JQ-1 and other pan-BET inhibitors (pan-BETis) blunts liver cancer cell proliferation and tumor growth. BET inhibition decreases glycolytic gene expression but enhances mitochondrial glucose and glutamine oxidative metabolism revealed by metabolomics and isotope labeling analysis. Specifically, BET inhibition downregulates miR-30a to upregulate glutamate dehydrogenase 1 (GDH1) independent of MYC, which produces α-ketoglutarate for mitochondrial oxidative phosphorylation (OXPHOS). Targeting GDH1 or OXPHOS is synthetic lethal to BET inhibition, and combined BET and OXPHOS inhibition therapeutically prevents liver tumor growth in vitro and in vivo. Together, we uncover an important epigenetic-metabolic crosstalk whereby BET inhibition induces MYC-independent and GDH1-dependent glutamine metabolic remodeling that can be exploited for innovative combination therapy of liver cancer.

Keywords:  BET; glutamate dehydrogenase 1; glutamine metabolism; oxidative phosphorylation; synthetic lethality

DOI:  https://doi.org/10.1093/lifemeta/loae016
Int J Mol Sci. 2025 Jan 16. pii: 718. [Epub ahead of print]26(2):

Infectious Spleen and Kidney Necrosis Virus ORF093R and ORF102R Regulate Glutamate Metabolic Reprogramming to Support Virus Proliferation by Interacting with c-Myc.

Yinjie Niu, Caimei Ye, Qiang Lin, Hongru Liang, Xia Luo, Baofu Ma, Ningqiu Li, Xiaozhe Fu.

  Glutamine metabolism is essential for infectious spleen and kidney necrosis virus (ISKNV) replication. Glutaminase 1 (GLS1), the key enzyme of the glutamine metabolism, and c-Myc positively regulate ISKNV infection, while c-Myc is closely correlated with GLS1. However, the regulatory mechanism among ISKNV, c-Myc and glutamine metabolism remains unclear. Here, we indicated that c-Myc increased glutamine uptake by increasing the GLS1, glutamate dehydrogenase (GDH) and isocitrate dehydrogenase (IDH2) expression of glutamine metabolism. ISKNV ORF102R, ORF093R and ORF118L co-located with c-Myc in CPB cells. Co-IP results showed that ISKNV ORF102R and ORF093R interacted with c-Myc, while ORF118L did not interact with c-Myc. The expression levels of c-Myc, GLS1 and IDH2 were increased in ISKNV ORF093R expression cells, and the mRNA and protein levels of GLS1 were upregulated in ISKNV 102R-expressing cells. These results indicated that ISKNV reconstructed glutamine metabolism to satisfy the energy and macromolecule requirements for virus proliferation by ORF093R and ORF102R interacting with c-Myc, which provides the foundation for innovative antiviral strategies.

Keywords:  ISKNV; c-Myc; glutamine metabolism

DOI:  https://doi.org/10.3390/ijms26020718
bioRxiv. 2025 Jan 14. pii: 2025.01.10.632174. [Epub ahead of print]

Inhibition of Glutamine Metabolism Suppresses Tumor Progression through Remodeling of the Macrophage Immune Microenvironment.

Tianhe Li, Sepehr Akhtarkhavari, Tu-Yung Chang, Yao-An Shen, JinMing Yang, Barbara Slusher, Ie-Ming Shih, Stephanie Gaillard, Tian-Li Wang.

Background: Targeting glutamine metabolism has emerged as a promising strategy in cancer therapy. However, several barriers, such as in vivo anti-tumor efficacy, drug toxicity, and safety, remain to be overcome to achieve clinical utility. Prior preclinical in vivo studies had generated encouraging data showing promises of cancer metabolism targeting drugs, although most were performed on immune-deficient murine models. It is being recognized that aside from tumor cells, normal cells such as immune cells in the tumor microenvironment may also utilize glutamine for maintaining physiological functions. To provide an in-depth view of glutamine antagonist (GLNi) treatment on the tumor immune microenvironment, the current study made several unique approaches.
Method: First, to evaluate GLNi treatment modality that potentially involves immune cells, the study was performed on immunocompetent murine models of gynecological cancers. Second, to enhance safety and reduce potential off-target effects, we developed a GLNi prodrug, JHU083, which is bio-activated restrictively in cancer tissues. Third, to unbiasedly decode the response of single cells in the tumor microenvironment to GLNi treatment, single-cell RNA sequencing (scRNA-seq) was performed on cells prepared from tumors of the JHU083 or vehicle control-treated mice.
Results: In both immunocompetent murine tumor models, we observed a significant anti-tumor efficacy, resulting in reduced tumor burden and impeded tumor progression. Similarly, in both tumor models, scRNA-seq revealed significantly impeded immunosuppressive M2-like macrophages by JHU083, while the treatment spared pro-inflammatory M1-like tumor macrophages. In many tumor microenvironment (TME) cells, JHU083 downregulated genes regulated by Myc and hypoxia. M2 macrophages' greater sensitivity to glutamine antagonism when compared to M1 macrophages or monocytes was further validated on ex vivo cultures of bone marrow-derived macrophages.
Conclusion: Our findings support a converged mechanism of glutamine metabolism antagonists. JHU083 exerted its anti-tumor efficacy through not only direct targeting of glutamine-addicted cancer cells but also by suppressing glutamine-dependent M2 macrophages, leading to a shift in the M1/M2 macrophage landscape in favor of an immune-stimulatory microenvironment.

DOI: https://doi.org/10.1101/2025.01.10.632174
Signal Transduct Target Ther. 2025 Jan 22. 10(1): 27

Identification of glutamine as a potential therapeutic target in dry eye disease.

Xiaoniao Chen, Chuyue Zhang, Fei Peng, Lingling Wu, Deyi Zhuo, Liqiang Wang, Min Zhang, Zhaohui Li, Lei Tian, Ying Jie, Yifei Huang, Xinji Yang, Xiaoqi Li, Fengyang Lei, Yu Cheng.

Dry eye disease (DED) is a prevalent inflammatory condition significantly impacting quality of life, yet lacks effective pharmacological therapies. Herein, we proposed a novel approach to modulate the inflammation through metabolic remodeling, thus promoting dry eye recovery. Our study demonstrated that co-treatment with mesenchymal stem cells (MSCs) and thymosin beta-4 (Tβ4) yielded the best therapeutic outcome against dry eye, surpassing monotherapy outcomes. In situ metabolomics through matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) revealed increased glutamine levels in cornea following MSC + Tβ4 combined therapy. Inhibition of glutamine reversed the anti-inflammatory, anti-apoptotic, and homeostasis-preserving effects observed with combined therapy, highlighting the critical role of glutamine in dry eye therapy. Clinical cases and rodent model showed elevated expression of glutaminase (GLS1), an upstream enzyme in glutamine metabolism, following dry eye injury. Mechanistic studies indicated that overexpression and inhibition of GLS1 counteracted and enhanced, respectively, the anti-inflammatory effects of combined therapy, underscoring GLS1's pivotal role in regulating glutamine metabolism. Furthermore, single-cell sequencing revealed a distinct subset of pro-inflammatory and pro-fibrotic corneal epithelial cells in the dry eye model, while glutamine treatment downregulated those subclusters, thereby reducing their inflammatory cytokine secretion. In summary, glutamine effectively ameliorated inflammation and the occurrence of apoptosis by downregulating the pro-inflammatory and pro-fibrotic corneal epithelial cells subclusters and the related IκBα/NF-κB signaling. The present study suggests that glutamine metabolism plays a critical, previously unrecognized role in DED and proposes an attractive strategy to enhance glutamine metabolism by inhibiting the enzyme GLS1 and thus alleviating inflammation-driven DED progression.

DOI: https://doi.org/10.1038/s41392-024-02119-1
Int J Mol Sci. 2024 Dec 26. pii: 92. [Epub ahead of print]26(1):

The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives.

Amer Ahmed, Giorgia Natalia Iaconisi, Daria Di Molfetta, Vincenzo Coppola, Antonello Caponio, Ansu Singh, Aasia Bibi, Loredana Capobianco, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte.

  Cancer cells undergo remarkable metabolic changes to meet their high energetic and biosynthetic demands. The Warburg effect is the most well-characterized metabolic alteration, driving cancer cells to catabolize glucose through aerobic glycolysis to promote proliferation. Another prominent metabolic hallmark of cancer cells is their increased reliance on glutamine to replenish tricarboxylic acid (TCA) cycle intermediates essential for ATP production, aspartate and fatty acid synthesis, and maintaining redox homeostasis. In this context, mitochondria, which are primarily used to maintain energy homeostasis and support balanced biosynthesis in normal cells, become central organelles for fulfilling the heightened biosynthetic and energetic demands of proliferating cancer cells. Mitochondrial coordination and metabolite exchange with other cellular compartments are crucial. The human SLC25 mitochondrial carrier family, comprising 53 members, plays a pivotal role in transporting TCA intermediates, amino acids, vitamins, nucleotides, and cofactors across the inner mitochondrial membrane, thereby facilitating this cross-talk. Numerous studies have demonstrated that mitochondrial carriers are altered in cancer cells, actively contributing to tumorigenesis. This review comprehensively discusses the role of SLC25 carriers in cancer pathogenesis and metabolic reprogramming based on current experimental evidence. It also highlights the research gaps that need to be addressed in future studies. Understanding the involvement of these carriers in tumorigenesis may provide valuable novel targets for drug development.

Keywords:  cancer; metabolic reprogramming; metabolism; mitochondria; mitochondrial carriers

DOI:  https://doi.org/10.3390/ijms26010092
Cell Rep Med. 2025 Jan 27. pii: S2666-3791(25)00001-1. [Epub ahead of print] 101928

Targeting pancreatic cancer glutamine dependency confers vulnerability to GPX4-dependent ferroptosis.

Xuqing Shen, Yueyue Chen, Yingying Tang, Ping Lu, Mingzhu Liu, Tiebo Mao, Yawen Weng, Feier Yu, Yimei Liu, Yujie Tang, Liwei Wang, Ningning Niu, Jing Xue.

  Pancreatic ductal adenocarcinoma (PDAC) relies heavily on glutamine (Gln) utilization to meet its metabolic and biosynthetic needs. How epigenetic regulators contribute to the metabolic flexibility and PDAC's response and adaptation to Gln scarcity in the tumor milieu remains largely unknown. Here, we elucidate that prolonged Gln restriction or treatment with the Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), leads to growth inhibition and ferroptosis program activation in PDAC. A CRISPR-Cas9 screen identifies an epigenetic regulator, Paxip1, which promotes H3K4me3 upregulation and Hmox1 transcription upon DON treatment. Additionally, ferroptosis-related repressors (e.g., Slc7a11 and Gpx4) are increased as an adaptive response, thereby predisposing PDAC cells to ferroptosis upon Gln deprivation. Moreover, DON sensitizes PDAC cells to GPX4 inhibitor-induced ferroptosis, both in vitro and in patient-derived xenografts (PDXs). Taken together, our findings reveal that targeting Gln dependency confers susceptibility to GPX4-dependent ferroptosis via epigenetic remodeling and provides a combination strategy for PDAC therapy.

Keywords:  PDAC; combination therapy; epigenetic remodeling; ferroptosis; pancreatic ductal adenocarcinoma; prolonged glutamine starvation

DOI:  https://doi.org/10.1016/j.xcrm.2025.101928
EMBO J. 2025 Jan 28.

Micropeptide hSPAR regulates glutamine levels and suppresses mammary tumor growth via a TRIM21-P27KIP1-mTOR axis.

Yan Huang, Hua Lu, Yao Liu, Jiabei Wang, Qingan Xia, Xiangmin Shi, Yan Jin, Xiaolin Liang, Wei Wang, Xiaopeng Ma, Yangyi Wang, Meng Gong, Canjun Li, Chunlei Cang, Qinghua Cui, Ceshi Chen, Tao Shen, Lianxin Liu, Xiangting Wang.

  mTOR plays a pivotal role in cancer growth control upon amino acid response. Recently, CDK inhibitor P27KIP1 has been reported as a noncanonical inhibitor of mTOR signaling in MEFs, via unclear mechanisms. Here, we find that P27KIP1 degradation via E3 ligase TRIM21 is inhibited by human micropeptide hSPAR through its C-terminus (hSPAR-C), causing P27KIP1's cytoplasmic accumulation in breast cancer cells. Furthermore, hSPAR/hSPAR-C also serves as an inhibitor of glutamine transporter SLC38A2 expression and thereby decreases the cellular glutamine levels specifically in cancer cells. The resultant glutamine deprivation sequentially triggers translocation of cytoplasmic P27KIP1 to lysosomes, where P27KIP1 disrupts the Ragulator complex and suppresses mTORC1 assembly. Administration of hSPAR or hSPAR-C significantly impedes breast cancer cell proliferation and tumor growth in xenograft models. These findings define hSPAR as an intrinsic control factor for cellular glutamine levels and as a novel tumor suppressor inhibiting mTORC1 assembly.

Keywords:  Breast Cancer; Micropeptide/microprotein; P27KIP1; TRIM21; mTOR

DOI:  https://doi.org/10.1038/s44318-024-00359-z
BMC Pharmacol Toxicol. 2025 Jan 28. 26(1): 19

Alzheimer's disease: an integrative bioinformatics and machine learning analysis reveals glutamine metabolism-associated gene biomarkers.

Naifei Xing, Jingwei Yan, Rong Gao, Aihua Zhang, Huiyan He, Man Zheng, Guojing Li.

   BACKGROUND: Alzheimer's disease (AD), a hallmark of age-related cognitive decline, is defined by its unique neuropathology. Metabolic dysregulation, particularly involving glutamine (Gln) metabolism, has emerged as a critical but underexplored aspect of AD pathophysiology, representing a significant gap in our current understanding of the disease.
METHODS: To investigate the involvement of GlnMgs in AD, we conducted a comprehensive bioinformatic analysis. We began by identifying differentially expressed GlnMgs from a curated list of 34 candidate genes. Subsequently, we employed GSEA and GSVA to assess the biological significance of these GlnMgs. Advanced techniques such as Lasso regression and SVM-RFE were utilized to identify key hub genes and evaluate the diagnostic potential of 14 central GlnMgs in AD. Additionally, we examined their correlations with clinical parameters and validated their expression across multiple independent AD cohorts (GSE5281, GSE37263, GSE106241, GSE132903, GSE63060).
RESULTS: Our rigorous analysis identified 14 GlnMgs-GLS2, GLS, GLUD2, GLUL, GOT1, HAL, AADAT, PFAS, ASNSD1, PPAT, NIT2, ALDH5A1, ASRGL1, and ATCAY-as potential contributors to AD pathogenesis. These genes were implicated in vital biological processes, including lipid transport and the metabolism of purine-containing compounds, in response to nutrient availability. Notably, these GlnMgs demonstrated significant diagnostic potential, highlighting their utility as both diagnostic and prognostic biomarkers for AD.
CONCLUSIONS: Our study uncovers 14 GlnMgs with potential links to AD, expanding our understanding of the disease's molecular underpinnings and offering promising avenues for biomarker development. These findings not only enhance the molecular landscape of AD but also pave the way for future diagnostic and therapeutic innovations, potentially reshaping AD diagnostics and patient care.

Keywords:  Alzheimer's disease (AD); Bioinformatics; Gln-metabolism genes (GlnMgs); Lasso regression; SVM-RFE

DOI:  https://doi.org/10.1186/s40360-025-00852-z
Analyst. 2025 Jan 29.

A mitochondria-targeted iridium(III) complex-based sensor for endogenous GSH detection in living cells.

Sha Xu, Qikai Ju, Xueting Mao, Tangxuan Cai, Daobin Zhang.

Glutathione (GSH) plays an important role in maintaining redox homeostasis in biological systems. Development of reliable glutathione sensors is of great significance to better understand the role of biomolecules in living cells and organisms. Based on the advantages of the photophysical properties of iridium complexes, we proposed a "turn-on" phosphorescent sensor. Ir-DNFB has the characteristics of a large Stokes shift, high sensitivity for GSH detection, low cytotoxicity, and extremely short response time, and can specifically analyze glutathione in living cells and highly target endogenous glutathione in mitochondria. The N-H group on the imidazole ring of Ir-DNFB could form a new electrostatic interaction with the α-carboxyl group on the glutamate moiety of glutathione. The nucleophilic attack reaction was regulated by the sulfhydryl group on GSH, following which the ether bond linking the 2,4-dinitrobenzene to probe Ir-DNFB was broken, accompanied with a phosphorescence enhancement. Most importantly, the process of recognizing glutathione was not affected by other amino acids. Overall, this work provided a very useful tool for rapidly distinguishing between normal, inflammatory, and progressive tumor cells.

DOI: https://doi.org/10.1039/d4an01465k
Int J Mol Sci. 2025 Jan 17. pii: 776. [Epub ahead of print]26(2):

Cellular Signaling of Amino Acid Metabolism in Prostate Cancer.

Ping Yao, Shiqi Cao, Ziang Zhu, Yunru Wen, Yawen Guo, Wenken Liang, Jianling Xie.

  Prostate cancer is one of the most common malignancies affecting men worldwide and a leading cause of cancer-related mortality, necessitating a deeper understanding of its underlying biochemical pathways. Similar to other cancer types, prostate cancer is also characterised by aberrantly activated metabolic pathways that support tumour development, such as amino acid metabolism, which is involved in modulating key physiological and pathological cellular processes during the progression of this disease. The metabolism of several amino acids, such as glutamine and methionine, crucial for tumorigenesis, is dysregulated and commonly discussed in prostate cancer. And the roles of some less studied amino acids, such as histidine and glycine, have also been covered in prostate cancer studies. Aberrant regulation of two major signalling pathways, mechanistic target of rapamycin (mTOR) and general amino acid control non-depressible 2 (GCN2), is a key driver of reshaping the amino acid metabolism landscape in prostate cancer. By summarising our current understanding of how amino acid metabolism is modulated in prostate cancer, here, we provide further insights into certain potential therapeutic targets for managing prostate cancer through metabolic interventions.

Keywords:  GCN2; amino acid; mTOR; metabolic reprogramming; prostate cancer

DOI:  https://doi.org/10.3390/ijms26020776
Int J Mol Sci. 2025 Jan 09. pii: 498. [Epub ahead of print]26(2):

Metabolic Reprogramming at the Edge of Redox: Connections Between Metabolic Reprogramming and Cancer Redox State.

José J Serrano, Miguel Ángel Medina.

  The importance of redox systems as fundamental elements in biology is now widely recognized across diverse fields, from ecology to cellular biology. Their connection to metabolism is particularly significant, as it plays a critical role in energy regulation and distribution within organisms. Over recent decades, metabolism has emerged as a relevant focus in studies of biological regulation, especially following its recognition as a hallmark of cancer. This shift has broadened cancer research beyond strictly genetic perspectives. The interaction between metabolism and redox systems in carcinogenesis involves the regulation of essential metabolic pathways, such as glycolysis and the Krebs cycle, as well as the involvement of redox-active components like specific amino acids and cofactors. The feedback mechanisms linking redox systems and metabolism in cancer highlight the development of redox patterns that enhance the flexibility and adaptability of tumor processes, influencing larger-scale biological phenomena such as circadian rhythms and epigenetics.

Keywords:  cancer; emergence; feedback; metabolism; redox; reprogramming

DOI:  https://doi.org/10.3390/ijms26020498
Cancer Lett. 2025 Jan 23. pii: S0304-3835(25)00030-8. [Epub ahead of print]612 217466

Metabolic reprogramming of neutrophils in the tumor microenvironment: Emerging therapeutic targets.

Shiyun Huang, Jiahao Shi, Jianfeng Shen, Xianqun Fan.

  Neutrophils are pivotal in the immune system and have been recognized as significant contributors to cancer development and progression. These cells undergo metabolic reprogramming in response to various stimulus, including infections, diseases, and the tumor microenvironment (TME). Under normal conditions, neutrophils primarily rely on aerobic glucose metabolism for energy production. However, within the TME featured by hypoxic and nutrient-deprived conditions, they shift to altered anaerobic glycolysis, lipid metabolism, mitochondrial metabolism and amino acid metabolism to perform their immunosuppressive functions and facilitate tumor progression. Targeting neutrophils within the TME is a promising therapeutic approach. Yet, focusing on their metabolic pathways presents a novel strategy to enhance cancer immunotherapy. This review synthesizes the current understanding of neutrophil metabolic reprogramming in the TME, with an emphasis on the underlying molecular mechanisms and signaling pathways. Studying neutrophil metabolism in the TME poses challenges, such as their short lifespan and the metabolic complexity of the environment, necessitating the development of advanced research methodologies. This review also discusses emerging solutions to these challenges. In conclusion, given their integral role in the TME, targeting the metabolic pathways of neutrophils could offer a promising avenue for cancer therapy.

Keywords:  Metabolism; Neutrophil; Therapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.217466
Mol Med Rep. 2025 Apr;pii: 83. [Epub ahead of print]31(4):

Adaptation mechanisms in cancer: Lipid metabolism under hypoxia and nutrient deprivation as a target for novel therapeutic strategies (Review).

Shiro Koizume, Yohei Miyagi.

  Tumor tissues generally exist in a relatively hypovascular state, and cancer cells must adapt to severe tissue conditions with a limited molecular oxygen and nutrient supply for their survival. Lipid metabolism serves a role in this adaptation. Lipids are supplied not only through the bloodstream but also through autonomous synthesis by cancer cells, and they function as sources of adenosine triphosphate and cell components. Although cancer‑associated lipid metabolism has been widely reviewed, how this metabolism responds to the tumor environment with poor molecular oxygen and nutrient supply remains to be fully discussed. The main aim of the present review was to summarize the findings on this issue and to provide insights into how cancer cells adapt to better cope with metabolic stresses within tumors. It may be suggested that diverse types of lipid metabolism have a role in enabling cancer cells to adapt to both hypoxia and nutrient‑poor conditions. Gaining a deeper understanding of these molecular mechanisms may reveal novel possibilities of exploration for cancer treatment.

Keywords:  amino acid deprivation; cancer; glucose deprivation; hypoxia; lipid metabolism

DOI:  https://doi.org/10.3892/mmr.2025.13448
Int J Mol Sci. 2025 Jan 14. pii: 669. [Epub ahead of print]26(2):

The Impact of Metabolic Rewiring in Glioblastoma: The Immune Landscape and Therapeutic Strategies.

Yuganthini Vijayanathan, Ivy A W Ho.

  Glioblastoma (GBM) is an aggressive brain tumor characterized by extensive metabolic reprogramming that drives tumor growth and therapeutic resistance. Key metabolic pathways, including glycolysis, lactate production, and lipid metabolism, are upregulated to sustain tumor survival in the hypoxic and nutrient-deprived tumor microenvironment (TME), while glutamine and tryptophan metabolism further contribute to the aggressive phenotype of GBM. These metabolic alterations impair immune cell function, leading to exhaustion and stress in CD8+ and CD4+ T cells while favoring immunosuppressive populations such as regulatory T cells (Tregs) and M2-like macrophages. Recent studies emphasize the role of slow-cycling GBM cells (SCCs), lipid-laden macrophages, and tumor-associated astrocytes (TAAs) in reshaping GBM's metabolic landscape and reinforcing immune evasion. Genetic mutations, including Isocitrate Dehydrogenase (IDH) mutations, Epidermal Growth Factor Receptor (EGFR) amplification, and Phosphotase and Tensin Homolog (PTEN) loss, further drive metabolic reprogramming and offer potential targets for therapy. Understanding the relationship between GBM metabolism and immune suppression is critical for overcoming therapeutic resistance. This review focuses on the role of metabolic rewiring in GBM, its impact on the immune microenvironment, and the potential of combining metabolic targeting with immunotherapy to improve clinical outcomes for GBM patients.

Keywords:  GBM; glioma; immune infiltration; metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms26020669
Cell Rep. 2025 Jan 23. pii: S2211-1247(25)00005-1. [Epub ahead of print]44(2): 115234

Emerging insights into the impact of systemic metabolic changes on tumor-immune interactions.

Andrea L Cote, Chad J Munger, Alison E Ringel.

  Tumors are inherently embedded in systemic physiology, which contributes metabolites, signaling molecules, and immune cells to the tumor microenvironment. As a result, any systemic change to host metabolism can impact tumor progression and response to therapy. In this review, we explore how factors that affect metabolic health, such as diet, obesity, and exercise, influence the interplay between cancer and immune cells that reside within tumors. We also examine how metabolic diseases influence cancer progression, metastasis, and treatment. Finally, we consider how metabolic interventions can be deployed to improve immunotherapy. The overall goal is to highlight how metabolic heterogeneity in the human population shapes the immune response to cancer.

Keywords:  CP: Cancer; CP: Metabolism; anti-tumor immunity; systemic metabolism; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2025.115234
Int J Mol Sci. 2025 Jan 15. pii: 687. [Epub ahead of print]26(2):

Nrf2 Regulates Basal Glutathione Production in Astrocytes.

Jiali He, Sandra J Hewett.

  Astrocytes produce and export glutathione (GSH), an important thiol antioxidant essential for protecting neural cells from oxidative stress and maintaining optimal brain health. While it has been established that oxidative stress increases GSH production in astrocytes, with Nrf2 acting as a critical transcription factor regulating key components of the GSH synthetic pathway, the role of Nrf2 in controlling constitutive GSH synthetic and release mechanisms remains incompletely investigated. Our data show that naïve primary mouse astrocytes cultured from the cerebral cortices of Nrf2 knockout (Nrf2-/-) pups have significantly less intracellular and extracellular GSH levels when compared to astrocytes cultured from Nrf2 wild-type (Nrf2+/+) pups. Key components of the GSH synthetic pathway, including xCT (the substrate-specific light chain of the substrate-importing transporter, system xc-), glutamate-cysteine ligase [catalytic (GCLc) and modifying (GCLm) subunits], were affected. To wit: qRT-PCR analysis demonstrates that naïve Nrf2-/- astrocytes have significantly lower basal mRNA levels of xCT and both GCL subunits compared to naïve Nrf2+/+ astrocytes. No change in mRNA levels of glutathione synthetase (GS) or the GSH exporting transporter, Mrp1, was found. Western blot analysis reveals reduced protein levels of both subunits of GCL, while (seleno)cystine uptake into Nrf2-/- astrocytes was reduced compared to Nrf2+/+ astrocytes, confirming decreased system xc- activity. These findings suggest that Nrf2 regulates the basal production of GSH in astrocytes through constitutive transcriptional regulation of GCL and xCT.

Keywords:  Nrf2; astrocytes; glutamate cysteine ligase; glutathione; oxidative stress; system xc−

DOI:  https://doi.org/10.3390/ijms26020687
J Hazard Mater. 2025 Jan 27. pii: S0304-3894(25)00339-5. [Epub ahead of print]488 137427

Multi-signal fluorescent probe for simultaneous differentiation and imaging of Hg2+, Cys, Hcy, and GSH in living cells and zebrafish.

Yang Li, Jing Li, Ting Yu, Hongyi Cai, Youyu Zhang, Haitao Li, Huijun Zhou, Peng Yin.

  The Mercury (II) ion (Hg²⁺) is a toxic heavy metal that threatens biological systems by inducing oxidative stress and disrupting the redox balance. Biothiols such as cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) are critical in maintaining redox homeostasis and are implicated in numerous physiological and pathological processes. Understanding the complex interactions between Hg²⁺ and biothiols requires molecular tools capable of simultaneous detection. Herein, we report a novel multi-signal fluorescent probe, DPC, designed with four specific recognition sites and rhodamine and coumarin fluorophores. The DPC probe enables the selective and sensitive differentiation of Mercury (II) ion (Hg²⁺), cysteine (Cys), homocysteine (Hcy), and glutathione (GSH), with distinct fluorescence signals. DPC can detect mercury (II) ions (Hg²⁺) in water samples with a high recovery rate ranging from 90.44 % to 112.27 %. DPC was also successfully applied for real-time imaging of these species in living cells and zebrafish, revealing that Hg²⁺ induces oxidative stress, reducing cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) levels. Furthermore, detoxifying agents such as sodium selenite (Na₂SeO₃), 2,3-dimercaptopropan-1-ol (DMPC), and L-selenocysteine (Sec) restored biothiol levels, counteracting Mercury (II) ion (Hg²⁺) toxicity. These results highlight the exceptional performance of DPC for the simultaneous imaging of Mercury (II) ions (Hg²⁺) and biothiols, providing insights into their interactions and proposing a chemobiological framework for studying heavy metal toxicity and developing detoxification strategies.

Keywords:  Bioimaging; Bioprobe; Biothiols; Mercury; Simultaneous detection

DOI:  https://doi.org/10.1016/j.jhazmat.2025.137427
Life Metab. 2024 Apr;3(2): loae002

IDH1 mutation inhibits differentiation of astrocytes and glioma cells with low oxoglutarate dehydrogenase expression by disturbing α-ketoglutarate-related metabolism and epigenetic modification.

Yuanlin Zhao, Ying Yang, Risheng Yang, Chao Sun, Xing Gao, Xiwen Gu, Yuan Yuan, Yating Nie, Shenhui Xu, Ruili Han, Lijun Zhang, Jing Li, Peizhen Hu, Yingmei Wang, Huangtao Chen, Xiangmei Cao, Jing Wu, Zhe Wang, Yu Gu, Jing Ye.

  Isocitrate dehydrogenase (IDH) mutations frequently occur in lower-grade gliomas and secondary glioblastomas. Mutant IDHs exhibit a gain-of-function activity, leading to the production of D-2-hydroxyglutarate (D-2HG) by reducing α-ketoglutarate (α-KG), a central player in metabolism and epigenetic modifications. However, the role of α-KG homeostasis in IDH-mutated gliomagenesis remains elusive. In this study, we found that low expression of oxoglutarate dehydrogenase (OGDH) was a common feature in IDH-mutated gliomas, as well as in astrocytes. This low expression of OGDH resulted in the accumulation of α-KG and promoted astrocyte maturation. However, IDH1 mutation significantly reduced α-KG levels and increased glutaminolysis and DNA/histone methylation in astrocytes. These metabolic and epigenetic alterations inhibited astrocyte maturation and led to cortical dysplasia in mice. Moreover, our results also indicated that reduced OGDH expression can promote the differentiation of glioma cells, while IDH1 mutations impeded the differentiation of glioma cells with low OGDH by reducing the accumulation of α-KG and increasing glutaminolysis. Finally, we found that l-glutamine increased α-KG levels and augmented the differentiation-promoting effects of AGI5198, an IDH1-mutant inhibitor, in IDH1-mutant glioma cells. Collectively, this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas, providing a potential strategy for the treatment of IDH-mutant gliomas by targeting α-KG homeostasis.

Keywords:  -glutamine; IDH1 mutation; OGDH; gliomas; l; α-ketoglutarate

DOI:  https://doi.org/10.1093/lifemeta/loae002
BMC Cancer. 2025 Jan 28. 25(1): 161

Predictive role of SLC1A5 in neuroblastoma prognosis and immunotherapy.

Jian Cheng, Miaomiao Sun, Xiao Dong, Yang Yang, Xiaohan Qin, Xing Zhou, Yongcheng Fu, Yuanyuan Wang, Jingyue Wang, Da Zhang.

   BACKGROUND: Neuroblastoma, a prevalent extracranial solid tumor in pediatric patients, demonstrates significant clinical heterogeneity, ranging from spontaneous regression to aggressive metastatic disease. Despite advances in treatment, high-risk neuroblastoma remains associated with poor survival. SLC1A5, a key glutamine transporter, plays a dual role in promoting tumor growth and immune modulation. However, its contributions to neuroblastoma biology remain largely unexplored.
METHODS: This study utilized clinical neuroblastoma samples from 20 patients and 1310 cases from four public datasets to investigate SLC1A5 expression, biological function, and prognostic significance. Differential expression, Kaplan-Meier survival analysis, gene set enrichment analysis, and weighted correlation network analysis were conducted. Functional validation included qPCR, immunohistochemistry, Western blotting, and cell proliferation assays using the SLC1A5 inhibitor V-9302. A prognostic signature, SRPS, was constructed and validated using machine-learning approaches. Immune infiltration analysis was performed to evaluate the tumor immune microenvironment.
RESULTS: SLC1A5 expression was significantly elevated in high-risk neuroblastoma and correlated with advanced stages and poor prognosis. GSEA revealed mTORC1 signaling enrichment in high SLC1A5 expression groups, validated by increased p-p70S6K levels in tumor samples and neuroblastoma cells. V-9302 treatment suppressed mTORC1 signaling and inhibited cell proliferation. Hub-genes were identified to form the SRPS model, which demonstrated superior prognostic performance compared to existing models. Immune infiltration analysis revealed a more immunosuppressive tumor microenvironment associated with high SLC1A5 expression. Additionally, SLC1A5 negatively regulated ST8SIA1, a gene crucial for GD2 biosynthesis, suggesting that SLC1A5 inhibition may enhance GD2-directed immunotherapies.
CONCLUSION: SLC1A5 plays a pivotal role in neuroblastoma by promoting tumor progression and shaping an immunosuppressive microenvironment. The SRPS model, incorporating SLC1A5-associated genes, offers robust prognostic utility. Targeting SLC1A5 through advanced drug delivery systems and combined metabolic-immunotherapeutic strategies may enhance treatment specificity and efficacy. These findings provide a foundation for novel therapeutic approaches to improve outcomes in high-risk neuroblastoma patients.

Keywords:  Anti-tumor immunity; Immunotherapy; Neuroblastoma; Prognosis; SLC1A5

DOI:  https://doi.org/10.1186/s12885-025-13560-y