bims-glucam 2025-05-04 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–05–04
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Transcription Factor YY2 inhibits tumor cell glutamine catabolism by regulating GLS1 RNA splicing isoform GAC.
Glutamine limits NLRP3 inflammasome activation and pyroptosis in macrophages by sustaining the IRG1/itaconate axis.
The Diabetes Gene Tcf7l2 Organizes Gene Expression in the Liver and Regulates Amino Acid Metabolism.
Mitochondrial metabolism in laryngeal cancer: Therapeutic mechanisms and prospects.
Epigenetic Activation of PTCD3 Promotes CRC Glutamine Metabolism and Metastasis via IGF2BP2-Mediated SLC38A2 m6A Modification.
Deciphering the landscape of allosteric glutaminase 1 inhibitors as anticancer agents.
Single-cell multi-omics elucidates the role of RPS27-RPS24 fusion gene in osteosarcoma chemoresistance and metabolic regulation.
Lactate-coated polyurea-siRNA dendriplex: a gene therapy-directed and metabolism-based strategy to impair glioblastoma (GBM).
Taurine-driven restoration of metabolic and redox balance in postovulatory aging porcine oocytes: A metabolomic perspective.
Understanding and Targeting Metabolic Vulnerabilities in Acute Myeloid Leukemia: An Updated Comprehensive Review.
Glutamine Peptides: Preparation, Analysis, Applications, and Their Role in Intestinal Barrier Protection.
Integrating transcriptomic and metabolomic analyses to characterize the potential function of SLC1A5 in thyroid cancer.
The suppressive role of GLS in radiosensitivity and irradiation-induced immune response in LUAD: integrating bioinformatics and experimental insights.
GLS1-Mediated Redundancy in Glutamate Accelerates Arterial Calcification via Activating NMDAR/Ca2+/β-Catenin Pathway.
A Cyanobacteria-derived RNA aptamer resensitizes prostate cancer to hormone therapy.
Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling.
Metabolomics approach using HR-MAS NMR spectroscopy for the assessment of metabolic profiles of uterine fibroids.

Am J Pathol. 2025 Apr 29. pii: S0002-9440(25)00142-7. [Epub ahead of print]

Transcription Factor YY2 inhibits tumor cell glutamine catabolism by regulating GLS1 RNA splicing isoform GAC.

Jingyi Liu, Juan Li, Yanjun Li, Mankun Wei, Debing Xiang, Hezhao Zhao, Makoto Miyagishi, Vivi Kasim, Shourong Wu.

Amino acids metabolic reprogramming is critical for tumorigenesis. Alterations in amino acid metabolism are frequently observed in tumors and are crucial for fulfilling the demand for macromolecular biosynthesis, redox balance, and energy production in tumor cells. Despite its importance, the mechanism regulating amino acid metabolic reprogramming in tumor cells has not been completely elucidated. Herein, using colorectal cancer and hepatocarcinoma cells, we reveal that YY2 significantly reduced the transcriptional activity of glutaminase 1 (GLS1), which hydrolyzes glutamine to glutamate, by decreasing the expression of glutaminase C (GAC), a splicing isoform of GLS1. This, in turn, promoted glutamine accumulation while decreasing that of glutamate, leading to a drop in DNA and de novo glutathione synthesis, followed by a reduction in tumor cell proliferation and antioxidant capacity. Subsequently, we showed that YY2/GLS1-mediated inhibition of glutamine catabolism significantly suppressed tumorigenic potential in vivo. Critically, mutant YY2, often found in clinical tumor samples, failed to exert this effect. Together, these results identify YY2/GAC as a negative regulator of glutamine catabolism in tumor cells and reveal a novel molecular mechanism underlying the tumor-suppressive effect of YY2. Moreover, these findings suggest that YY2 could serve as an antitumor therapeutic agent by targeting glutamine metabolism.

DOI: https://doi.org/10.1016/j.ajpath.2025.04.003
FEBS J. 2025 Apr 28.

Glutamine limits NLRP3 inflammasome activation and pyroptosis in macrophages by sustaining the IRG1/itaconate axis.

Xiaoli Chen, Yuanfeng Zhu, Lin Xia, Sen Su, Shijun Fan, Yongling Lu, Qian Chen, Yan Wei, Qianying Huang, Xin Liu, Xi Peng.

  Aberrant activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome increases the release of mature pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and enhances pyroptosis; thereby necessitating tight regulation of the NLRP3 inflammasome. Dysfunctional glutamine metabolism contributes to the pathogenesis of multiple inflammatory disorders, and the precise mechanism remains to be elucidated. Here, we provide evidence that glutamine deprivation enhances NLRP3 inflammasome activation in macrophages. Indeed, the absence of exogenous glutamine specifically enhanced NLRP3 inflammasome assembly, thereby accelerating pyroptosis and promoting the maturation of IL-1β and IL-18. Inhibition of glutaminolysis exhibited a similar effect to glutamine deprivation, whereas this effect was reversed by α-ketoglutarate (α-KG), a tricarboxylic acid (TCA)-cycle intermediate that can be replenished by glutamine supply. We further observed reduced generation of endogenous itaconate by glutamine deprivation and verified that both exogenous supplementation of itaconate derivative and increased endogenous itaconate production by overexpressing immune-responsive gene 1 [IRG1; also known as aconitate decarboxylase 1 (ACOD1)] could replace glutamine to inhibit the NLRP3 inflammasome. Mechanistically, glutamine deprivation decreased the source of substrate and inhibited transcription factor EB (TFEB)-dependent transcriptional upregulation of IRG1, thereby impairing the IRG1/itaconate axis that suppresses the NLRP3 inflammasome. Furthermore, glutamine deficiency was detected in a murine sepsis model, whereas extrinsic glutamine supplementation conferred protection against intestinal inflammation and tissue damage in septic mice. Taken together, our findings provide a novel insight into the link between glutamine metabolism and NLRP3 inflammasome activation, highlighting the target of glutamine metabolism, which holds as a potential therapeutic strategy for inflammatory diseases.

Keywords:  IRG1/itaconate axis; NLRP3 inflammasome; glutamine metabolism; itaconate; pyroptosis

DOI:  https://doi.org/10.1111/febs.70119
bioRxiv. 2025 Apr 08. pii: 2025.04.03.647067. [Epub ahead of print]

The Diabetes Gene Tcf7l2 Organizes Gene Expression in the Liver and Regulates Amino Acid Metabolism.

Joanna Krawczyk, William O'Connor, Pedro Vendramini, Mareike Schell, Kiran J Biddinger, George Pengo, Tiffany Fougeray, Krishna G Aragam, Marcia Haigis, Wouter H Lamers, Linus T Tsai, Sudha B Biddinger.

TCF7L2 harbors the strongest genetic association with diabetes identified thus far. However, its function in liver has remained unclear. Here, we find using mice with liver-specific deletion, that Tcf7l2 plays a central role in maintaining hepatic zonation. That is, in the normal liver, many genes show gradients of expression across the liver lobule; in the absence of Tcf7l2 , these gradients collapse. One major consequence is the disorganization of glutamine metabolism, with a loss of the glutamine production program, ectopic expression of the glutamine consumption program, and a decrease in glutamine levels. In parallel, metabolomic profiling shows glutamine to be the most significantly decreased metabolite in individuals harboring the rs7903146 variant in TCF7L2 . Taken together, these data indicate that hepatic TCF7L2 has a secondary role in glycemic control, but a primary role in maintaining transcriptional architecture and glutamine homeostasis.

DOI: https://doi.org/10.1101/2025.04.03.647067
Biochim Biophys Acta Rev Cancer. 2025 Apr 29. pii: S0304-419X(25)00077-0. [Epub ahead of print] 189335

Mitochondrial metabolism in laryngeal cancer: Therapeutic mechanisms and prospects.

Yun-Jing Hou, Xin-Xin Yang, Hong-Xue Meng.

  Tumours reprogram pathways that regulate nutrient uptake and metabolism to meet the biosynthetic, bioenergetic, and redox requirements of cancer cells. This phenomenon is known as metabolic reprogramming and is edited by the deletion of oncogenes and the activation of proto-oncogenes. This article highlights the pathological mechanisms associated with metabolic reprogramming in laryngeal cancer (LC), including enhanced glycolysis, tricarboxylic acid cycle, nucleotide synthesis, lipid synthesis and metabolism, and amino acid metabolism, with a special emphasis on glutamine, tryptophan, and arginine metabolism. All these changes are regulated by HPV infection, hypoxia, and metabolic mediators in the tumour microenvironment. We analyzed the function of metabolic reprogramming in the development of drug resistance during standard LC treatment, which is challenging. In addition, we revealed recent advances in targeting metabolic strategies, assessing the strengths and weaknesses of clinical trials and treatment programs to attack resistance. This review summarises some currently important biomarkers and lays the foundation for therapeutic pathways in LC.

Keywords:  Laryngeal cancer (LC); Metabolic reprogramming; Mitochondria; Pathological mechanisms; Tumour microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2025.189335
FASEB J. 2025 May 15. 39(9): e70558

Epigenetic Activation of PTCD3 Promotes CRC Glutamine Metabolism and Metastasis via IGF2BP2-Mediated SLC38A2 m6A Modification.

Weihui Peng, Zhijun Zeng.

  Cancer cells undergo metabolic reprogramming, shifting their programs toward aerobic glycolysis and enhanced glutaminolysis to fulfill the requirements of rapid proliferation. Investigating the mechanisms underlying glutaminolysis and its connection with colorectal cancer (CRC) could aid in identifying novel therapeutic targets. PTCD3, a mitochondrial RNA-binding protein, is implicated in cancer progression, and IGF2BP2 regulates mRNA stability and translation. SLC38A2, a key transporter in glutamine metabolism, plays a crucial role in supporting cancer cell growth. This study aims to develop inhibitors of PTCD3 or SLC38A2 to prevent metabolic changes in cancer cells that facilitate rapid growth and metastasis in CRC. RT-qPCR, western blot, IHC, and IF staining assays confirmed the targeted gene and protein expression. Proliferation, migration, and invasion were evaluated using CCK-8 assay, scratch assay, and Transwell assay, respectively. Co-IP, RIP, and dual-luciferase assays were conducted to investigate the interactions among PTCD3, IGF2BP2, and SLC38A2. A CRC xenograft nude mice model was established for additional in vivo validation. PTCD3 was upregulated in CRC and positively correlated with GLS1. PTCD3 knockdown suppressed CRC cell glutaminolysis, thereby inhibiting CRC migration and invasion. PTCD3 promoted SLC38A2 mRNA stability in an IGF2BP2-dependent manner. KAT2A promoted the expression of PTCD3 by increasing H3K27 acetylation. The inhibitory effect of PTCD3 depletion on the glutaminolysis of CRC cells, as well as CRC cell proliferation and migration, was reversed by SLC38A2 overexpression. The in vivo mouse experiments further confirmed that silencing of PTCD3 inhibited CRC tumor growth. In summary, KAT2A upregulates PTCD3 expression by promoting H3K27 acetylation, which promotes glutaminolysis and metastasis in CRC via enhancing SLC38A2 mRNA stability in an IGF2BP2-dependent manner.

Keywords:  H3K27 acetylation; KAT2A; PTCD3; SLC38A2; colorectal cancer; glutaminolysis; m6A modification

DOI:  https://doi.org/10.1096/fj.202401788RR
Bioorg Chem. 2025 Apr 26. pii: S0045-2068(25)00403-1. [Epub ahead of print]161 108523

Deciphering the landscape of allosteric glutaminase 1 inhibitors as anticancer agents.

Chiara Vagaggini, Pasqualina D'Ursi, Federica Poggialini, Paola Fossa, Valeria Francesconi, Gabriele Trombetti, Alessandro Orro, Elena Dreassi, Silvia Schenone, Michele Tonelli, Anna Carbone.

  Glutamine is the second most utilised energy source after glucose for cancer cells to support their proliferation and survival. Glutaminase 1 (GLS1) is the rate-limiting enzyme during the glutaminolysis pathway and thus represents a promising therapeutic target for the development of innovative antitumor agents. Two main classes of GLS1 inhibitors, based on their different binding mode, are reported: the substrate active site and the allosteric site inhibitors. Despite the intense efforts made to date, only two GLS1 inhibitors (i.e.,CB-839 and IPN60090) have entered clinical trials. Therefore, this research field remains to be explored to improve the effectiveness of anticancer therapy. Hence, we describe the discovery and development of reversible allosteric GLS1 inhibitors disclosed in the last six years, dividing them based on their structural similarity with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and CB-839. Furthermore, macrocyclic and thiadiazole derivatives, and other structurally different compounds are discussed to present a wider picture of the chemical space under investigation. The study of the binding interactions governing GLS1 inhibition is also analyzed, to help prospectively refine the structural features for greater efficacy. Interestingly, an overview of a new class of irreversible allosteric inhibitors targeting GLS1 Lys320 key residue is provided for the first time. We also summarize the most important biological studies conducted on CB-839 and IPN60090 and their significance for further assessment. The insights garnered from this paper are expected to guide future drug design endeavours toward the identification of novel therapeutics targeting GLS1 to complement and potentially enhance the arsenal of anticancer medications.

Keywords:  Anticancer agents; BPTES analogues; GLS1; GLS1 inhibitors; Glutaminase; Glutamine

DOI:  https://doi.org/10.1016/j.bioorg.2025.108523
Cell Death Discov. 2025 Apr 25. 11(1): 197

Single-cell multi-omics elucidates the role of RPS27-RPS24 fusion gene in osteosarcoma chemoresistance and metabolic regulation.

Zhiwei Tao, Pingan Zou, Zhengxu Yang, Tao Xiong, Zhi Deng, Qincan Chen.

Osteosarcoma (OS) presents significant treatment challenges due to chemoresistance. This study explores the molecular mechanisms underlying chemoresistance in OS, focusing on the novel fusion gene RPS27-RPS24. Using single-cell multi-omics techniques, we identified a significant upregulation of RPS27-RPS24 in chemoresistant OS cells. Our analyses revealed that RPS27-RPS24 enhances glutaminase (GLS)-mediated glutamine metabolism and inhibits copper-induced cell death, thereby promoting chemoresistance. In vitro experiments with adriamycin-resistant (ADMR) OS cells confirmed that overexpression of RPS27-RPS24 leads to increased cell viability and proliferation under chemotherapy. In vivo studies further validated these findings, demonstrating that targeting glutamine metabolism can reverse chemoresistance. Our results suggest that the RPS27-RPS24 fusion gene plays a critical role in OS chemoresistance through metabolic reprogramming, providing a potential therapeutic target for improving OS treatment outcomes. The application of multiple analytical techniques in this study (as shown in the upper image) and the hypothesized mechanism (as shown in the lower image).

DOI: https://doi.org/10.1038/s41420-025-02487-9
Cancer Gene Ther. 2025 Apr 27.

Lactate-coated polyurea-siRNA dendriplex: a gene therapy-directed and metabolism-based strategy to impair glioblastoma (GBM).

Filipa Martins, Renata Arada, Hélio Barros, Paulo Matos, José Ramalho, Valentín Ceña, Vasco D B Bonifácio, Luís G Gonçalves, Jacinta Serpa.

Glioblastoma (GBM) is a highly lethal disease with limited treatment options due to its infiltrative nature and the lack of efficient therapy able to cross the protective blood-brain barrier (BBB). GBMs are metabolically characterized by increased glycolysis and glutamine dependence. This study explores a novel metabolism-based therapeutic approach using a polyurea generation 4 dendrimer (PUREG4) surface functionalized with lactate (LA) (PUREG4-LA24), to take advantage of glucose-dependent monocarboxylate transporters (MCTs) overexpression, loaded with selenium-chrysin (SeChry) and temozolomide (TMZ) or complexed with anti-glutaminase (GLS1) siRNAs to abrogate glutamine dependence. The nanoparticles (PUREG4-LA24) were efficient vehicles for cytotoxic compounds delivery, since SeChry@PUREG4-LA24 and TMZ@PUREG4-LA24 induced significant cell death in GBM cell lines, particularly in U251, which exhibits higher MCT1 expression. The anti-GLS1 siRNA-dendriplex with PUREG4-LA12 (PUREG4-LA12-anti-GLS1-siRNA) knocked down GLS1 in the GBM cell lines. In two in vitro BBB models, these dendriplexes successfully crossed the BBB, decreased GLS1 expression and altered the exometabolome of GBM cell lines, concomitantly with autophagy activation. Our findings highlight the potential of targeting glucose and glutamine pathways in GBM using dendrimer-based nanocarriers, overcoming the BBB and disrupting key metabolic processes in GBM cells. PUREG4-LA12-anti-GLS1-siRNA dendriplexes cross the blood-brain barrier (BBB) and impair glioblastoma (GBM) metabolism. The BBB is formed by a thin monolayer of specialized brain microvascular endothelial cells joined together by tight junctions that selectively control the passage of substances from the blood to the brain. It is a major obstacle in the treatment of GBM, since many chemotherapeutic drugs are unable to penetrate the brain. Therefore, we developed a strategy to overcome this obstacle: a lactate-coated polyurea dendrimer generation 4 (PUREG4) able to cross the BBB in vitro, that act as a nanocarrier of drugs and siRNA to the GBM cells. PUREG4-LA12 are nanoparticles functionalized with lactate (LA) to target MCT1, a lactate transporter highly expressed by GBM cells. Moreover, a complex of this nanoparticle with anti-GLS1 (glutaminase) siRNA (PUREG4-LA12-anti-GLS1-siRNA) was made, to target glutamine metabolism. It efficiently knocked down GLS1. Moreover, PUREG4-LA24 loaded with SeChry led to BBB disruption.

DOI: https://doi.org/10.1038/s41417-025-00906-8
Free Radic Biol Med. 2025 Apr 25. pii: S0891-5849(25)00252-7. [Epub ahead of print]235 137-149

Taurine-driven restoration of metabolic and redox balance in postovulatory aging porcine oocytes: A metabolomic perspective.

Zihao Zhang, Feixue Wang, Wenjun Zeng, Zhaokang Cui, Qian Gao, Bingqian Liu, Najun Huang, Xiaofan Sun, Na Li, Bo Xiong, Yilong Miao.

  Oocyte quality is closely linked to metabolic integrity, and age-related metabolic dysregulation is a key factor contributing to oocyte aging. In this study, we utilized non-targeted metabolomics to explore the impact of taurine supplementation on the metabolic profile of postovulatory aging (POA) porcine oocytes. Our analysis revealed that taurine supplementation significantly altered the metabolic landscape, restoring key metabolic pathways associated with energy production, amino acid metabolism, and oxidative stress regulation. Notably, taurine supplementation enhanced mitochondrial function, increased ATP synthesis, and improved the redox balance by upregulating reduced glutathione (GSH) levels and reducing oxidative damage. Metabolomics data also indicated a restoration of critical metabolic intermediates, including those involved in the glutathione synthesis pathway and amino acid metabolism. These findings suggest that taurine can modulate oocyte metabolism, improve cellular energy status, and mitigate oxidative stress, thereby enhancing oocyte quality at the metabolic level.

Keywords:  Metabolomics; Oxidative stress; POA; Porcine oocyte; Taurine

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.042
Cancers (Basel). 2025 Apr 18. pii: 1355. [Epub ahead of print]17(8):

Understanding and Targeting Metabolic Vulnerabilities in Acute Myeloid Leukemia: An Updated Comprehensive Review.

Sridevi Addanki, Lana Kim, Alexandra Stevens.

  Acute Myeloid Leukemia (AML) is characterized by aggressive proliferation and metabolic reprogramming that support its survival and resistance to therapy. This review explores the metabolic distinctions between AML cells and normal hematopoietic stem cells (HSCs), emphasizing the role of altered mitochondrial function, oxidative phosphorylation (OXPHOS), and biosynthetic pathways in leukemic progression. AML cells exhibit distinct metabolic vulnerabilities, including increased mitochondrial biogenesis, reliance on glycolysis and amino acid metabolism, and unique signaling interactions that sustain leukemic stem cells (LSCs). These dependencies provide potential therapeutic targets, as metabolic inhibitors have demonstrated efficacy in disrupting AML cell survival while sparing normal hematopoietic cells. We examine current and emerging metabolic therapies, such as inhibitors targeting glycolysis, amino acid metabolism, and lipid biosynthesis, highlighting their potential in overcoming drug resistance. However, challenges remain in translating these strategies into clinical practice due to AML's heterogeneity and adaptability. Further research into AML's metabolic plasticity and precision medicine approaches is crucial for improving treatment outcomes. Understanding and exploiting AML's metabolic vulnerabilities could pave the way for novel, more effective therapeutic strategies.

Keywords:  acute myeloid leukemia; atovoquone; azactidine; glycolysis; hematopoietic stem cells; leukemic stem cells; metabolism; oxidative phosphorylation; venetoclax

DOI:  https://doi.org/10.3390/cancers17081355
Nutrients. 2025 Mar 14. pii: 1017. [Epub ahead of print]17(6):

Glutamine Peptides: Preparation, Analysis, Applications, and Their Role in Intestinal Barrier Protection.

Jinyu Wang, Yating He, Zedan Liu, Xiaolan Liu, Yan Jing.

  Background: Glutamine peptides refer to a series of peptides containing glutamine, and the activity of glutamine peptides is characterized by the content of non-nitrogen terminal glutamine in the peptide. It has been found that glutamine peptides are a stable substitute for glutamine monomer, and they are increasingly studied in nutrition and physiology due to their functional properties. Methods: An extensive search of the literature was conducted in the PubMed, Web of Science, Scopus, and Google Scholar databases up to December 2024. Inclusion criteria focused on the role of glutamine peptides in intestinal health, and the included literature was screened and summarized. Results: This study systematically reviews the current status of research on the preparation, analysis, applications of glutamine peptides and their role in intestinal barrier protection. Furthermore, the challenges faced by the current research and the development direction in the future are discussed. Conclusions: Glutamine peptides can play a role in protecting the intestinal barrier by regulating tight junctions, mucin, inflammatory response, and intestinal flora. In addition, further and intensive investigations are urgently required to address the current challenges pertaining to the structure-activity relationships of glutamine peptides and their transport and absorption mechanism in the gut. This review contributes to a better understanding of the mechanism of glutamine peptides to protect intestinal barrier function and also provides a reference for the development of functional foods with protective effects of intestinal barrier function.

Keywords:  glutamine peptides; intestinal barrier function; intestinal health

DOI:  https://doi.org/10.3390/nu17061017
BMC Cancer. 2025 May 01. 25(1): 817

Integrating transcriptomic and metabolomic analyses to characterize the potential function of SLC1A5 in thyroid cancer.

Fengling Shan, Lan Wang, Xinyu Lu, Meihong Zhou, Zi Wang, Jingjing Lou, Xingdang Liu.

   BACKGROUND: Alanine Serine Cysteine transporter 2 (ASCT2/SLC1A5) is a key glutamine transporter in cancer cells and has been shown in a variety of cancers to promote tumor growth by reprogramming glutamine metabolism and altering the tumor microenvironment. However, the role in thyroid cancer remains unknown.
METHODS: To investigate the expression and prognostic value of SLC1A5 in thyroid cancer using publically available databases, and to define the relationship with clinical characteristics. SLC1A5 expression in TPC-1 and B-CPAP was knocked down using SLC1A5 siRNA to investigate its effects on cell growth and apoptosis. Transcriptome sequencing and metabolite analysis were carried out in the SLC1A5 siRNA group to identify major transcriptomic or metabolite changes that could lead to apoptosis. In addition, we explored for the connection of SLC1A5 with the tumor microenvironment using algorithms like ESTIMATE and CIBERSORT.
RESULTS: High SLC1A5 expression in THCA is related with a poor prognosis and advanced clinical stage. In vitro findings showed that SLC1A5 knockdown reduced THCA cell activity and accelerated apoptosis, and the results were consistent with the effect of SLC1A5 inhibitor GPNA. While RNA sequencing analysis revealed that NF-κb signaling was enhanced and oxidative phosphorylation levels were lowered. Metabolomics findings indicated that Glutathione and purine metabolism were dramatically affected in the SLC1A5 siRNA group. Furthermore, immune microenvironment study revealed that SLC1A5 had a positive correlation with the amount of CD4 + T memory-activated cells and T cell follicular helper cells.
CONCLUSION: SLC1A5 may be a possible target in THCA. Our findings indicate that DEGs and differential metabolites are mostly linked to numerous signaling pathways and immunological modulation, which may play an important role in SLC1A5 regulation of THCA development.

Keywords:  Metabolomics; SLC1A5; Thyroid cancer; Transcriptomics; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12885-025-14123-x
Front Immunol. 2025 ;16 1582587

The suppressive role of GLS in radiosensitivity and irradiation-induced immune response in LUAD: integrating bioinformatics and experimental insights.

Peicheng Jiang, Zhifeng Jiang, Su Li, Ye-Xiong Li, Yuqiong Chen, Xinyan Li.

   Background: Radiotherapy elicits immune activation, thereby synergistically enhancing systemic tumor control when combined with immunotherapy. Glutaminase (GLS), a key enzyme for glutamine metabolism, has been found to regulate glutamine availability within tumor microenvironment (TME). However, the precise mechanisms through which GLS modulates radiosensitivity and irradiation-induced immune responses in lung adenocarcinoma (LUAD) and its clinical value remain to be fully elucidated.
Methods: We employed bulk RNA-seq and single-cell transcriptomics to explore the role of GLS expression in radiosensitivity and immune infiltration. The bioinformatic results were validated by in vitro and in vivo experiments. Co-culture assays and flow cytometry were used to validate the impact of GLS expression on CD8+ T cell activation and cytotoxicity. Moreover, a GLS-DSBr (double strand break repair) prognostic model was developed using machine learning with data from 2,066 LUAD patients.
Results: In vitro and in vivo experiments demonstrated that GLS silence inhibited DSB repair and promoted ferroptosis, therefore enhancing radiosensitivity. Single-cell and spatial transcriptomics revealed the immunomodulatory effects of GLS expression in the TME. Further, Co-culture assays and flow cytometry experiments indicated that silencing GLS in LUAD cells potentiated the activation and cytotoxicity of CD8+ T cells in the context of radiotherapy. The GLS-DSBr model demonstrated robust predictive performance for overall survival, as well as the efficacy of radiotherapy and immunotherapy in LUAD. The applicability of GLS-DSBr model was further validated through pan-cancer analysis.
Conclusion: In the contexts of radiotherapy, GLS downregulation exerts dual regulatory effects by modulating ferroptosis and remodeling the immune landscapes, particularly enhancing CD8+ T cell cytotoxicity. Our work suggests that strategies preferentially targeting GLS in tumor cells may represent promising and translatable therapeutic approaches to promote antitumor efficacy of radiotherapy plus immune checkpoint blockade in LUAD patients. Furthermore, the established GLS-DSBr model serves as a robust predictive tool for prognosis and effects of radiotherapy and immunotherapy, which assists personalized treatment optimization in LUAD.

Keywords:  glutamine metabolism; immunity; lung cancer; prognostic model; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1582587
Adv Sci (Weinh). 2025 Apr 28. e2414252

GLS1-Mediated Redundancy in Glutamate Accelerates Arterial Calcification via Activating NMDAR/Ca2+/β-Catenin Pathway.

Ziting Zhou, Bing Dong, Dayu He, Jianshuai Ma, Yun Kong, Huijin Zhu, Chen Xie, Tiecheng Yang, Xin Zhen, Zhengzhipeng Zhang, Zhaohui He, Jinkun Cheng, Aoran Huang, Jie Chen, Ruo Wu, Huiyong Yin, Yanlian Chen, Jun Tao, Hui Huang.

  Arterial calcification is a powerful predictor of both the events and mortality associated with cardiovascular diseases in chronic kidney disease (CKD) patients. GLS1 (glutaminase 1), a rate-limiting enzyme catalyzing the conversion of glutamine to glutamate, is disordered in various cardiovascular diseases. However, the potential interplay between GLS1-mediated glutamate production and arterial calcification remains poorly understood. Here, LC-MS/MS analysis of CKD patients' samples shows an abnormally elevated activity of GLS1, reflected by the increased glutamate/glutamine ratio. Moreover, GLS1 activity is positively correlated with arterial calcification progression, and its expression is upregulated in calcified arteries. Treatment with GLS1 inhibitors or knockdown of GLS1 alleviates osteogenic reprogramming. In contrast, glutamate administration boosts the development of arterial calcification. Mechanistically, GLS1 redundancy-regulated glutamate superfluity stimulates the activation of N-methyl-d-aspartate receptors (NMDAR), leading to Ca2+ influx and extracellular regulated protein kinases (ERK) phosphorylation, followed by the nuclear translocation of β-Catenin and acceleration of osteogenic reprogramming of vascular smooth muscle cells (VSMCs) in further. This research defines GLS1 as a key contributor to arterial calcification. Glutamate, a major product of GLS1-mediated glutamine metabolism, exerts a deleterious effect on arterial calcification by activating NMDAR and subsequently triggering Ca2+ influx, which in turn exacerbates β-Catenin-regulated osteogenic reprogramming in VSMCs.

Keywords:  GLS1; NMDAR; arterial calcification; glutamate; osteogenic reprogramming; β‐Catenin

DOI:  https://doi.org/10.1002/advs.202414252
Cancer Res. 2025 Apr 28.

A Cyanobacteria-derived RNA aptamer resensitizes prostate cancer to hormone therapy.

Carlos D Cruz-Hernández, Bethany Smith, Sandrine Billet, Manish Thiruvalluvan, Gabrielle Gonzales, David M Underhill, Ekihiro Seki, Shelly C Lu, Neil A Bhowmick.

Prostate adenocarcinoma (PCa) resistance to androgen receptor (AR) signaling inhibitor therapy is associated with elevated glutamine (L-Gln). Glutamine sensors, present in conserved riboswitches (glnA), control nitrogen metabolism in many organisms, like cyanobacteria. Iterative in silico modifications of glnA found in Synechococcus elongatus and thermodynamic analysis of a 56mer aptamer resulted in high L-Gln specificity and affinity. The optimized aptamer depleted L-Gln from PCa cells by both L-Gln sequestration and extracellular glutaminase activation, serving as an allosteric activator. Glutamine depletion reduced FOXM1 transcriptional occupancy on the promoter of fibroblast growth factor 8 (FGF8), a known mediator of PCa castration resistance. A point mutation in the binding pocket of the 56mer rendered the aptamer ineffective in L-Gln binding and FGF8 regulation. Accordingly, the L-Gln-depleting aptamer, with demonstrated serum stability, limited the proliferation and promoted cell death of castration-resistant PCa alone and in combination therapy with AR antagonists, enzalutamide and apalutamide, in subcutaneous and orthotopic mouse models. Further selective tumor targeting was achieved by functionalizing gold nanoparticles with either the optimized L-Gln aptamer or the point-mutant aptamer. Castration sensitivity was restored by the L-Gln-depleting aptamer but not by the point-mutant. The functionalized nanoparticle demonstrated superior anti-tumor efficacy in an orthotopic PCa model over the untargeted aptamer. The anti-tumor activity of the aptamer helped support L-Gln as an oncometabolite in PCa that can be targeted to sensitize tumors to hormone therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4039
Cancer Res. 2025 Apr 28. OF1-OF13

Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling.

Jianqiang Yang, Fanghui Chen, Zhenzhen Fu, Fan Yang, Nabil F Saba, Yong Teng.

The tricarboxylic acid (TCA) cycle is often rewired or dysregulated to meet the increased energy and biosynthetic demands of rapidly dividing cancer cells, and targeting the TCA cycle is a potential therapeutic strategy for treating cancer. However, tumor cell metabolism can impact other cells in the tumor microenvironment, and disrupting the TCA cycle in cancer cells could impact the antitumor immune response. In this study, using CPI-613 as a model drug for TCA cycle inhibition, we identified a molecular mechanism by which blocking the TCA cycle enhances T-cell-mediated antitumor immunity in the context of head and neck squamous cell carcinoma (HNSCC). Impairment of mitochondrial metabolism by CPI-613 induced endoplasmic reticulum stress in HNSCC cells, leading to increased expression of spliced X-box-binding protein 1. This, in turn, directly suppressed the transcriptional activity of the thrombospondin-2 gene. Correspondingly, CPI-613 reduced the secretion of thrombospondin-2 from HNSCC cells, enhancing the proliferation and cytotoxic potential of tumor-infiltrating CD36+CD8+ T cells by upregulating AKT-mTOR signaling. This mechanism ultimately enhanced antitumor immunity in a syngeneic mouse model of orthotopic HNSCC following CPI-613 treatment. These findings uncover the immunomodulatory role of the TCA cycle in cancer cells and suggest that targeting it is a promising approach to harness tumor-reactive immune cells. Significance: The immunomodulatory role of the TCA cycle in cancer cells provides a therapeutic opportunity to enhance antitumor immunity by targeting tumor cell metabolism.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3477
Anal Biochem. 2025 Apr 29. pii: S0003-2697(25)00123-X. [Epub ahead of print] 115885

Metabolomics approach using HR-MAS NMR spectroscopy for the assessment of metabolic profiles of uterine fibroids.

Senem Arda Düz, Akın Mumcu, Berat Doğan, Erdinç Sarıdoğan, Görkem Tuncay, Taylan Onat, Abdullah Karaer.

  The aim of this study is to determine dysregulated metabolites and metabolic pathways in uterine fibroids and in the myometrial tissue from which uterine fibroids are derived. Fifteen (15) patients underwent hysterectomy because of uterine fibroids and 14 controls were included in this study. 1H HR-MAS NMR spectroscopy data were obtained from uterine fibroid tissue, the adjacent healthy myometrial tissue from cases, and myometrial tissue from controls. PCA and PLS-DA score plots from multivariate statistical analysis of pre-processed spectral data demonstrated a distinction between cases and control groups. The levels of lactate, alanine, glutamate, glutamine, methionine, acetone, isocitrate, choline, glycerophosphocholine, phosphocholine, o-phosphoethanolamine, taurine, myo-inositol, p-methylhistidine, phenylacetate, ascorbate, glucose, and methylhistidine were significantly higher in uterine fibroid tissue compared to the neighboring healthy myometrial tissue. Additionally, when adjacent healthy myometrial tissue was compared to control myometrial tissue, significantly lower levels of valine, leucine, isoleucine, ethanol, arginine, N-acetyl tyrosine, acetone, p-methylhistidine, glucose, phenylacetate, myo-inositol, and alpha-glucose were observed. The study provides a foundational framework by revealing the metabolomic heterogeneity of uterine fibroids. Strategies should be developed to target the metabolic alterations that contribute to the growth of these common tumors.

Keywords:  Metabolomics; Myometrium; NMR spectroscopy; Uterine fibroids

DOI:  https://doi.org/10.1016/j.ab.2025.115885