bims-glucam 2025-03-16 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–03–16
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glucose Metabolism and Tumor Microenvironment: Mechanistic Insights and Therapeutic Implications.
Parallel multiOMIC analysis reveals glutamine deprivation enhances directed differentiation of renal organoids.
Deciphering Colorectal Cancer-Hepatocyte Interactions: A Multiomics Platform for Interrogation of Metabolic Crosstalk in the Liver-Tumor Microenvironment.
Glutamine binds HSC70 to transduce signals inhibiting IFN-β-mediated immunogenic cell death.
Exploring Phytochemicals as Potential Inhibitors of Cancer Cell Metabolic Pathways: A Computational Study.
The ERN1 signaling pathway of unfolded protein controls the expression of EDEM1 and its hypoxic regulation in glioblastoma cells.
HOTAIR Participation in Glycolysis and Glutaminolysis Through Lactate and Glutamate Production in Colorectal Cancer.
Reprogramming of Thyroid Cancer Metabolism: from Mechanism to Therapeutic Strategy.
Interleukin-16 enhances anti-tumor immune responses by establishing a Th1 cell-macrophage crosstalk through reprogramming glutamine metabolism in mice.
The Glutamate/GABA-Glutamine Cycle: Insights, Updates, and Advances.
Succinate dehydrogenase activity supports de novo purine synthesis.
Research Progress of Liver Cancer Recurrence Based on Energy Metabolism of Liver Cancer Stem Cells.
Pathway Coessentiality Mapping Reveals Complex II is Required for de novo Purine Biosynthesis in Acute Myeloid Leukemia.
Transcriptomic and proteo-metabolic determinants of the grading system in clear cell renal cell carcinoma.
A single-cell network approach to decode metabolic regulation in gynecologic and breast cancers.
αKG-induced oxidative stress and mTOR inhibition as a therapeutic strategy for liver cancer.
Glutathione Contributes to Caloric Restriction-Triggered Shift in Taurine Homeostasis.

Int J Mol Sci. 2025 Feb 22. pii: 1879. [Epub ahead of print]26(5):

Glucose Metabolism and Tumor Microenvironment: Mechanistic Insights and Therapeutic Implications.

Wiktoria Andryszkiewicz, Julia Gąsiorowska, Maja Kübler, Karolina Kublińska, Agata Pałkiewicz, Adam Wiatkowski, Urszula Szwedowicz, Anna Choromańska.

  Metabolic reprogramming in cancer cells involves changes in glucose metabolism, glutamine utilization, and lipid production, as well as promoting increased cell proliferation, survival, and immune resistance by altering the tumor microenvironment. Our study analyzes metabolic reprogramming in neoplastically transformed cells, focusing on changes in glucose metabolism, glutaminolysis, and lipid synthesis. Moreover, we discuss the therapeutic potential of targeting cancer metabolism, focusing on key enzymes involved in glycolysis, the pentose phosphate pathway, and amino acid metabolism, including lactate dehydrogenase A, hexokinase, phosphofructokinase and others. The review also highlights challenges such as metabolic heterogeneity, adaptability, and the need for personalized therapies to overcome resistance and minimize adverse effects in cancer treatment. This review underscores the significance of comprehending metabolic reprogramming in cancer cells to engineer targeted therapies, personalize treatment methodologies, and surmount challenges, including metabolic plasticity and therapeutic resistance.

Keywords:  cancer stem cells; glycolysis; hexokinase; lactate dehydrogenase A; phosphofructokinase; pyruvate kinase; the Warburg effect; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/ijms26051879
bioRxiv. 2025 Mar 01. pii: 2025.02.27.640060. [Epub ahead of print]

Parallel multiOMIC analysis reveals glutamine deprivation enhances directed differentiation of renal organoids.

Iman Sarami, Katherine E Hekman, Ashwani Kumar Gupta, Justin M Snider, David Ivancic, Manja Zec, Manoj Kandpal, Issam Ben-Sahra, Rajasree Menon, Edgar A Otto, Floyd H Chilton, Jason A Wertheim.

Metabolic pathways play a critical role in driving differentiation but remain poorly understood in the development of kidney organoids. In this study, parallel metabolite and transcriptome profiling of differentiating human pluripotent stem cells (hPSCs) to multicellular renal organoids revealed key metabolic drivers of the differentiation process. In the early stage, transitioning from hPSCs to nephron progenitor cells (NPCs), both the glutamine and the alanine-aspartate-glutamate pathways changed significantly, as detected by enrichment and pathway impact analyses. Intriguingly, hPSCs maintained their ability to generate NPCs, even when deprived of both glutamine and glutamate. Surprisingly, single cell RNA-Seq analysis detected enhanced maturation and enrichment for podocytes under glutamine-deprived conditions. Together, these findings illustrate a novel role of glutamine metabolism in regulating podocyte development.

DOI: https://doi.org/10.1101/2025.02.27.640060
Int J Mol Sci. 2025 Feb 25. pii: 1976. [Epub ahead of print]26(5):

Deciphering Colorectal Cancer-Hepatocyte Interactions: A Multiomics Platform for Interrogation of Metabolic Crosstalk in the Liver-Tumor Microenvironment.

Alisa B Nelson, Lyndsay E Reese, Elizabeth Rono, Eric D Queathem, Yinjie Qiu, Braedan M McCluskey, Alexandra Crampton, Eric Conniff, Katherine Cummins, Ella Boytim, Senali Dansou, Justin Hwang, Sandra E Safo, Patrycja Puchalska, David K Wood, Kathryn L Schwertfeger, Peter A Crawford.

  Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt to and exploit their microenvironment for sustained growth. The liver is a common site of metastasis, but the interactions between tumor cells and hepatocytes remain poorly understood. In the context of liver metastasis, these interactions play a crucial role in promoting tumor survival and progression. This study leverages multiomics coverage of the microenvironment via liquid chromatography and high-resolution, high-mass-accuracy mass spectrometry-based untargeted metabolomics, 13C-stable isotope tracing, and RNA sequencing to uncover the metabolic impact of co-localized primary hepatocytes and a colon adenocarcinoma cell line, SW480, using a 2D co-culture model. Metabolic profiling revealed disrupted Warburg metabolism with an 80% decrease in glucose consumption and 94% decrease in lactate production by hepatocyte-SW480 co-cultures relative to SW480 control cultures. Decreased glucose consumption was coupled with alterations in glutamine and ketone body metabolism, suggesting a possible fuel switch upon co-culturing. Further, integrated multiomics analysis indicates that disruptions in metabolic pathways, including nucleoside biosynthesis, amino acids, and TCA cycle, correlate with altered SW480 transcriptional profiles and highlight the importance of redox homeostasis in tumor adaptation. Finally, these findings were replicated in three-dimensional microtissue organoids. Taken together, these studies support a bioinformatic approach to study metabolic crosstalk and discovery of potential therapeutic targets in preclinical models of the tumor microenvironment.

Keywords:  cancer metabolism; metabolomics; multiomics; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms26051976
Dev Cell. 2025 Mar 07. pii: S1534-5807(25)00117-0. [Epub ahead of print]

Glutamine binds HSC70 to transduce signals inhibiting IFN-β-mediated immunogenic cell death.

Deyu Zhang, Songze Song, Jing Lin, Tianxing Ye, Xiao Yang, Qiwei Jiang, Yue Mi, Mengting Zhang, Xiangwei Ge, Yanjie Shen, Peizhe Du, Yanzhu Shi, Xiujuan Zhang, Ling Li, Yanan Zhang, Lihua Ding, Jie Liu, Youzhi Zhang, Shan Gao, Qinong Ye.

  Glutamine plays a role in cell signaling that regulates gene expression and impacts tumorigenesis. However, it is still unclear how glutamine transduces signals in cells. Here, we show that glutamine binds to heat shock cognate protein 70 (HSC70) to stimulate the deubiquitinase otubain domain containing protein (OTUD4) independently of known glutamine metabolic or signaling pathways, resulting in lactate dehydrogenase A (LDHA) stabilization via the microautophagy-lysosome pathway, increased lactate production and decreased expression of interferon (IFN)-β and its targets, hallmarks of immunogenic cell death (ICD). In cancer cell lines and patient-derived organoids and xenografts, glutamine depletion or glutamine transport inhibition combined with ICD-inducing chemotherapeutic drugs synergistically activates IFN-β, promotes CD8+ T cell recruitment, and inhibits cancer cell growth via the OTUD4/LDHA axis. CD8 expression is negatively correlated with expression of the glutamine transporter alanine/serine/cysteine transporter 2 (ASCT2), OTUD4, and LDHA in cancer patients. Thus, we identify an intracellular glutamine signaling pathway, and targeting this pathway is a promising strategy for cancer treatment.

Keywords:  HSC70; IFN-β; LDHA; glutamine; immunogenic cell death; signal transduction

DOI:  https://doi.org/10.1016/j.devcel.2025.02.012
Med Chem. 2025 ;21(3): 211-228

Exploring Phytochemicals as Potential Inhibitors of Cancer Cell Metabolic Pathways: A Computational Study.

Yagyesh Kapoor, Yasha Hasija.

   OBJECTIVE: The objective of this study is to explore the therapeutic potential of phytochemicals in cancer cell metabolism by investigating their ability to inhibit key molecular targets involved in tumor growth and drug resistance.
METHODS: We evaluated specific phytochemicals against critical cancer-related targets such as GLS1, CKα, MGLL, IDH1, PDHK1, and PHGDH. Molecular docking methods were used to understand the binding interactions between phytochemicals and their selected targets. ADME (absorption, distribution, metabolism, and excretion) analysis and molecular dynamics (MD) simulations were conducted to assess pharmacokinetic properties and ligand-protein interaction dynamics, respectively. MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) calculations were utilized to estimate binding free energies.
RESULTS: Molecular dynamics simulations demonstrate that phytochemicals like EGCG, Diosgenin, Withaferin A, and Celastrol exhibit stable binding to their respective targets, suggesting potential therapeutic benefits. Specifically, EGCG shows strong and non-toxic binding affinity with GLS1, making it a promising candidate for cancer treatment.
CONCLUSION: Our study underscores the potential of phytochemicals as effective inhibitors of cancer cell metabolism. The stable binding interactions highlight promising avenues for developing innovative cancer therapies. Further experimental investigations are warranted to validate these findings and advance the development of hybrid phytochemical-based treatments for combating chemoresistance.

Keywords:  MD simulations; MMPBSA/GBSA calculations.; Phytochemicals; cancer metabolism; citric acid cycle; glutamine metabolism; lipid biosynthesis; serine metabolism

DOI:  https://doi.org/10.2174/0115734064325567240930044647
Endocr Regul. 2025 Jan 01. 59(1): 1-9

The ERN1 signaling pathway of unfolded protein controls the expression of EDEM1 and its hypoxic regulation in glioblastoma cells.

Oleksandr H Minchenko, Vita O Hrebennykova, Yuliia M Viletska, Oksana S Hnatiuk, Myroslava Y Sliusar, Halyna E Kozynkevych, Dmytro O Minchenko.

  Objective. For the effective growth of malignant tumors, including glioblastoma, the necessary factors involve endoplasmic reticulum (ER) stress, hypoxia, and the availability of nutrients, particularly glucose. The ER degradation enhancing alpha-mannosidase like protein 1 (EDEM1) is involved in ER-associated degradation (ERAD) targeting misfolded glycoproteins for degradation in an N-glycan-independent manner. EDEM1 was also identified as a new modulator of insulin synthesis and secretion. The present study aims to investigate the regulation of the EDEM1 gene expression in U87MG glioblastoma cells by hypoxia and glucose or glutamine deprivations depending on the knockdown of ERN1 (endoplasmic reticulum to nucleus signaling 1) with the intent to reveal the role of ERN1 signaling in the regulation of this gene expression and function in tumorigenesis. Methods. The U87MG glioblastoma cells (transfected by an empty vector; control) and ERN1 knockdown cells with inhibited ERN1 endoribonuclease and protein kinase (dnERN1) or only ERN1 endoribonuclease (dnrERN1) were used. Hypoxia was introduced by dimethyloxalylglycine (4 h). For glucose and glutamine deprivations, the cells were exposed to DMEM medium without glucose and glutamine, respectively, for 16 h. The expression level of the EDEM1 gene was studied by quantitative RT-PCR and normalized to the ACTB mRNA. Results. It was found that inhibition of endoribonuclease and protein kinase activities of ERN1 led to down-regulation of EDEM1 gene expression in glioblastoma cells. Moreover, the expression of this gene was also decreased after silencing ERN1 in glioblastoma cells. At the same time, the expression of EDEM1 gene did not significantly change in cells with inhibited ERN1 endoribonuclease only. The expression of the EDEM1 gene was increased under hypoxia in control U87MG cells, but resistant to hypoxia in cells with ERN1 knockdown. Furthermore, the expression of this gene was up-regulated under glucose and glutamine deprivations in control glioblastoma cells. However, the ERN1 knockdown increased the sensitivity of EDEM1 gene expression to glucose and decreased to glutamine deprivations. Conclusion. The results of the present study demonstrate that inhibition of ERN1 down-regulated the expression of the EDEM1 gene through protein kinase activity of ERN1 and that the regulation of this gene expression by hypoxia and nutrient supply, especially glucose, is differently controlled by ERN1 in glioblastoma cells.

Keywords:  EDEM1; ERN1 knockdown; ERN1 protein kinase; gene expression; glioblastoma cells; hypoxia; nutrient deprivation

DOI:  https://doi.org/10.2478/enr-2025-0001
Cells. 2025 Mar 06. pii: 388. [Epub ahead of print]14(5):

HOTAIR Participation in Glycolysis and Glutaminolysis Through Lactate and Glutamate Production in Colorectal Cancer.

Laura Cecilia Flores-García, Verónica García-Castillo, Eduardo Pérez-Toledo, Samuel Trujano-Camacho, Oliver Millán-Catalán, Eloy Andrés Pérez-Yepez, Jossimar Coronel-Hernández, Mauricio Rodríguez-Dorantes, Nadia Jacobo-Herrera, Carlos Pérez-Plasencia.

  Metabolic reprogramming plays a crucial role in cancer biology and the mechanisms underlying its regulation represent a promising study area. In this regard, the discovery of non-coding RNAs opened a new regulatory landscape, which is in the early stages of investigation. Using a differential expression model of HOTAIR, we evaluated the expression level of metabolic enzymes, as well as the metabolites produced by glycolysis and glutaminolysis. Our results demonstrated the regulatory effect of HOTAIR on the expression of glycolysis and glutaminolysis enzymes in colorectal cancer cells. Specifically, through the overexpression and inhibition of HOTAIR, we determined its influence on the expression of the enzymes PFKFB4, PGK1, LDHA, SLC1A5, GLUD1, and GOT1, which had a direct impact on lactate and glutamate production. These findings indicate that HOTAIR plays a significant role in producing "oncometabolites" essential to maintaining the bioenergetics and biomass necessary for tumor cell survival by regulating glycolysis and glutaminolysis.

Keywords:  HOTAIR; cancer; glutaminolysis and colorectal cancer; glycolysis; metabolism

DOI:  https://doi.org/10.3390/cells14050388
Mol Cancer. 2025 Mar 11. 24(1): 74

Reprogramming of Thyroid Cancer Metabolism: from Mechanism to Therapeutic Strategy.

Yuxuan Wan, Guoqing Li, Gaoyuan Cui, Saili Duan, Shi Chang.

  Thyroid cancer as one of the most prevalent malignancies of endocrine system, has raised public concern and more research on its mechanism and treatment. And metabolism-based therapies have advanced rapidly, for the exclusive metabolic profiling of thyroid cancer. In thyroid cancer cells, plenty of metabolic pathways are reprogrammed to accommodate tumor microenvironment. In this review, we initiatively summarize recent progress in the full-scale thyroid cancer metabolic rewiring and the interconnection of various metabolites. We also discuss the efficacy and prospect of metabolic targeted detection as well as therapy. Comprehending metabolic mechanism and characteristics of thyroid cancer roundly will be highly beneficial to managing individual patients.

Keywords:  Carcinogenesis; Diagnosis; Genetics; Metabolism; Targeted therapy; Thyroid cancer

DOI:  https://doi.org/10.1186/s12943-025-02263-4
Nat Commun. 2025 Mar 10. 16(1): 2362

Interleukin-16 enhances anti-tumor immune responses by establishing a Th1 cell-macrophage crosstalk through reprogramming glutamine metabolism in mice.

Zhenzhen Wen, Tong Liu, Xutao Xu, Nandini Acharya, Zhida Shen, Yunkun Lu, Junjie Xu, Ke Guo, Shuying Shen, Yuening Zhao, Pinli Wang, Shumin Li, Weiyu Chen, Hui Li, Yimin Ding, Min Shang, Hongshan Guo, Yu Hou, Bijun Cui, Manlu Shen, Youling Huang, Ting Pan, Wang Qingqing, Qian Cao, Kai Wang, Peng Xiao.

Overcoming immunosuppression in the tumor microenvironment (TME) is crucial for developing novel cancer immunotherapies. Here, we report that IL-16 administration enhances the polarization of T helper 1 (Th1) cells by inhibiting glutamine catabolism through the downregulation of glutaminase in CD4+ T cells and increases the production of Th1 effector cytokine IFN-γ, thus improving anti-tumor immune responses. Moreover, we find that establishing an IL-16-dependent, Th1-dominant TME relies on mast cell-produced histamine and results in the increased expression of the CXCR3 ligands in tumor-associated macrophages (TAM), thereby improving the therapeutic effectiveness of immune checkpoint blockade (ICB). Cancer patients exhibit impaired production of IL-16, which correlates with poorer prognosis. Additionally, low IL-16 production is associated with unresponsiveness to immunotherapy in cancer patients. Collectively, our findings provided new insights into the biological function of IL-16, emphasizing its potential clinical significance as a therapeutic approach to augment anti-tumor immunity and sensitize ICB-based cancer immunotherapy.

DOI: https://doi.org/10.1038/s41467-025-57603-1
J Neurochem. 2025 Mar;169(3): e70029

The Glutamate/GABA-Glutamine Cycle: Insights, Updates, and Advances.

Jens V Andersen.

  Synaptic homeostasis of the principal neurotransmitters glutamate and GABA is tightly regulated by an intricate metabolic coupling between neurons and astrocytes known as the glutamate/GABA-glutamine cycle. In this cycle, astrocytes take up glutamate and GABA from the synapse and convert these neurotransmitters into glutamine. Astrocytic glutamine is subsequently transferred to neurons, serving as the principal precursor for neuronal glutamate and GABA synthesis. The glutamate/GABA-glutamine cycle integrates multiple cellular processes, including neurotransmitter release, uptake, synthesis, and metabolism. All of these processes are deeply interdependent and closely coupled to cellular energy metabolism. Astrocytes display highly active mitochondrial oxidative metabolism and several unique metabolic features, including glycogen storage and pyruvate carboxylation, which are essential to sustain continuous glutamine release. However, new roles of oligodendrocytes and microglia in neurotransmitter recycling are emerging. Malfunction of the glutamate/GABA-glutamine cycle can lead to severe synaptic disruptions and may be implicated in several brain diseases. Here, I review central aspects and recent advances of the glutamate/GABA-glutamine cycle to highlight how the cycle is functionally connected to critical brain functions and metabolism. First, an overview of glutamate, GABA, and glutamine transport is provided in relation to neurotransmitter recycling. Then, central metabolic aspects of the glutamate/GABA-glutamine cycle are reviewed, with a special emphasis on the critical metabolic roles of glial cells. Finally, I discuss how aberrant neurotransmitter recycling is linked to neurodegeneration and disease, focusing on astrocyte metabolic dysfunction and brain lipid homeostasis as emerging pathological mechanisms. Instead of viewing the glutamate/GABA-glutamine cycle as individual biochemical processes, a more holistic and integrative approach is needed to advance our understanding of how neurotransmitter recycling modulates brain function in both health and disease.

Keywords:  Alzheimer's disease; astrocytes; lipid metabolism; mitochondrial function; neurodegeneration; neurotransmitter recycling

DOI:  https://doi.org/10.1111/jnc.70029
bioRxiv. 2025 Mar 01. pii: 2025.02.26.640389. [Epub ahead of print]

Succinate dehydrogenase activity supports de novo purine synthesis.

Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.

The de novo purine synthesis pathway is fundamental for nucleic acid production and cellular energetics, yet the role of mitochondrial metabolism in modulating this process remains underexplored. In many cancers, metabolic reprogramming supports rapid proliferation and survival, but the specific contributions of the tricarboxylic acid (TCA) cycle enzymes to nucleotide biosynthesis are not fully understood. Here, we demonstrate that the TCA cycle enzyme succinate dehydrogenase (SDH) is essential for maintaining optimal de novo purine synthesis in normal and cancer cells. Genetic or pharmacological inhibition of SDH markedly attenuates purine synthesis, leading to a significant reduction in cell proliferation. Mechanistically, SDH inhibition causes an accumulation of succinate, which directly impairs the purine biosynthetic pathway. In response, cancer cells compensate by upregulating the purine salvage pathway, a metabolic adaptation that represents a potential therapeutic vulnerability. Notably, co-inhibition of SDH and the purine salvage pathway induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings not only reveal a signaling role for mitochondrial succinate in regulating nucleotide metabolism but also provide a promising therapeutic strategy for targeting metabolic dependencies in cancer.

DOI: https://doi.org/10.1101/2025.02.26.640389
J Hepatocell Carcinoma. 2025 ;12 467-480

Research Progress of Liver Cancer Recurrence Based on Energy Metabolism of Liver Cancer Stem Cells.

Mingming Wu, Huayu Wang, Xiangxiang Wu, Huahui Zeng, Mingsan Miao, Yagang Song.

   Objective: The aim of this study is to investigate the recurrence and progression of liver cancer by focusing on the energy metabolism of liver cancer stem cells.
Methods: A comprehensive literature search was conducted using databases including CNKI, PubMed, Wanfang, and Citexs to analyze the etiology and treatment of hepatocellular carcinoma (HCC), the factors and mechanisms contributing to HCC recurrence, and the impact of energy metabolism in HCC stem cells on the development of HCC. Furthermore, the association between HCC recurrence and the energy metabolism of HCC stem cells was examined.
Results: The primary targets associated with the glycolytic metabolism of HCC stem cells included HK2, PFK, PK, LDH, among others. Glutamine metabolism primarily involves the tricarboxylic acid (TCA) cycle, with main targets such as mTORC1 and reactive oxygen species (ROS). The principal pathway in lipid metabolism is fatty acid (FA) biosynthesis, with key targets being fatty acid synthase (FASN), acetyl-coenzyme A carboxylase (ACC), stearoyl-coenzyme A desaturase-1 (SCD1), and adenosine monophosphate-activated protein kinase (AMPK). Targets in the oxidative phosphorylation pathway include PGC1a. Finally, key targets in iron metabolism encompass System Xc, glutathione peroxidase 4 (GPX4), and DMT1.
Conclusion: The glycolytic metabolism of HCC stem cells represents a primary metabolic pathway in HCC stem cells, with key targets including HK2, PFK, PK, and LDH warranting closer attention. Glutamine metabolism should focus on the TCA cycle and targets such as mTORC1 and ROS. Lipid metabolism pathway involves FA biosynthesis, with significant targets being FASN, ACC, SCD1, and AMPK. Iron metabolism, specifically System Xc, GPX4, and DMT1 targets, should be carefully considered. Therefore, interventions for the prevention and treatment of liver cancer recurrence should be directed towards these aspects of liver cancer stem cells.

Keywords:  energy metabolism; liver cancer recurrence; liver cancer stem cells

DOI:  https://doi.org/10.2147/JHC.S500638
bioRxiv. 2025 Mar 02. pii: 2025.02.26.640463. [Epub ahead of print]

Pathway Coessentiality Mapping Reveals Complex II is Required for de novo Purine Biosynthesis in Acute Myeloid Leukemia.

Amy E Stewart, Derek K Zachman, Pol Castellano-Escuder, Lois M Kelly, Ben Zolyomi, Michael D I Aiduk, Christopher D Delaney, Ian C Lock, Claudie Bosc, John Bradley, Shane T Killarney, Olga R Ilkayeva, Christopher B Newgard, Navdeep S Chandel, Alexandre Puissant, Kris C Wood, Matthew D Hirschey.

Understanding how cellular pathways interact is crucial for treating complex diseases like cancer, yet our ability to map these connections systematically remains limited. Individual gene-gene interaction studies have provided insights 1,2 , but they miss the emergent properties of pathways working together. To address this challenge, we developed a multi-gene approach to pathway mapping and applied it to CRISPR data from the Cancer Dependency Map 3 . Our analysis of the electron transport chain revealed certain blood cancers, including acute myeloid leukemia (AML), depend on an unexpected link between Complex II and purine metabolism. Through stable isotope metabolomic tracing, we found that Complex II directly supports de novo purine biosynthesis and exogenous purines rescue AML from Complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that Complex II must oxidize to sustain purine synthesis. This connection translated to a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML to Complex II inhibition. In mouse models, targeting Complex II triggered rapid disease regression and extended survival in aggressive AML. The clinical relevance of this pathway emerged in human studies, where higher Complex II gene expression correlates with both resistance to mitochondria-targeted therapies and worse survival outcomes specifically in AML patients. These findings establish Complex II as a central regulator of de novo purine biosynthesis and identify it as a promising therapeutic target in AML.

DOI: https://doi.org/10.1101/2025.02.26.640463
Urol Oncol. 2025 Mar 12. pii: S1078-1439(25)00065-1. [Epub ahead of print]

Transcriptomic and proteo-metabolic determinants of the grading system in clear cell renal cell carcinoma.

Giuseppe Lucarelli, Francesco Lasorsa, Martina Milella, Antonio d'Amati, Giuseppe Ingravallo, Mariella Silecchia, Mariella Errede, Cristina Bianchi, Marco Spilotros, Michele Battaglia, Pasquale Ditonno, Monica Rutigliano.

   BACKGROUND: Pathological grade is a morphological parameter of clear cell-renal cell carcinoma (ccRCC) and an independent predictor of cancer-specific survival. The aim of this study was to identify grade-dependent metabolic signatures and corresponding gene and protein expression changes that connect variations in cancer metabolism with nuclear grade, especially in high-grade tumors.
METHODS: Forty ccRCC samples were collected and stratified according to nuclear grade: 23 low-grade (LG = G1-G2) and 17 high-grade (HG = G3-G4) samples. In addition, 122 patients with sarcomatoid ccRCC (sRCC) were classified according to the abundance of sarcomatoid features as low sarcomatoid (LS; sarcomatoid component<20%; n = 67) or high sarcomatoid (HS; sarcomatoid component≥20%; n = 55). Untargeted metabolomic analysis was performed. To study the relative changes in gene and protein expression in HG vs. LG ccRCC, data from 4 different datasets were downloaded and stratified according to nuclear grade. Immunohistochemistry and immunofluorescence were used to evaluate protein expression. Cancer-specific survival (CSS) and progression-free survival (PFS) were calculated using Kaplan-Meier analysis. Multivariate analysis was performed using a Cox regression model.
RESULTS: The Warburg effect, in association with changes in Krebs cycle intermediates and related metabolites, was more prominent in HG ccRCC than in LG ccRCC. Additional alterations included metabolic reprogramming in the urea cycle and modulation of glutathione metabolism with the accumulation of reduced glutathione and carnitine derivatives in HG tumors, while the concentrations of long- and medium-chain fatty acids were greater in LG ccRCC. CSS and PFS were significantly decreased in patients with HS tumors. According to the multivariate analysis, the abundance of the sarcomatoid component was an adverse prognostic factor.
CONCLUSIONS: ccRCC is characterized by a particular grade-dependent metabolic reprogramming. Metabolic pathways and associated molecular alterations are grade-specific and could represent potential therapeutic targets, especially in HG tumors. sRCC subclassification based on the abundance of sarcomatoid components into HS vs. LS tumors have prognostic value.

Keywords:  Clear cell; Grade; Metabolism; Metabolomics; Prognosis; Renal cell carcinoma; Sarcomatoid

DOI:  https://doi.org/10.1016/j.urolonc.2025.02.016
NPJ Syst Biol Appl. 2025 Mar 13. 11(1): 26

A single-cell network approach to decode metabolic regulation in gynecologic and breast cancers.

Akansha Srivastava, P K Vinod.

Cancer metabolism is characterized by significant heterogeneity, presenting challenges for treatment efficacy and patient outcomes. Understanding this heterogeneity and its regulatory mechanisms at single-cell resolution is crucial for developing personalized therapeutic strategies. In this study, we employed a single-cell network approach to characterize malignant heterogeneity in gynecologic and breast cancers, focusing on the transcriptional regulatory mechanisms driving metabolic alterations. By leveraging single-cell RNA sequencing (scRNA-seq) data, we assessed the metabolic pathway activities and inferred cancer-specific protein-protein interactomes (PPI) and gene regulatory networks (GRNs). We explored the crosstalk between these networks to identify key alterations in metabolic regulation. Clustering cells by metabolic pathways revealed tumor heterogeneity across cancers, highlighting variations in oxidative phosphorylation, glycolysis, cholesterol, fatty acid, hormone, amino acid, and redox metabolism. Our analysis identified metabolic modules associated with these pathways, along with their key transcriptional regulators. These findings provide insights into the complex interplay between metabolic rewiring and transcriptional regulation in gynecologic and breast cancers, paving the way for potential targeted therapeutic strategies in precision oncology. Furthermore, this pipeline for dissecting coregulatory metabolic networks can be broadly applied to decipher metabolic regulation in any disease at single-cell resolution.

DOI: https://doi.org/10.1038/s41540-025-00506-0
Med Oncol. 2025 Mar 13. 42(4): 105

αKG-induced oxidative stress and mTOR inhibition as a therapeutic strategy for liver cancer.

Sung Kyung Choi, Myoung Jun Kim, Jueng Soo You.

  Despite the availability of targeted therapies, liver cancer remains a severe health burden. The need for adjuvant therapy to improve treatment efficacy and prevent recurrence is emerging. Alpha-ketoglutarate (αKG) is an intermediate in the tricarboxylic acid cycle and a cofactor for various oxygenases. A critical role of this multifunctional metabolite has started to be revealed in physiological and pathological conditions. We found that αKG exerts various anti-tumor effects in liver cancer cells. Our kinetic transcriptome study suggested that increasing reactive oxygen species and inhibiting mTORC1 signaling underlies. Indeed, αKG treatment elevated oxidative stress and induced DNA damage, presumably caused by early downregulation of the antioxidant gene SLC7A11. Further, we validated impaired mTOR signaling and decreased cellular energy production. This unique mechanism underscores αKG's potential as a liver cancer therapy by harnessing oxidative stress and disrupting metabolic signaling. These findings could provide valuable insights into further exploration of αKG as a promising therapeutic agent in liver cancer.

Keywords:  ATP; Alpha-Ketoglutarate; Anti-tumor; Liver cancer; ROS; mTOR

DOI:  https://doi.org/10.1007/s12032-025-02653-0
Nutrients. 2025 Feb 23. pii: 777. [Epub ahead of print]17(5):

Glutathione Contributes to Caloric Restriction-Triggered Shift in Taurine Homeostasis.

András Gregor, Manuel Malleier, Arturo Auñon-Lopez, Sandra Auernigg-Haselmaier, Jurgen König, Marc Pignitter, Kalina Duszka.

   BACKGROUND/OBJECTIVES: Previously, we found that caloric restriction (CR) in mice increases taurine levels by stimulating hepatic synthesis, secretion into the intestine and deconjugation of taurine-conjugated bile acids (BA). Subsequently, in the intestine, taurine conjugates various molecules, including glutathione (GSH). The current study explores the mechanisms behind forming taurine-GSH conjugate and its consequences for taurine, other taurine conjugates, and BA in order to improve understanding of their role in CR.
METHODS: The non-enzymatic conjugation of taurine and GSH was assessed and the uptake of taurine, GSH, and taurine-GSH was verified in five sections of the small intestine. Levels of taurine, gavaged 13C labeled taurine, taurine conjugates, taurine-GSH, and GSH were measured in various tissues of ad libitum and CR mice. Next, the taurine-related CR phenotype was challenged by applying the inhibitors of taurine transporter (SLC6A6) and GSH-S transferases (GST).
RESULTS: The CR-related increase in taurine in intestinal mucosa was accompanied by the uptake and distribution of taurine towards selected organs. A unique composition of taurine conjugates characterized each tissue. Although taurine-GSH conjugate could be formed in non-enzymatic reactions, GST activity contributed to taurine-related CR outcomes. Upon SLC6A6 and GST inhibition, the taurine-related parameters were affected mainly in the ileum rather than the liver. Meanwhile, BA levels were somewhat affected by GST inhibition in the ileum and in the liver by SLC6A6 inhibitor.
CONCLUSIONS: The discovered CR phenotype involves a regulatory network that adjusts taurine and BA homeostasis. GSH supports these processes by conjugating taurine, impacting taurine uptake from the intestine and its availability to form other types of conjugates.

Keywords:  bile acids; caloric restriction; glutathione; intestine; liver; taurine

DOI:  https://doi.org/10.3390/nu17050777