bims-glucam 2025-11-16 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–11–16
nineteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine metabolism reprogramming promotes bladder cancer progression via PYCR1: a multi-omics and functional validation study.
GLS1 inhibitor CB-839 inhibits the malignant progression of 5-FU resistant hepatoma cells by regulating glutamine metabolism.
DNAJ-PKAc induces metabolic rewiring and enhanced glutamine flux in fibrolamellar HCC.
Bile acid metabolism and invasion-related genes as therapeutic monitoring biomarkers in non-small cell lung cancer.
Metabolic reprogramming in macrophages: A glutamine rescue in β-catenin mutant hepatocellular carcinoma.
The Effect of Nutritional Supplementation in Ex Vivo Lung Perfusion Perfusate on Human Lung Endothelial Cell Function.
Metabolomics and metabolites in cancer diagnosis and treatment.
SPINK1-Driven cellular heterogeneity and interaction Networks in intrahepatic cholangiocarcinoma revealed by integrated multi-omics analysis.
Beyond the Warburg Effect: Modeling the Dynamic and Context-Dependent Nature of Tumor Metabolism.
Biomimetic nanoplatform-mediated CRISPR/Cas9 delivery for dual-pathway metabolic blockade in head and neck squamous cell carcinoma.
Glutaminase as a metabolic checkpoint in NK cell cytotoxicity: mechanistic uncertainties and translational implications.
13C metabolic tracing in human SGBS cells provides a potential new approach methodology for assessing metabolism-disrupting properties of environmental chemicals.
HBV reactivation and its metabolomic profile after liver transplantation for hepatocellular carcinoma in non-alcoholic steatohepatitis.
Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation.
Comparative omics profiling reveals differences in biomass, energy production, and vesicle transport between CHO and fast-growing CHL-YN cells.
The SLC1A1/EAAT3 dicarboxylic amino acid transporter is an epigenetically dysregulated nutrient carrier that sustains oncogenic metabolic programs.
Adaptive Gene Expression Induced by a Combination of IL-1β and LPS in Primary Cultures of Mouse Astrocytes.
Hepatocellular adenomas with high-risk molecular alterations undetected by "high-risk" β-catenin and/or glutamine synthetase staining patterns.
From microbiome to metabolism: Bridging a two-decade translational gap.

J Transl Med. 2025 Nov 13. 23(1): 1277

Glutamine metabolism reprogramming promotes bladder cancer progression via PYCR1: a multi-omics and functional validation study.

Xinjia Ding, Enkui Zhang, Zhou Huang, Xiaohui Li, Zhigao Wang, Yanping Wu, Chao Liu, Shikai Wu.

   BACKGROUND: Bladder cancer (BLCA) is a prevalent malignancy worldwide, with advanced stages linked to poor prognosis. Although immune checkpoint inhibitors (ICIs) show clinical promise in treating both operable and advanced BLCA, predicting patient responses remains a major challenge. Glutamine metabolism, a key aspect of metabolic reprogramming, has been implicated in tumor progression and immune modulation. However, the exact role of glutamine metabolism in BLCA remains poorly understood. This study aims to explore its association with clinical outcomes and immunotherapy response while functionally validating key regulatory genes.
METHODS: An integrated approach combining targeted metabolomics, single-cell RNA sequencing, and bulk transcriptomic data was used to profile glutamine metabolism in BLCA comprehensively and identify potential metabolic biomarkers. A prognostic model, termed GMscore, based on glutamine metabolism, was constructed using principal component analysis (PCA). Key regulatory genes were identified through random forest analysis. Functional assays, including in vitro proliferation, migration, and metabolic assays, as well as in vivo xenograft models, were employed to validate the findings.
RESULTS: Targeted metabolomics revealed increased glutamine metabolism in BLCA cell lines. The GMscore model, developed and validated across multiple cohorts, accurately predicted patient survival. In two immunotherapy cohorts (IMvigor210 and GSE91061), a lower GMscore correlated with improved therapeutic response, suggesting its potential as a predictive biomarker for immunotherapy efficacy. PYCR1 was identified as a key regulatory gene, exhibiting high expression in epithelial cells and cancer-associated fibroblasts (CAFs). Functional assays demonstrated that PYCR1 knockdown inhibited cell proliferation and migration and suppressed tumor growth in vivo. Mechanistically, PYCR1 facilitated proline synthesis through P5CS and activated the PI3K/AKT/mTOR signaling pathway, which modulated glutamine utilization and metabolic reprogramming in BLCA.
CONCLUSIONS: This study provides a comprehensive analysis of glutamine metabolism in BLCA and introduces a clinically relevant prognostic model. PYCR1 was identified as a central metabolic regulator, underscoring its critical role in tumor development and progression.

Keywords:  Bladder cancer; Glutamine metabolism; Metabolic reprogramming; PYCR1; Prognostic model; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-025-07386-2
Chem Biol Interact. 2025 Nov 08. pii: S0009-2797(25)00442-9. [Epub ahead of print] 111812

GLS1 inhibitor CB-839 inhibits the malignant progression of 5-FU resistant hepatoma cells by regulating glutamine metabolism.

Hao Wang, Xiao-Yan Wang, Jian-Bo Ji, Zong-Xue Zheng, Peng-Fei Shang, Xiu-Li Guo.

  Liver cancer, primary hepatocellular carcinoma (HCC), posing a significant threat to human health due to its high prevalence and limited treatment options. As a first-line chemotherapeutic agent for HCC, 5-fluorouracil (5-FU) has demonstrated significant efficacy in suppressing tumor cell proliferation through its cytotoxic mechanisms. Yet, prolonged 5-FU administration often induces chemo-resistant phenotypes in cancer cells, severely compromising the long-term efficacy of 5-FU-based treatment regimens and becoming a major barrier to successful HCC therapy. In this study, we investigated the mechanism underlying 5-FU resistance in Bel7402 hepatoma cells and found that it is closely related to metabolic reprogramming of glutamine. Notably, we demonstrated that CB-839, which is an inhibitor of glutamine metabolism's rate-limiting enzyme (glutaminase), has no notable anti-tumor activity alone but effectively enhances resistant HCC cells' sensitivity to 5-FU both in vitro and in vivo. The mechanism underlying this sensitization involves the disruption of cellular redox homeostasis. Specifically, the combination of CB-839 and 5-FU increases the accumulation of reactive oxygen species (ROS) and induces oxidative stress by consuming intracellular glutathione (GSH) reserves. Furthermore, this combination therapy elevates intracellular Fe2+levels and promotes lipid peroxidation, ultimately triggering ferroptosis. Collectively, these findings tentatively address certain aspects of the unclear mechanism underlying 5-FU resistance in HCC. Specifically, they may suggest targeting glutamine metabolism as a potential avenue for intervention and offer novel perspectives on understanding this resistance. Concurrently, these discoveries provide some support for optimizing chemotherapy regimens, with the aim of surmounting the current clinical challenges in reversing drug resistance.

Keywords:  5-FU resistance; GLS1; GLS1 inhibitor; Glutamine; Hepatocellular carcinoma

DOI:  https://doi.org/10.1016/j.cbi.2025.111812
J Hepatol. 2025 Nov 06. pii: S0168-8278(25)02610-8. [Epub ahead of print]

DNAJ-PKAc induces metabolic rewiring and enhanced glutamine flux in fibrolamellar HCC.

Zeal Kamdar, Ethan Neumann, Kathryn Howe, Donald Long, Waqar Arif, Daniel H Shu, Aditya Mohan, Emma Kartalia, Jeric Hernandez, Solomon Levin, Kylie Belanger, Kayla Bendinelli, Tamara Y Lopez-Vidal, James M Leatherman, Kabeer Munjal, Cissy Zhang, Pratik Khare, Paul G Thomas, Daniel J Zabransky, Won Jin Ho, Robert D Leone, Robert A Anders, Anne Le, Praveen Sethupathy, Chi V Dang, Elizabeth M Jaffee, Mark Yarchoan.

   BACKGROUND: Fibrolamellar carcinoma (FLC) is a pediatric and adolescent liver cancer that is characterized by a recurrent fusion of DNAJB1 and PRKACA, yielding a chimeric translated protein, DNAJ-PKAc. PRKACA encodes the catalytic subunit of protein kinase A (PKA), a regulator of cellular metabolism.
METHODS: We generated a syngeneic murine model of FLC, TIBxDNAJ-PKAc. We utilized preclinical models of FLC and human specimens to characterize the metabolic and immune effects of DNAJ-PKAc.
RESULTS: DNAJ-PKAc induced a high glycolytic and glutamine flux to support nucleotide metabolism. As compared to parental TIBx tumors, TIBxDNAJ-PKAc tumors demonstrated reduced T cell infiltration with impaired T cell activation. Systemic administration of a glutamine antagonist reversed the immune-inactivated phenotype of TIBxDNAJ-PKAc tumors and provided tumor control in combination with immune checkpoint inhibitors (ICI).
CONCLUSION: The presence of DNAJ-PKAc creates a vulnerability to the combination of glutamine antimetabolite and ICI therapy in FLC.
IMPACT AND IMPLICATIONS: The DNAJ-PKAc fusion in fibrolamellar carcinoma (FLC) induces metabolic reprogramming including enhanced glutamine metabolism, which promotes immune evasion. Targeting this metabolic vulnerability with a glutamine antagonist, in combination with immune checkpoint inhibitors, reverses the immunosuppressive tumor microenvironment (TME), offering a promising therapeutic strategy for FLC treatment.

Keywords:  FLC; Fibrolamellar; glutamine; hepatocellular; immunometabolism; immunotherapy

DOI:  https://doi.org/10.1016/j.jhep.2025.10.027
Discov Oncol. 2025 Nov 10. 16(1): 2075

Bile acid metabolism and invasion-related genes as therapeutic monitoring biomarkers in non-small cell lung cancer.

Guangteng Wu, Lin Zhu, Feng Xue, Yanyi Zhao.

  Non-small cell lung cancer (NSCLC) persists as a major contributor to global cancer morbidity and mortality. This study explores the complex interplay between bile acid metabolism (BAM), tumor invasion, and the immune microenvironment in NSCLC pathogenesis. While traditionally known for digestive functions, bile acids are crucial signaling molecules, and their metabolic pathways, coupled with invasion-related genes (IRGs), are increasingly implicated in tumorigenesis. Using the NSCLC dataset GSE225620, we identified 109 differentially expressed genes at the intersection of BAM and invasion (BAM&IRDEGs). Functional analysis revealed their significant enrichment in metabolic pathways, including fatty acid metabolism, which are critical for shaping the tumor microenvironment and fostering aggressive growth. Immune infiltration analysis indicated significant remodeling, particularly highlighting a strong correlation between activated CD8⁺ T cells and central memory CD4⁺ T cells. Key genes, including the glutamine transporter SLC1A5 and the fatty acid translocase CD36, emerged as critical nodes. Our analysis suggests these genes contribute to an immunosuppressive microenvironment by fueling tumor metabolic reprogramming and inducing CD8⁺ T cell dysfunction through altered lipid and glutamine metabolism. Leveraging these key genes, we established a therapeutic monitoring model using LASSO regression and support vector machine (SVM) algorithms. The model demonstrated robust performance in predicting treatment efficacy, underscoring its potential for monitoring therapeutic response and guiding individualized treatment decisions. Our findings highlight the clinical relevance of the metabolic-immune axis in NSCLC and propose that key BAM&IRDEGs, particularly SLC1A5 and CD36, are not only potential therapeutic targets but also promising candidates for inclusion in liquid biopsy panels. Such non-invasive tools could enable dynamic monitoring of disease progression and early detection of relapse, paving the way for more precise NSCLC management.

Keywords:  Bile acid metabolism; Differentially expressed genes; Invasion; Non-small cell lung cancer; Therapeutic monitoring model

DOI:  https://doi.org/10.1007/s12672-025-03925-x
Hepatology. 2025 Nov 13.

Metabolic reprogramming in macrophages: A glutamine rescue in β-catenin mutant hepatocellular carcinoma.

Gregory Kenneth Muliawan, Terence Kin Wah Lee.

DOI: https://doi.org/10.1097/HEP.0000000000001619
Cells. 2025 Oct 25. pii: 1668. [Epub ahead of print]14(21):

The Effect of Nutritional Supplementation in Ex Vivo Lung Perfusion Perfusate on Human Lung Endothelial Cell Function.

Dejan Bojic, Kimberly Main, Tanroop Aujla, Olivia Hough, Shaf Keshavjee, Mingyao Liu.

  Clinical application of ex vivo lung perfusion (EVLP) has increased marginal donor lung utilization. It has been developed as a platform for donor lung reconditioning. However, many of the current repair strategies are limited by a maximum reliable EVLP circuit duration of 12 h. Past studies have successfully extended EVLP through nutrient supplementation, but the exact components and respective mechanisms by which EVLP is extended remains unknown. As such, the focus of this study was to systematically evaluate the effects of nutritional supplements in EVLP perfusates on cell apoptosis, viability, confluence, and migration. To test this, we developed a high-throughput human lung endothelial cell culture platform where experimental perfusates with various combinations of GlutaMAX (a glutamine dipeptide), Travasol (amino acids), Intralipid (lipids), Multi-12 (vitamins), cysteine, and glycine were tested using the Incucyte Live imaging system. GlutaMAX supplementation alone significantly reduced apoptosis, improved viability and cell migration beyond all other supplements and further outperformed standard endothelial cell culture medium. Travasol offered short-term benefits, while Intralipid offered minimal functional support. Multi-12 improved viability and apoptosis independently and in combination with other supplements. The best experimental perfusate targeted the glutathione synthesis pathway, combining GlutaMAX, cysteine and glycine and further reduced apoptosis compared with GlutaMAX alone. Collectively, these results suggest that nutrient selection during EVLP is critical and highlights the need to systematically evaluate perfusate modifications as opposed to broad-spectrum nutrient delivery. This in vitro model provides a cost-effective platform for preclinical screening of perfusate modifications to enhance organ viability during EVLP.

Keywords:  EVLP; glutamine; glutathione; nutritional supplementation; perfusate optimization

DOI:  https://doi.org/10.3390/cells14211668
Mol Biomed. 2025 Nov 14. 6(1): 109

Metabolomics and metabolites in cancer diagnosis and treatment.

Minyi Cai, Haiyan Liu, Chen Shao, Tingting Li, Jun Jin, Yahui Liang, Jinhu Wang, Ji Cao, Bo Yang, Qiaojun He, Xuejing Shao, Meidan Ying.

  Cancer is a leading cause of death worldwide. Metabolic reprogramming in cancers plays an important role in tumor initiation, malignant progression and therapeutic response. Based on this, significant progress has been made in the development of the metabolite-based early cancer detection and targeted interventions. Over the past decade, metabolomics has been widely applied to detect metabolic alterations in tumor cells as well as their microenvironment. However, an up-to-date systematic review to summarize the current metabolomic and metabolites in cancer, especially their connections to cancer diagnostics/prognostic biomarkers and therapeutic strategies, is lacking. Here, we first introduced the platforms and analytical processes of metabolomics, as well as their application in different biological matrix of tumor patients. Then, we summarized representative cancer studies in which specific metabolites was found to be act as diagnostic or prognostic/stratification biomarkers. Furthermore, we reviewed the current therapeutic strategies targeting cancer metabolism, particularly the drugs/compounds that are either market-approved or in clinical trials, and also analyzed the potential of metabolites in personalizing precision treatment. Finally, we discussed the key challenges in this field, including the technical limitations of metabolomics and the clinical limitations of therapeutic targeting cancer metabolism, and further explored the future directions such as multi-omics perspective and lifestyle interventions. Taken together, we provides a comprehensive overview from technological platforms of metabolomics to translational applications of metabolites, facilitating the discovery of novel biomarkers and targeting strategies for precision oncology.

Keywords:  Biomarkers; Cancer; Metabolites; Metabolomics; Therapeutic targets

DOI:  https://doi.org/10.1186/s43556-025-00362-8
J Adv Res. 2025 Nov 12. pii: S2090-1232(25)00906-3. [Epub ahead of print]

SPINK1-Driven cellular heterogeneity and interaction Networks in intrahepatic cholangiocarcinoma revealed by integrated multi-omics analysis.

Xiaoxiang Rong, Jiayun Guan, Chanqi Ye, Qiong Li, Mingyu Wan, Wenguang Fu, Jinzhang Chen, Dayong Zheng, Ruyin Chen, Rui Zhou, Gautam Sethi, Yunlu Jia, Jian Ruan.

   INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) is a highly heterogeneous and aggressive malignancy with poor prognosis and limited treatment options. The lack of precise molecular classification and incomplete understanding of the tumor microenvironment (TME) impede therapeutic development.
OBJECTIVES: This study aims to dissect the cellular heterogeneity and intercellular interactions in ICC, with a particular focus on SPINK1-overexpressing epithelial subsets. We sought to determine the role of SPINK1 in modulating immune cell recruitment and tumor metabolism, and to evaluate its clinical relevance.
METHODS: We performed single-cell RNA sequencing (scRNA-seq) on human ICC tumors and adjacent normal tissues to construct a transcriptomic atlas. Integrative proteomic analysis, transwell assays, co-culture systems, and functional perturbation experiments (SPINK1 knockdown and ASCT2 inhibition) were conducted to explore epithelial-macrophage interactions and metabolic dynamics.
RESULTS: ScRNA-seq identified a SPINK1-overexpressing epithelial subcluster enriched in ICC tumors. High SPINK1 expression correlated with significantly shorter patient survival. SPINK1-overexpressing epithelial subcluster secretes CCL20, which recruits lipid-associated macrophages (LAMs). This effect was reversed by CCL20 neutralizing antibodies. In co-culture, LAMs increased intracellular glutamine levels in SPINK1-overexpressing epithelial subcluster, promoting proliferation. Disruption of SPINK1 expression or glutamine transport abolished this metabolic support.
CONCLUSION: Our findings uncover a novel SPINK1-CCL20-LAMs axis that orchestrates immune recruitment and metabolic reprogramming in ICC. SPINK1 facilitates tumor growth by establishing a glutamine-rich microenvironment via LAMs. These insights highlight SPINK1 as a potential therapeutic target and prognostic biomarker in ICC.

Keywords:  Immunosuppression; Intrahepatic cholangiocarcinoma; Metabolic reprogramming; SPINK1; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.jare.2025.11.011
Cancers (Basel). 2025 Nov 03. pii: 3563. [Epub ahead of print]17(21):

Beyond the Warburg Effect: Modeling the Dynamic and Context-Dependent Nature of Tumor Metabolism.

Pierre Jacquet, Angélique Stéphanou.

  Background: The Warburg effect, historically regarded as a hallmark of cancer metabolism, is often interpreted as a universal metabolic feature of tumor cells. However, accumulating experimental evidence challenges this paradigm, revealing a more nuanced and context-dependent metabolic landscape. Methods: In this study, we present a hybrid multiscale model of tumor metabolism that integrates cellular and environmental dynamics to explore the emergence of metabolic phenotypes under varying conditions of stress. Our model combines a reduced yet mechanistically informed description of intracellular metabolism with an agent-based framework that captures spatial and temporal heterogeneity across tumor tissue. Each cell is represented as an autonomous agent whose behavior is shaped by local concentrations of key diffusive species-oxygen, glucose, lactate, and protons-and governed by internal metabolic states, gene expression levels, and environmental feedback. Building on our previous work, we extend existing metabolic models to include the reversible transport of lactate and the regulatory role of acidity in glycolytic flux. Results: Simulations under different environmental perturbations-such as oxygen oscillations, acidic shocks, and glucose deprivation-demonstrate that the Warburg effect is neither universal nor static. Instead, metabolic phenotypes emerge dynamically from the interplay between a cell's history and its local microenvironment, without requiring genetic alterations. Conclusions: Our findings suggest that tumor metabolic behavior is better understood as a continuum of adaptive states shaped by thermodynamic and enzymatic constraints. This systems-level perspective offers new insights into metabolic plasticity and may inform therapeutic strategies targeting the tumor microenvironment rather than intrinsic cellular properties alone.

Keywords:  environmental stress; metabolic plasticity; systems biology; tumor metabolism

DOI:  https://doi.org/10.3390/cancers17213563
Biomaterials. 2025 Nov 07. pii: S0142-9612(25)00756-2. [Epub ahead of print]328 123837

Biomimetic nanoplatform-mediated CRISPR/Cas9 delivery for dual-pathway metabolic blockade in head and neck squamous cell carcinoma.

Ting Fang, Chang Peng, Rui Ding, Yinzhen Fan, Jiajia Jia, Jiajie Chen, XinHang Zhang, Dongkai Wang, Ji Li.

  Head and neck squamous cell carcinoma (HNSCC) continues to exhibit a poor prognosis, largely due to late diagnosis and the development of cisplatin resistance. Tumor proliferation in HNSCC is closely associated with upregulation of key glycolytic enzymes. However, monotherapeutic targeting of glycolysis paradoxically enhances compensatory glutaminolysis via glutamate overproduction. To overcome this metabolic adaptation, we developed biomimetic nanoparticles P-T-p@CM, fabricated from the pH/reduction dual-responsive copolymer poly(lactic acid)-polyhistidine-polyethylenimine (PLA-pHis-ss-PEI). This nanoplatform enables coordinated co-delivery of telaglenastat (a glutaminase 1 (GLS1) inhibitor) and a CRISPR-Cas9 plasmid encoding sgRNA targeting HIF-1α. This system utilizes homologous cancer cell membrane coating for precise tumor homing, with stimuli-responsive release enabling simultaneous dual metabolic blockade: CRISPR-mediated HIF-1α knockout attenuates glycolysis while telaglenastat suppresses glutamine-to-glutamate conversion. Metabolic analyses confirmed significant reduction in Glycolysis proton efflux rate (GlycoPER), the oxygen consumption rate (OCR) and ATP generation, as well as the related metabolites including the lactate production and glutamate. This dual-starvation strategy depleted energy reserves and biosynthetic precursors, inducing severe metabolic disruption. Notably, in vivo studies showed a 90 % tumor inhibition rate (TIR) after 15 days of treatment, through enhanced apoptosis, reduced proliferation, and tumor glucose/glutamate depletion. Collectively, P-T-p@CM establishes a paradigm-shifting approach to disrupt metabolic compensation in the treatment of HNSCC.

Keywords:  Biomimetic nanoparticles; Glutaminolysis; Glycolysis; HNSCC; Metabolic compensation

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123837
Immunol Res. 2025 Nov 13. 73(1): 164

Glutaminase as a metabolic checkpoint in NK cell cytotoxicity: mechanistic uncertainties and translational implications.

DuJiang Yang, GuoYou Wang.

  In their recent study, Jedlička et al. demonstrate that glutaminase (GLS) activity is indispensable for sustaining human natural killer (NK) cell cytotoxicity, positing it as a key metabolic regulator of effector function. While this work provides a valuable foundation for understanding NK cell immunometabolism, our analysis identifies several critical areas requiring deeper exploration. This letter offers a prospective critique, highlighting the incomplete delineation of the downstream metabolic mechanisms-specifically regarding energy production, biosynthetic precursor synthesis, and redox homeostasis-that link GLS activity to the cytolytic machinery. Furthermore, we question the physiological relevance of these in vitro findings within the nutrient-deprived and competitive tumor microenvironment (TME), where NK cells must exhibit metabolic flexibility. A paramount concern is the translational double-edged sword of GLS inhibition, which may inadvertently suppress anti-tumor immunity. We conclude that future research must employ integrated multi-omics and in vivo models to resolve these complexities, which is essential for harnessing NK cell metabolism without compromising its therapeutic potential.

Keywords:  GlutaminaseNatural Killer cellsImmunometabolismCytotoxicityGlutaminolysisTumor microenvironment

DOI:  https://doi.org/10.1007/s12026-025-09724-4
J Hazard Mater. 2025 Nov 04. pii: S0304-3894(25)03304-7. [Epub ahead of print]500 140384

13C metabolic tracing in human SGBS cells provides a potential new approach methodology for assessing metabolism-disrupting properties of environmental chemicals.

Cornelius Goerdeler, Beatrice Engelmann, Helen Broghammer, Alix Sarah Aldehoff, Martin Wabitsch, Kristin Schubert, Matthias Blüher, John T Heiker, Ulrike Rolle-Kampczyk, Martin von Bergen.

  Human exposure to certain environmental chemicals, including phthalates, is linked to metabolic disruption and may thereby contribute to diseases like obesity. However, regulatory methods to evaluate such effects are lacking. DINCH was introduced as a substitute for banned phthalate plasticizers, but its primary metabolite, MINCH, has been shown to promote adipogenesis in human preadipocytes and alter the lipid metabolism of mature adipocytes. To investigate its potential metabolism-disrupting effects, we assessed changes in the central carbon metabolism activity of human preadipocytes and mature adipocytes by 13C metabolic tracing. In preadipocytes, MINCH increased glycolysis, pentose phosphate pathway activity, acetyl-CoA production from glucose and glutamine, and pyruvate anaplerosis, indicating a metabolic shift toward adipogenesis. In mature adipocytes, MINCH enhanced glycolysis, glyceroneogenesis, fatty acid oxidation, and oxidative TCA cycle activity, pathways associated with the browning of adipocytes. Elevated UCP1 expression confirmed MINCH-induced browning. Most pronounced effects occurred at micromolar concentrations, whereas subtle changes were already observed at nanomolar concentrations in preadipocytes, the biological relevance of which should be further investigated. Overall, our findings demonstrate the utility of 13C metabolic tracing as a New Approach Methodology for detecting chemical-induced metabolic alterations, thus providing a new perspective for the hazard and risk assessment of environmental contaminants.

Keywords:  (13)C metabolic tracing; DINCH; Metabolic disruption; New Approach Methodology; Plasticizer

DOI:  https://doi.org/10.1016/j.jhazmat.2025.140384
Chin J Cancer Res. 2025 Oct 30. 37(5): 865-878

HBV reactivation and its metabolomic profile after liver transplantation for hepatocellular carcinoma in non-alcoholic steatohepatitis.

Jinyan Chen, Leyi Chen, Huigang Li, Zhihang Hu, Jianyong Zhuo, Xingzhu Chen, Ruijie Zhao, Chiyu He, Xiang Wu, Zhanyi Lin, Jiancai Sun, Rongsen Wang, Xuyong Wei, Shusen Zheng, Xiao Xu, Di Lu.

   Objective: The role of non-alcoholic steatohepatitis (NASH) in hepatitis B virus (HBV) reactivation following liver transplantation for hepatocellular carcinoma (HCC) remains unclear, and the metabolic differences between patients with NASH and those with HBV reactivation are also yet to be elucidated. This study is to investigate the impact of NASH on HBV reactivation risk and prognosis following liver transplantation for HCC, and to develop a predictive model and identify therapeutic targets.
Methods: This study included 274 patients who underwent liver transplantation for HCC. The HBV reactivation status of patients with NASH was analyzed, and the metabolic characteristics of peripheral blood were examined to compare NASH and non-NASH patients with or without HBV reactivation.
Results: The HBV reactivation free survival was better in non-NASH patients (P<0.0001). Furthermore, NASH patients with HBV reactivation had worse recurrence-free survival (RFS) than non-NASH patients with HBV reactivation (P=0.016). In contrast, the RFS of NASH patients without HBV reactivation was comparable to that of non-NASH patients without HBV reactivation (P=0.810). Subsequently, we constructed a model to predict HBV reactivation by incorporating 7 clinical indicators using the Least Absolute Shrinkage and Selection Operator-Cox (LASSO-Cox) approach. The area under the receiver operating characteristic curve (AUROC) values for predictions at 500, 1,000, and 1,500 d were 0.759, 0.809, and 0.814, respectively. Finally, metabolic pathway analysis identified key pathways involved in HBV reactivation, and glutamine was found to be an independent protective factor against HBV reactivation following liver transplantation for HCC.
Conclusions: NASH patients are more prone to HBV reactivation following liver transplantation for HCC and exhibit worse recurrence-free survival. Glutamine may serve as a potential therapeutic target or predictive biomarker for HBV reactivation.

Keywords:  Hepatitis B virus reactivation; NASH; hepatocellular carcinoma recurrence; liver transplantation; metabolomics

DOI:  https://doi.org/10.21147/j.issn.1000-9604.2025.05.15
Blood. 2025 Nov 14. pii: blood.2025028933. [Epub ahead of print]

Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation.

Tianyi Ling, Cristiana O'Brien, Jonathan St-Germain, Vincent Rondeau, Mary Shi, Jacob M Berman, Adrianna Kinga Cepa, Paula Saez Raez, Mark Wunderlich, Katharine Carter, Cody Stillwell, Christina R Sexton, Rachel Culp-Hill, Julie A Reisz, Saeer A Adeel, Andy G X Zeng, Suraj Bansal, Emily Tsao, He Tian Tony Chen, John E Dick, Mark D Minden, Andrea Arruda, Maria L Amaya, Anastasia N Tikhonova, Kristin Hope, Angelo D'Alessandro, Brian Raught, Courtney L Jones.

Acute myeloid leukemia (AML) patients have a poor five-year survival rate highlighting the need for the identification of new approaches to target this disease. AML is highly dependent on glutathione (GSH) metabolism for survival. While the metabolic role of GSH is well-characterized in AML, the contribution of protein glutathionylation-a reversible modification that protects protein thiols from oxidative damage-remains largely unexplored. Therefore, we sought to elucidate the role of protein glutathionylation in AML pathogenesis. Here, we demonstrate that protein glutathionylation is essential for AML cell survival. Specifically, the loss of glutaredoxin 2 (GLRX2), an enzyme that removes glutathione modifications, resulted in selective primary AML cell death while sparing normal human hematopoietic stem and progenitor cells. Unbiased proteomic analysis revealed increased mitochondrial protein glutathionylation upon GLRX2 depletion, accompanied by mitochondrial dysfunction, including impaired oxidative phosphorylation, reduced mitochondrial membrane potential, and increased opening of the mitochondrial permeability transition pore (mPTP). Further investigation identified ATP5PO, a key regulator of mPTP opening and a component of the ATP synthase complex, as a critical GLRX2 target. Disruption of ATP5PO glutathionylation partially restored mPTP function and rescued AML cell viability following GLRX2 depletion. Moreover, both genetic and pharmacologic inhibition of mPTP opening restored the leukemic potential of primary AML specimens in the absence of GLRX2. By disrupting glutathionylation-dependent mitochondrial homeostasis, this study reveals a novel vulnerability in AML that could inform future therapeutic strategies.

DOI: https://doi.org/10.1182/blood.2025028933
Sci Rep. 2025 Nov 13. 15(1): 39784

Comparative omics profiling reveals differences in biomass, energy production, and vesicle transport between CHO and fast-growing CHL-YN cells.

Yu Tsunoda, Rintaro Arishima, Tatiana Boronina, Robert Cole, Noriko Yamano-Adachi, Michael Betenbaugh, Takeshi Omasa.

  Chinese hamster lung (CHL)-YN cells are promising novel hosts for producing therapeutic antibodies with the potential to shorten the research, development, and manufacturing timelines in biopharmaceutical production. CHL-YN cells grow twice as fast as Chinese hamster ovary (CHO) cells, with a doubling time of 8.1 h. These cells possess strong glutamine synthetase activity, allowing them to be cultured in glutamine-free media. In this study, we conducted comparative transcriptomics and proteomics among CHL-YN cells, CHO cells, and lung tissue from Chinese hamster to better understand the global characteristics of CHL-YN cells and determine whether these features are tissue-derived or unique to the cell line. Omics profiling revealed that CHL-YN cells, in contrast to CHO cells, exhibit highly activated processes and pathways related to biomass and energy production, such as translation and biosynthesis of amino acids, but less activated vesicle transport processes, such as Golgi-related vesicle transport. This study highlights distinct characteristics of CHL-YN cells, contributing to streamlined operations, shortened development timelines, and expanded options for selectable cell lines. The findings here could contribute to identifying potential biomarkers and targets for cell engineering toward improving antibody productivity and growth rate in both traditional CHO cells and next-generation host cells, CHL-YN.

Keywords:  Chinese hamster ovary cell; Proteomics; Transcriptomics

DOI:  https://doi.org/10.1038/s41598-025-23503-z
Nat Commun. 2025 Nov 14. 16(1): 10012

The SLC1A1/EAAT3 dicarboxylic amino acid transporter is an epigenetically dysregulated nutrient carrier that sustains oncogenic metabolic programs.

Treg Grubb, Pooneh Koochaki, Sayed Matar, Fatme Ghandour, Marc Machaalani, Eddy Saad, Cerise Tang, Eduard Reznik, Jesminara Khatun, Carleigh Salem, Noah Dubasik, David A Orlando, Matthew G Guenther, Gyanu Parajuli, Raghvendra M Srivastava, Steven R Martinez, Jesse A Coker, Ritesh R Kotecha, A Ari Hakimi, John M Asara, Timothy A Chan, Sakari Vanharanta, Shaun R Stauffer, William G Kaelin, Sabina Signoretti, Toni K Choueiri, Abhishek A Chakraborty.

Epigenetic dysregulation, including accumulation of Histone H3 lysine 27 acetylation (H3K27ac), is a hallmark of pVHL-deficient clear cell Renal Cell Carcinomas (ccRCCs). Using an in vivo positive selection ORF screen in poorly tumorigenic pVHL-proficient cells and mechanistic studies in pVHL-deficient cells, we discovered that the aspartate (Asp) and glutamate (Glu) transporter, SLC1A1/EAAT3, is a metabolic dependency in ccRCC. pVHL loss promotes Hypoxia Inducible Factor (HIF)-independent SLC1A1 expression via H3K27ac dysregulation. SLC1A1 inactivation, genetically or pharmacologically, depletes Asp/Glu-derived metabolites (e.g., Tricarboxylic acid cycle and nucleotide intermediates), impedes ccRCC growth, and sensitizes ccRCCs to anti-metabolite drugs (e.g., glutaminase blockers). In human tumors, higher SLC1A1 expression is associated with reduced immune infiltration, oncogenic metabolic programs, and advanced stage/metastatic disease. Finally, in ccRCC animal models, SLC1A1 inactivation diminishes lung metastasis and the outgrowth of established renal tumors. Altogether, our studies credential SLC1A1 as an actionable, HIF-independent, metabolic dependency in pVHL-deficient ccRCCs.

DOI: https://doi.org/10.1038/s41467-025-64983-x
Cells. 2025 Nov 05. pii: 1737. [Epub ahead of print]14(21):

Adaptive Gene Expression Induced by a Combination of IL-1β and LPS in Primary Cultures of Mouse Astrocytes.

Thierry Coppola, Gwénola Poupon, Hélène Rangone, Stéphane Martin, Patricia Lebrun.

  Astrocytes are vital cells within the central nervous system (CNS), as they perform a critical role in supporting neurons by providing nutrients, such as lactate for energy, and safeguarding them against the toxicity of excessive neurotransmitters, such as glutamate. This study investigates astrocyte adaptive mechanisms in response to chronic inflammation. The primary aim is to assess the long-term effects of an inflammation-induced environment using a combination of lipopolysaccharide (LPS) and interleukin-1β (IL-1β), on the expression of key genes involved in essential metabolic pathways for astrocyte function, including glutamate metabolism and clearance, lactate synthesis and transport, and glucose metabolism. We observed an upregulation of the glutamate transporter eaat2 (but not eaat1), leading to glutamate accumulation and altered glutamate-glutamine cycling, as well as increased glycolytic activity and lactate production/export via hexokinases (hk1 and hk2) and the mct4 lactate transporter. Interestingly, these mechanisms are reversible, indicating a precisely controlled adaptive system. This investigation facilitated the identification of the signaling pathways involved in astrocyte adaptive responses to stress. This will further guide our investigations towards the more complex domain of resistance and adaptation of CNS in pathophysiological conditions.

Keywords:  astrocyte; glutamate; inflammation; lactate; solute carriers

DOI:  https://doi.org/10.3390/cells14211737
Am J Clin Pathol. 2025 Nov 14. pii: aqaf115. [Epub ahead of print]

Hepatocellular adenomas with high-risk molecular alterations undetected by "high-risk" β-catenin and/or glutamine synthetase staining patterns.

Hailey L Gosnell, Daniel E Roberts, Xuefeng Zhang, Elizabeth M Azzato, Maureen A Jacubowski, Paula Toro, Germán Corredor, Yu-Wei Cheng, Josephine Dermawan, Julien Calderaro, Rondell P Graham, Sanjay Kakar, Daniela S Allende.

   OBJECTIVE: β-Catenin-mutated hepatocellular adenomas (HCAs) carry an increased malignant transformation risk and are screened by interpreting glutamine synthetase (GS) and β-catenin by immunohistochemistry (IHC). Our study aims to assess GS and β-catenin interpretation guidelines for applicability and reproducibility in predicting high-risk HCA and other relevant molecular alterations.
METHODS: Hematoxylin and eosin (H&E), β-catenin, GS, and CD34 stains from 75 HCAs were interpreted by three pathologists using Method A (GS interpretation: negative, perivenular patchy, map-like, diffuse, and indeterminate) and Method B criteria (similar GS interpretation scheme based on a recent publication, with and without CD34 expression patterns). Ease of application and interpretation confidence level were assessed. High-risk IHC was defined as nuclear β-catenin and/or diffuse homogeneous GS. Molecular testing was performed on a subset of HCAs and controls.
RESULTS: There were 57 resections and 18 biopsy specimens examined. Methods A and B (GS only) were rated as easy to apply, with high interpretation confidence (≥90% using both methods). Consensus rate was comparable in biopsy specimens (100% for both methods) and resections (88% for Method A, 93% for Method B). While the same cases were stratified into high-risk GS categories using both systems, clinically significant genetic alterations (TERT promoter, EGFR, MTOR, and TP53) were identified in 25% of cases stratified as not high risk by IHC.
CONCLUSIONS: Both methods have a similar ease of application and level of interpretation confidence, and they also detected β-catenin mutations as expected. Other relevant molecular alterations associated with risk of neoplastic progression and/or bleeding were detected in 25% of HCAs with the non-high-risk IHC phenotype, suggesting the value of molecular testing in this subset.

Keywords:  adenoma; carcinoma; hepatocellular; liver; molecular

DOI:  https://doi.org/10.1093/ajcp/aqaf115
Cell Metab. 2025 Nov 13. pii: S1550-4131(25)00445-0. [Epub ahead of print]

From microbiome to metabolism: Bridging a two-decade translational gap.

Matthias Van Hul, Patrice D Cani.

  The mapping of the human genome sparked high expectations for biomedical breakthroughs, yet attention has since shifted toward the human microbiome as a key player in health and disease. Pioneering studies revealed striking inter-individual variability and numerous associations between gut microbiota and a wide range of conditions (i.e., obesity, diabetes, cardiovascular and inflammatory bowel diseases, autism, allergies, neurodegenerative diseases, and cancers). However, the field has faced a deluge of correlative "dysbiosis" studies with limited causal evidence. Although animal models have provided crucial mechanistic insights, translating these findings to humans has proven challenging. Interventions such as fecal microbiota transplantation, prebiotics, probiotics, and postbiotics often yield inconsistent or modest effects in clinical trials. This gap highlights the need for precision, functional profiling, and integration of multi-omics , for instance, through artificial intelligence. In this perspective, we discuss what microbiome research offers as a transformative shift and how we conceptualize disease, favoring systems biology and personalized interventions over reductionist approaches.

Keywords:  circadian rhythm; glutamine; intestinal clock; sleep-wake cycle

DOI:  https://doi.org/10.1016/j.cmet.2025.10.011