bims-glucam 2025-11-23 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–11–23
eighteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Metabolic nanoblockers for synergistic cancer treatment through glutaminase inhibition and sonodynamic therapy.
Title: Resveratrol ameliorates liver fibrosis by inhibiting ATF4 to regulate glutamine metabolism in hepatic stellate cells.
Glutamine-Dependent Slc25a39-Nrf2 Axis Couples Mitochondrial Dynamics with Metabolic Reprogramming to Establish Myogenic Commitment.
FOXO1 links KRAS G12D and G12V alleles to glutamine and nitrogen metabolism in colorectal cancer.
Targeted Metabolomic Methods for 13C Stable Isotope Labeling with Uniformly Labeled Glucose and Glutamine Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).
Glutamine antagonism suppresses tumor growth in adrenocortical carcinoma through inhibition of de novo nucleotide biosynthesis.
Müller cell glutamine metabolism links photoreceptor and endothelial injury in diabetic retinopathy.
Intestinal clock shapes sleep-wake cycle via sustaining glutamine homeostasis.
Metabolic Flexibility of Microglia: Energy Substrate Utilization and Impact on Neuronal Metabolism.
Recent progress in immune evasion mechanisms of triple-negative breast cancer.
Metabolic pathways involved in retinal angiogenesis: Molecular mechanisms and therapeutic targets.
Telomere maintenance meets cancer metabolism: Mechanistic insights and clinical opportunities.
Fibulin7 C-terminal bioactive peptide regulates metabolic profiling of macrophages during inflammation via integrin α5β1.
Treatment with L-type amino acid transporter 1 inhibitor JPH203 enhances protein synthesis in C2C12 myotubes.
Immune suppression in MTAP-deficient cancers via glutamate metabolism and CXCL10 downregulation.
Spatial multi-omics guides ASCT2-targeted delivery of glycolysis inhibitor for cervical cancer suppression and chemoresistance reversal.
Metabolomic Profiling by UPLC-QTOF/MS Reveals Potential Biomarkers and Metabolic Alterations in Pediatric Septic Shock.
Prognostic modeling and immune infiltration analysis in hepatocellular carcinoma using glutathione metabolism-associated genes.

Ultrason Sonochem. 2025 Nov 14. pii: S1350-4177(25)00459-6. [Epub ahead of print]123 107680

Metabolic nanoblockers for synergistic cancer treatment through glutaminase inhibition and sonodynamic therapy.

Wen Zhao, Jintao Du, Yunxuan Song, Zilin Ma, Songyan Li, Yuhua Wei, Guiqiang Zhang.

  The immunotherapeutic potential of sonodynamic therapy (SDT) is hindered by tumor defense mechanisms driven by glutamine metabolism, including glutathione (GSH)-dependent redox homeostasis and an immunosuppressive tumor microenvironment (TME). To address these challenges, we herein developed metabolic nanoblockers (CBE@AM NPs) by encapsulating a glutamine metabolism inhibitor CB839 and a sonosensitizer chlorin e6 (Ce6) into melanin-inspired nanoparticles. The resulting nanoblockers triggered robust reactive oxygen species (ROS) production upon ultrasound irradiation, thereby destroying tumor cells and inducing immunogenic cell death (ICD). Concurrently, they inhibited the glutamine metabolism in the tumor, disrupting redox homeostasis and remodeling the immunosuppressive TME, thereby amplifying both SDT-generated oxidative stress and ICD-induced antitumor immunity. CBE@AM NPs demonstrated a potent tumor-inhibitory effect in tumor-bearing mice, highlighting their potential for immunometabolic reprogramming to enhance the therapeutic efficacy of SDT.

Keywords:  Glutamine metabolism; Immunosuppressive tumor microenvironment; Redox homeostasis; Sonodynamic therapy

DOI:  https://doi.org/10.1016/j.ultsonch.2025.107680
Arch Pharm Res. 2025 Nov 19.

Title: Resveratrol ameliorates liver fibrosis by inhibiting ATF4 to regulate glutamine metabolism in hepatic stellate cells.

Huiya Ying, Yixiao Wang, Dandan Zhu, Jun Xu, Xiangting Zhang, Hong Pan, Yuan Zeng, Xiao Wu, Weimin Cai, Ruoru Zhou, Ziqiang Xia, Fujun Yu.

  Resveratrol has been shown to mitigate liver fibrosis by inhibiting the activation of hepatic stellate cells (HSCs). However, the precise mechanisms remain incompletely understood. Resveratrol demonstrates therapeutic potential in alleviating liver fibrosis by promoting HSC ferroptosis through the dual regulation of endoplasmic reticulum stress (ERS) and glutamine metabolism, as shown by in vivo and in vitro investigations. In carbon tetrachloride (CCl4) induced fibrotic mice, resveratrol significantly attenuated liver injury, extracellular matrix (ECM) deposition, and collagen synthesis. Cellular experiments revealed its dose-dependent inhibition of HSC activation via glutathione (GSH) depletion, iron accumulation, and downregulation of GSH peroxidase 4 (GPX4), with ferroptosis inhibitor Ferrostatin-1 (Fer-1) reversing these effects. Mechanistically, resveratrol suppressed activating transcription factor 4 (ATF4) -mediated ERS signaling, subsequently reducing alanine-serine-cysteine transporter 2 (ASCT2) dependent glutamine uptake essential for GSH biosynthesis. Genetic manipulation experiments confirmed the central regulatory role of ATF4, whose overexpression counteracted resveratrol's effects, while ATF4 knockdown or Jumonji domain-containing protein D3 (JMJD3) inhibition epigenetically silenced ASCT2 transcription through enhanced trimethylation of histone H3 at lysine 27 (H3K27me3). These findings revealed a novel pathway by which resveratrol induces HSC ferroptosis through metabolic and epigenetic regulation, offering a multi-targeted strategy against hepatic fibrosis that bridges amino acid metabolism, redox homeostasis, and chromatin remodeling processes.

Keywords:  Endoplasmic reticulum stress; Ferroptosis; Glutamine metabolism; Hepatic stellate cells; Resveratrol

DOI:  https://doi.org/10.1007/s12272-025-01586-6
bioRxiv. 2025 Oct 04. pii: 2025.10.02.680066. [Epub ahead of print]

Glutamine-Dependent Slc25a39-Nrf2 Axis Couples Mitochondrial Dynamics with Metabolic Reprogramming to Establish Myogenic Commitment.

Brian Kelly, Chia-Hua Wu, Kaan I Eskut, Elizabeth McCauley, Sajina Dhungel, Samantha Pavlecic, Grace Bieghler, Jelena Perovanovic, Dean Tantin, Jakub Famulski, Jeramiah Smith, Chintan Kikani.

Myogenic commitment is a decisive and irreversible step in skeletal muscle regeneration, necessitating proliferating myoblasts to integrate metabolic cues with nuclear transcriptional programs. Among amino acids, glutamine is uniquely positioned to influence this transition by coupling energy production to macromolecule biosynthesis and epigenetic regulation. We reasoned that myoblasts must sense glutamine availability to ensure orderly progression toward commitment, and we tested this by examining the molecular consequences of acute glutamine withdrawal. We find that continued glutamine oxidation is required to sustain glycolysis, maintain mitochondrial fission, and preserve a redox balance that supports progression towards myogenic commitment. In its absence, myoblasts undergo a reductive shift, characterized by mitochondrial elongation, membrane depolarization, and suppression of glycolysis, ultimately leading to growth arrest. Transcriptomic profiling reveals reduced MyoD and MKi67 , accompanied by increased Sprouty1 levels, defining a reversible non-proliferative state that resembles but is distinct from quiescent and reserve cells. We term this state Poised Metabolic Arrest (PMA), a cellular response to glutamine limitation during myogenic progression. Mechanistically, PMA is driven by Nrf2-dependent increased glutathione (GSH) biosynthesis and upregulation of mitochondrial GSH carrier Slc25a39 when glutamine is limited. Depleting mitochondrial glutathione or silencing Slc25a39 forces exit from PMA. However, this premature exit compromises subsequent differentiation potential, indicating PMA serves to preserve differentiation competence when glutamine is limited. Consistent with this, both loss and overexpression of Slc25a39 impair myoblast differentiation in vitro and disrupt regeneration in vivo. Together, these data suggest that a reciprocal Slc25a39-Nrf2 redox axis functions as a nutrient-dependent checkpoint, coupling glutamine availability to mitochondrial remodeling and metabolic reprogramming, necessary to establish irreversible myogenic commitment.

DOI: https://doi.org/10.1101/2025.10.02.680066
EMBO Rep. 2025 Nov 20.

FOXO1 links KRAS G12D and G12V alleles to glutamine and nitrogen metabolism in colorectal cancer.

Suzan Ber, Ming Yang, Marco Sciacovelli, Shamith Samarajiwa, Khushali Patel, Efterpi Nikitopoulou, Annie Howitt, Simon J Cook, Ashok R Venkitaraman, Christian Frezza, Alessandro Esposito.

  Mutations in KRAS, particularly at codon 12, are frequent in adenocarcinomas of the colon, lungs and pancreas, driving carcinogenesis by altering cell signalling and reprogramming metabolism. However, the specific mechanisms by which different KRAS G12 alleles initiate distinctive patterns of metabolic reprogramming are unclear. Using isogenic panels of colorectal cell lines harbouring the G12A, G12C, G12D and G12V heterozygous mutations and employing transcriptomics, metabolomics, and extensive biochemical validation, we characterise distinctive features of each allele. We demonstrate that cells harbouring the common G12D and G12V oncogenic mutations significantly alter glutamine metabolism and nitrogen recycling through FOXO1-mediated regulation compared to parental lines. Moreover, with a combination of small molecule inhibitors targeting glutamine and glutamate metabolism, we also identify a common vulnerability that eliminates mutant cells selectively. These results highlight a previously unreported mutant-specific effect of KRAS alleles on metabolism and signalling that could be potentially harnessed for cancer therapy.

Keywords:  Colorectal Cancer; FOXO Signalling; Glutamine Metabolism; Glutamine Synthase; KRAS Mutation

DOI:  https://doi.org/10.1038/s44319-025-00641-z
J Proteome Res. 2025 Nov 20.

Targeted Metabolomic Methods for 13C Stable Isotope Labeling with Uniformly Labeled Glucose and Glutamine Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

Erin Q Jennings, W Kimryn Rathmell, Jeffrey C Rathmell.

  Heavy carbon labeling has emerged as a popular way to study metabolic diseases. However, most carbon labeling techniques use untargeted mass spectrometry, which typically requires dependence on a research core and specialized software. By combining published 13C labeling patterns and known enzyme reactions, an optimized targeted mass spectrometry method was generated to measure stable isotope labeling with carbon-13 through glycolysis, the tricarboxylic acid cycle, the hexosamine biosynthetic pathway, and glutaminolysis using uniformly labeled glucose or glutamine. This method provides a novel and adaptable approach to investigate pointed hypotheses on the utilization of glucose or glutamine in disease states and models.

Keywords:  carbon tracing; stable isotope labeling; tandem mass spectrometry; targeted metabolomics

DOI:  https://doi.org/10.1021/acs.jproteome.5c00514
bioRxiv. 2025 Sep 29. pii: 2025.09.28.674326. [Epub ahead of print]

Glutamine antagonism suppresses tumor growth in adrenocortical carcinoma through inhibition of de novo nucleotide biosynthesis.

Vasileios Chortis, Kleiton Silva Borges, Cong-Hui Yao, Claudio Ribeiro, Luis Fernando Nagano, Mesut Berber, Alessandro Prete, Lukáš Najdekr, Michail E Klontzas, Andris Jankevics, Pedro Vendramini, Jean Lucas Kremer, Liam Kelley, Sathuwarman Raveenthiraraj, Stylianos Tsagarakis, Magdalena Macech, Ivana D Pupovac, Thomas G Papathomas, Betul Haykir, Catherine Winder, Marcus Quinkler, M Conall Dennedy, Grethe Å Ueland, Felix Beuschlein, Antoine Tabarin, Martin Fassnacht, Angela E Taylor, Darko Kastelan, Urszula Ambroziak, Dimitra A Vassiliadi, Katja Kiseljak-Vassiliades, Irina Bancos, Diana L Carlone, Warwick B Dunn, Wiebke Arlt, Marcia C Haigis, David T Breault.

Dysregulation of cellular metabolism is a hallmark of cancer, which remains poorly understood in adrenocortical carcinoma (ACC). Here, we dissected ACC metabolism by integrating transcriptional profiling from human and mouse ACC, targeted tissue metabolomics from a mouse ACC model, and untargeted serum metabolomics from a large patient cohort, providing cross-species validation of metabolic rewiring in ACC. This study revealed global metabolic dysregulation, involving glutamine-dependent pathways such as non-essential amino-acid and hexosamine biosynthesis, nucleotide metabolism, and glutathione biosynthesis, suggesting glutamine catabolism is a critical metabolic vulnerability in ACC. Treatment with glutamine antagonists 6-Diazo-5-Oxo-L-Norleucine (DON) and JHU-083 elicited robust anti-tumor responses. Mechanistic studies revealed DON's anti-tumor effect was primarily driven by selective inhibition of glutamine-fueled de novo nucleotide biosynthesis. Additionally, DON led to DNA damage, which yielded potent synergism with inhibition of the DNA damage response pathway. Collectively, this work highlights glutamine metabolism as a central metabolic dependency and therapeutic target in ACC.

DOI: https://doi.org/10.1101/2025.09.28.674326
Life Sci Alliance. 2026 Feb;pii: e202503434. [Epub ahead of print]9(2):

Müller cell glutamine metabolism links photoreceptor and endothelial injury in diabetic retinopathy.

Katia Corano Scheri, Yi-Wen Hsieh, Thomas Tedeschi, James B Hurley, Amani A Fawzi.

We characterized the timeline of molecular dysfunction in diabetic retinopathy (DR) and diabetic retinal disease (DRD) by studying the streptozotocin (STZ)-induced mouse retina over the course of 6 mo of diabetes. We performed bulk RNA-Seq on endothelial and retinal cells, separately, at 1, 3, and 6 mo of diabetes and single-cell RNA-Seq (scRNA-Seq) at 3 months. Transcriptomics changes were validated by in vitro and ex vivo assays and immunohistochemistry of mouse and human tissue. Bulk RNA-Seq revealed inflammation in endothelial cells at 1 mo. At 3 mo, scRNA-Seq identified glutamine-driven anaplerotic dysfunction in Müller cells, confirmed by retinal culture. We posited this glutamine deficiency would impact the photoreceptors and endothelial cells. We validated this hypothesis using endothelial cells in vitro, and immunohistochemistry of disrupted photoreceptor ribbon synapses in mouse and human diabetic retinas. In addition, glutamine deprivation increased the expression of apoptotic genes in endothelial cells. At 6 mo, we observed significant down-regulation of angiogenic pathways and elevated profibrotic markers. Our results suggest that dysfunction of the metabolic ecosystem linking the Müller-photoreceptor-endothelial cells is central to the early stages of DRD pathogenesis, impacting photoreceptor synapses and endothelial cells, before the appearance of the classic microvascular features of DR.

DOI: https://doi.org/10.26508/lsa.202503434
Cell Metab. 2025 Nov 17. pii: S1550-4131(25)00444-9. [Epub ahead of print]

Intestinal clock shapes sleep-wake cycle via sustaining glutamine homeostasis.

Lianxia Guo, Yifei Xiao, Zanjin Li, Yuwei Huang, Haobin Cen, Zicong Wu, Hongbo Wang, Xinyu Liu, Zhehan Yang, Caifeng Zhao, Tingying Hao, Hui Chen, Meng Jin, Danyi Lu, Min Chen, Baojian Wu.

  The intestinal clock plays a role in transmitting feeding signals and generating circadian events, but how this clock system may time homeostatic processes related to sleep-wake regulation is unknown. Our functional dissections of the circadian clock in intestinal epithelial cells (IECs) demonstrate that its integrity is required for maintenance of the diurnal sleep-wake cycle. In IECs, BMAL1 generates diurnal rhythmic SLC6A19 expression that promotes intestinal absorption of glutamine during the active phase, which enhances glutamatergic neuron activities in hypothalamic nuclei and contributes to increased wakefulness and decreased sleep. The involvement of glutamine homeostasis in sleep-wake regulation is also pronounced during the rest phase, as an elevation of glutamine in the rest phase caused by IEC deficiency of REV-ERBα is causally linked to sleep abnormalities characterized by reduced sleep. Overall, the intestinal clock shapes the diurnal sleep-wake cycle through temporally gating glutamine homeostasis and serves as a potential target for boosting the sleep rhythm and for managing sleep disorders.

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

DOI:  https://doi.org/10.1016/j.cmet.2025.10.010
J Neurochem. 2025 Nov;169(11): e70304

Metabolic Flexibility of Microglia: Energy Substrate Utilization and Impact on Neuronal Metabolism.

Emil W Westi, Rebecca Birch Carlsen, Jens Velde Andersen, Zeliha Kilic, Dana Alnajar, Nadia K Holmgaard, Belén García Sintes, Agustin Cota-Coronado, Sonia Sanz Muñoz, Céline Galvagnion, Blanca I Aldana.

  Microglia, the main resident immune cells of the brain, play critical roles in maintaining neuronal function and homeostasis. Microglia's metabolic flexibility enables rapid adaptation to environmental changes, yet the full extent of their metabolic capabilities and influence on neuronal metabolism remains unclear. While microglia predominantly rely on glucose oxidative metabolism under homeostatic conditions, they shift towards glycolysis upon proinflammatory activation. In this study, we investigated microglial metabolism and its impact on neuronal metabolic homeostasis using isotope tracing with stable carbon 13C-enriched substrates and gas chromatography-mass spectrometry (GC-MS) analysis. Primary microglia were incubated with 13C-labeled glucose, glutamine, or GABA in the presence or absence of lipopolysaccharide (LPS) to assess metabolic adaptations upon an inflammatory challenge. Additionally, neurons co-cultured with quiescent or activated microglia (either with LPS or amyloid-β) were incubated with 13C-enriched glucose to examine microglia-neuron metabolic interactions. Our findings confirm that microglia readily metabolize glucose and glutamine, with LPS stimulation slightly changing the glycolytic activity, as indicated by subtle changes in extracellular lactate. Importantly, we demonstrate for the first time that microglia take up and metabolize the inhibitory neurotransmitter GABA, suggesting a novel metabolic function. Furthermore, microglial presence directly influences neuronal metabolism and neurotransmitter homeostasis, highlighting a previously unrecognized aspect of neuron-microglia metabolic crosstalk. Collectively, these findings provide new insights into microglial metabolism and its role in neuronal function, with implications for neuroinflammatory and neurodegenerative diseases in which microglial metabolism is dysregulated.

Keywords:  GABA metabolism; amyloid‐beta; glutamine; metabolic flexibility; neuroimmune interactions; neurons

DOI:  https://doi.org/10.1111/jnc.70304
J Transl Med. 2025 Nov 18. 23(1): 1314

Recent progress in immune evasion mechanisms of triple-negative breast cancer.

Yiyan Yang, Weidong Wang.

  Significant progress has been made in understanding the complex immune evasion mechanisms of triple-negative breast cancer (TNBC), paving the way for more effective immunotherapies. This review highlights key advances in elucidating the molecular basis of TNBC immune escape, including aberrant immune checkpoint expression, metabolic reprogramming, epigenetic regulation, immune evasion by associated cellular components, and clinical trials of emerging immunotherapies. Specifically, overexpression of immune checkpoint inhibitors such as PD-L1 on TNBC cells and within the tumor microenvironment (TME) plays a critical role in suppressing antitumor immunity. Secondly, TNBC cells evade immune surveillance through metabolic reprogramming. For instance, upregulated glutamine metabolism supports tumor growth and modulates the TME toward immunosuppression by limiting nutrient availability to immune cells. Competitive consumption of amino acids such as tryptophan and arginine further compromises immune cell function, promoting immune escape. Epigenetic modifications, including DNA methylation and histone modifications, are increasingly recognized as key contributors to immune evasion in TNBC. These mechanisms can silence genes involved in antigen presentation and immune activation while promoting the expression of immunosuppressive factors. Long non-coding RNAs (lncRNAs) have been identified as central regulators of immune evasion in TNBC, offering new therapeutic targets for intervention. Moreover, TNBC actively shapes its microenvironment to establish immunosuppression, including recruitment of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2-polarized macrophages, which collectively inhibit effector T cell function. Building on these mechanistic insights, this review also integrates findings from clinical trials evaluating next-generation immunotherapies, including bispecific antibodies targeting PD-1/CTLA-4, LAG-3 inhibitors, and CD47-SIRPα blockers, as well as potential biomarkers. These novel combination strategies aim to overcome resistance to single-agent checkpoint inhibitors, while research explores monoclonal antibodies, bispecific antibodies, and antibody-drug conjugates (ADCs) within biomarker-driven personalized treatment frameworks. The ultimate goal is to improve survival and quality of life for TNBC patients through tailored immunotherapies.

Keywords:  Immune evasion; Immunosuppression; Immunotherapy; Triple negative breast cancer; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-025-07370-w
Exp Eye Res. 2025 Nov 14. pii: S0014-4835(25)00525-1. [Epub ahead of print]262 110752

Metabolic pathways involved in retinal angiogenesis: Molecular mechanisms and therapeutic targets.

Min Zhao, Hui-Min Zhu, Yu-Kun Zhou, Zheng Nie, Yong-Xuan Liu, Meng-Zhu Wang, Wen Zhou, Rui Zhang, Wei Shen.

  Cell metabolism represents a promising and novel therapeutic target for pathological retinal angiogenesis. Cellular metabolic regulatory networks comprise six core synergistic pathways-the glucose, lipid, amino acid, nucleotide, heme, and vitamin D metabolism axes-and disbalances between these can cause various abnormalities and pathogenic conditions, including retinal angiogenesis in blinding retinal disorders. With regard to glucose metabolism, glucose transporters supply substrates, while rate-limiting enzymes regulate glycolytic flow, adenosine triphosphate generation, redox balance, and the supply of nucleotide precursors. Both the transporters and enzymes have a synergistic influence on endothelium-dependent angiogenesis. Lipid metabolism provides dual regulatory targets in retinal angiogenesis via the fatty acid β-oxidation pathway driven by carnitine palmitoyltransferase-1α and the de novo lipid synthesis pathway mediated by fatty acid synthase. In the context of amino acid metabolism, the focus is mainly on the glutamine and arginine metabolism axes. Glutamine regulates retinal angiogenesis through a dynamic balance of anabolism/catabolism that involves amino acid transporters, glutaminase, and glutamine synthetase, while arginine metabolism inhibits pathological retinal neovascularization through the arginase-1 and endothelial nitric oxide synthase signaling pathways. The nucleotide synthesis pathway regulates pyrimidine metabolic flow through key enzymes such as carbamoyl phosphate synthetase II, which maintains tip cell differentiation through dynamic regulation of Notch signaling. Finally, the heme oxygenase-1/carbon monoxide metabolism axis and vitamin D receptor signaling have recently been shown to have unique roles in retinal angiogenesis. This review highlights the main facets of these six metabolic pathways involved in retinal angiogenesis and addresses the potential of targeting them to develop novel therapy for pathological retinal angiogenesis.

Keywords:  Epigenetic-metabolic coupling; Metabolic checkpoint; Metabolic reprogramming; Retinal angiogenesis

DOI:  https://doi.org/10.1016/j.exer.2025.110752
Crit Rev Oncol Hematol. 2025 Nov 13. pii: S1040-8428(25)00405-6. [Epub ahead of print]217 105017

Telomere maintenance meets cancer metabolism: Mechanistic insights and clinical opportunities.

Ji-Yong Sung, Kihwan Hwang.

  Telomere maintenance and metabolic reprogramming are two fundamental and interdependent hallmarks of cancer. While telomerase reactivation or the alternative lengthening of telomeres (ALT) enables cancer cells to evade replicative senescence, metabolic rewiring sustains the bioenergetic and biosynthetic demands of uncontrolled proliferation. Emerging evidence indicates a dynamic bidirectional relationship between telomere dynamics and metabolism, influenced by the tumor microenvironment (TME), inflammatory stress, and hypoxia. This review provides a comprehensive, cancer-type-specific analysis of telomere-metabolism crosstalk across glioblastoma, hepatocellular carcinoma, colorectal cancer, breast and prostate cancers, gastric cancer, and hematologic malignancies. We highlight the distinct metabolic phenotypes associated with telomerase activation or ALT engagement and examine how these pathways converge on mitochondrial function, redox balance, and chromatin remodeling. Furthermore, we discuss emerging therapeutic strategies, including the development of telomerase inhibitors, metabolic modulators (e.g., glutaminase and fatty acid synthesis inhibitors), and combination regimens currently in clinical trials. Novel biomarker-based approaches for patient stratification-such as TERT promoter mutations, ALT activity signatures, and metabolomic flux-are also explored. Understanding the intricate interplay between telomere maintenance and metabolism offers a promising axis for next-generation precision oncology.

Keywords:  Alternative lengthening of telomeres (ALT); Metabolic reprogramming; Telomerase (hTERT); Telomere maintenance; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.critrevonc.2025.105017
Biochem Biophys Res Commun. 2025 Nov 19. pii: S0006-291X(25)01721-8. [Epub ahead of print]793 153005

Fibulin7 C-terminal bioactive peptide regulates metabolic profiling of macrophages during inflammation via integrin α5β1.

Saloni Gupta, Shubham Kumar Rai, Rama N Behera, Saikat Roy, Kiran Ambatipudi, Pranita P Sarangi.

  Inflammation can trigger metabolic changes in monocytes and macrophages. Previous studies have shown that a C-terminal fragment of the adhesion protein Fibulin7 (Fbln7-C) and its bioactive peptide (FC-10) can regulate their migration and inflammatory functions of monocytes and macrophages via integrin α5β1, which is associated with the modulation of metabolic pathways in pathological conditions. This study investigates the possible correlation between FC-10-integrin α5β1-mediated cellular and immuno-metabolic programming in macrophages under inflammation. Our results show that FC-10 promoted the anti-inflammatory state in THP-1 and blood monocyte-derived macrophages stimulated with Lipopolysaccharide (LPS), with higher expression of M2 markers (e.g., CD206, IL-10). Further, liquid chromatography coupled tandem mass spectrometry LC-MS/MS based proteomics, metabolomics, and gene expression studies showed a reduced expression of inflammatory, differentiation, and glycolytic proteins (hexokinase and pyruvate kinase). Conversely, expression of the TCA cycle (citrate synthase) and glutamine metabolism proteins (Glutamate Dehydrogenase (GDH1) and SLC1A5) were elevated in the presence of FC-10, depicting an anti-inflammatory phenotype, compared to the control peptide. Furthermore, blocking integrin α5β1 increased the expression of glycolytic proteins (hexokinase) and decreased the glutamine-metabolism-associated proteins (GDH1). In conclusion, our data suggest that FC-10 can regulate metabolic processes in monocytes and macrophages during inflammation and has potential for anti-inflammatory therapeutics.

Keywords:  FC-10; Inflammation; Integrins; Macrophages; Metabolism

DOI:  https://doi.org/10.1016/j.bbrc.2025.153005
Sci Rep. 2025 Nov 19. 15(1): 40805

Treatment with L-type amino acid transporter 1 inhibitor JPH203 enhances protein synthesis in C2C12 myotubes.

Junya Takegaki, Takaoki Saneyasu, Kazuhisa Honda.

  Excessive muscle protein synthesis causes skeletal muscle hypertrophy. Essential amino acids are substrates for muscle proteins and stimulate muscle protein synthesis. Several essential amino acids are taken up into muscle cells through L-type amino acid transporter 1 (LAT1). However, LAT1 may influence protein synthesis in an amino acid uptake-independent manner. Here, we investigated the effects of LAT1 inhibition on protein synthesis in C2C12 myotubes and the associated mechanisms. JPH203 (50 μM), a selective inhibitor of LAT1, stimulated protein synthesis without changing expression of phosphorylated p70S6K (T389) and 4EBP1 (T37/46), an indicator of mTORC1 activity. Culturing in amino acid-free media did not suppress JPH203-induced protein synthesis. The mTORC1 inhibitor rapamycin (100 nM) did not suppress JPH203-induced protein synthesis. ATP-competitive mTOR inhibitor AZD8055 (1 μM) suppressed JPH203-induced protein synthesis. JPH203 treatment increased intracellular glutamine concentration. These results suggest that inhibition of LAT1 function augments muscle protein synthesis, possibly through the activation of rapamycin-insensitive mTOR signaling; elevated intracellular glutamine levels may contribute to the enhancement of muscle protein synthesis induced by LAT1 inhibition.

Keywords:  L-type amino acid transporter 1; Leucine; Mechanistic target of rapamycin; Muscle protein synthesis; Myotubes

DOI:  https://doi.org/10.1038/s41598-025-24534-2
Front Immunol. 2025 ;16 1634342

Immune suppression in MTAP-deficient cancers via glutamate metabolism and CXCL10 downregulation.

Wen-Hsin Chang, Jun Zhang, Qi-Sheng Hong, Ching-Hsien Chen.

   Background: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy; however, their efficacy remains limited in certain tumor subtypes, including those deficient in methylthioadenosine phosphorylase (MTAP). MTAP-deficient cancers are characterized by immunosuppressive tumor microenvironments (TMEs) and poor T cell infiltration, as suggested by large-scale transcriptomic analyses. Yet, the underlying mechanisms and therapeutic vulnerabilities remain poorly defined.
Methods: We employed murine tumor models and transcriptomic profiling to investigate the immunosuppressive features of MTAP-deficient tumors. To identify actionable vulnerabilities, we conducted a high-throughput screen using the LOPAC1280 compound library. Functional assays were performed to evaluate the effects of candidate compounds on tumor growth and immune signaling.
Results: MTAP-deficient tumors exhibited significantly reduced CD45+ immune cell infiltration and resistance to ICI therapy. Transcriptomic analyses revealed that MTAP-deficient cancer cells reprogram immune signaling pathways and suppress the expression of CXCL10, a key chemokine for T cell recruitment, thereby contributing to a non-inflamed, "cold" TME. High-throughput screening revealed an increased dependence on glutamate metabolism in MTAP-deficient cells. Several glutamate pathway inhibitors, including the clinically tested glutaminase inhibitor CB-839, selectively impaired their growth. Remarkably, CB-839 also restored CXCL10 expression, particularly under immune co-culture conditions, indicating a dual effect of direct cytotoxicity and immune activation.
Conclusion: These findings uncover a novel link between glutamate metabolism and immune modulation in MTAP-deficient tumors. Our study provides mechanistic and preclinical support for targeting glutamate pathways to both suppress tumor growth and convert immune-cold tumors into more immunoresponsive states, offering a promising strategy to enhance ICI efficacy in this challenging cancer subtype.

Keywords:  CXCL10; MTAP deficiency; glutamate metabolism; immunosuppression; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1634342
J Adv Res. 2025 Nov 16. pii: S2090-1232(25)00931-2. [Epub ahead of print]

Spatial multi-omics guides ASCT2-targeted delivery of glycolysis inhibitor for cervical cancer suppression and chemoresistance reversal.

Xiaojiao Li, Xiangchuan Qin, Xiejun Zhao, Yufeng Liu, Ling Wang, Kefeng Li, Jinqiu Li, Jia Ma, Liangliang Dai, Ayshamgul Hasim.

   INTRODUCTION: Cervical carcinoma (CC) mortality remains high due to chemoresistance. Targeting glycolytic reprogramming is promising since CC cells depend on enhanced glycolysis for proliferation and chemoresistance. However, clinical translation faces two barriers: the lack of spatially resolved validation of glycolytic vulnerability in CC specimens, and absence of CC-specific delivery systems for lonidamine (LND), a potent glycolytic inhibitor with poor bioavailability and hepatotoxicity.
OBJECTIVES: Here, we aim to establish spatially resolved validation of tumor-associated glycolytic reprogramming and identify differentially enriched receptors within malignant regions in clinical CC specimens. Leveraging these findings, we will design a tumor-targeted nanoplatform for the precise delivery of a glycolytic inhibitor to CC cells, to achieve tumor suppression and reverse chemoresistance.
METHODS: Spatial metabolomics and spatial transcriptomics analyses were employed to validate tumor-associated glycolytic reprogramming and identify specifically overexpressed receptors within malignant regions of clinical CC specimens.
RESULTS: Through spatial multi-omics analysis, we demonstrated upregulated glycolysis in malignant regions of CC and identified solute carrier family 1 member 5 (ASCT2), a glutamine transporter, as a superior CC-specific surface marker compared to the pan-cancer nanocarrier targets like CD44. These findings were corroborated through multi-platform validation spanning single-cell RNA-seq dataset, TCGA cohorts, paired patient specimens, matched murine samples, and multiple CC cell lines. In this context, we designed a glutamine-functionalized liposomal system that exploits ASCT2 overexpression to enable CC-selective accumulation of LND. Our findings reveal that this nanoagonist significantly impedes CC growth by disrupting ATP supply and inducing ROS-mediated cellular damage. Moreover, this nanoagonist effectively reverses cisplatin (DDP)-induced chemoresistance in CC by inhibiting MRP2-mediated DDP efflux and blocking ribose-5-phosphate-mediated DNA repair.
CONCLUSION: By integrating spatial multi-omics with rational nanocarrier design, we designed a glutamine-functionalized liposomal system that exploits ASCT2 overexpression for tumor-selective accumulation of LND. Our findings revealed that this nanoagonist achieves significant CC suppression and chemoresistance reversal.

Keywords:  ASCT2; Cervical Cancer; Chemoresistance Reversal; Glycolysis; HKⅡ; Spatial multi-omics analysis

DOI:  https://doi.org/10.1016/j.jare.2025.11.035
J Inflamm Res. 2025 ;18 15645-15655

Metabolomic Profiling by UPLC-QTOF/MS Reveals Potential Biomarkers and Metabolic Alterations in Pediatric Septic Shock.

Changxue Xiao, Chenhao Wang, Sa Wang, Feng Xu, Yingfu Chen.

   Purpose: Septic shock is a major cause of mortality in pediatric intensive care units (PICU). This study aimed to investigate metabolic alterations in PICU patients with septic shock using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) to identify potential biomarkers and unique metabolic pathways for early diagnosis and improved treatment strategies.
Patients and Methods: Serum and urine samples from septic shock survivors (SS), septic shock non-survivors (SNS), and non-infected systemic inflammatory response syndrome (SIRS) patients were analyzed using UPLC-QTOF/MS. All differential metabolites from serum samples were subjected to multiple regression analysis. Bioinformatics analysis was conducted on metabolite data obtained from urine and serum samples of the SS and SNS groups to further investigate differences in metabolic pathways.
Results: Combinational metabolites demonstrated superior diagnostic performance compared with individual metabolites, with an area under the receiver operating characteristic curve (AUC) of 0.925 for SS vs SIRS and 0.901 for SNS vs SIRS. Key metabolic pathways, including glycerophospholipid metabolism, arginine and proline metabolism, were implicated in the development of septic shock. Importantly, alterations in glutamine and glutamate metabolism were associated with survival, suggesting the significant potential for further investigation.
Conclusion: Metabolomic profiling using UPLC-QTOF/MS represents a promising approach for early diagnosis of pediatric septic shock. The identified biomarkers and metabolic pathways provide insights into the pathogenic mechanisms and may assist in the development of targeted therapeutic strategies. Further validation in larger, prospective cohorts is required before clinical application.

Keywords:  biomarker; metabolic pathways; metabolomics; pediatric; septic shock

DOI:  https://doi.org/10.2147/JIR.S551775
Eur J Med Res. 2025 Nov 19. 30(1): 1141

Prognostic modeling and immune infiltration analysis in hepatocellular carcinoma using glutathione metabolism-associated genes.

Fuqiang Ma, LiLi, Ziyi Xu, Yingda Xie, Yanpin Ma, Penghui Li.

   BACKGROUND: Glutathione (GSH) plays a central role in multiple physiological processes, including the maintenance of intracellular redox homeostasis and the detoxification of xenobiotics. While previous studies have linked GSH metabolism to the pathogenesis and treatment of hepatocellular carcinoma (HCC), systematic analysis of the expression profiles of GSH metabolism-related genes in HCC and their consistent correlation with patient prognosis remains insufficiently addressed.
METHODS: In this study, the ribonucleic acid sequencing (RNA-seq) data and clinical information data of HCC were downloaded from public databases. Following Cox regression and consensus clustering analyses, three GSH metabolism-related subtypes with differential survival probability and immune infiltration status were identified in patients with HCC. Next, CDCA8, KIF20A, TRNP1, and ADH4 were chosen to establish a prognostic model.
RESULTS: Compared with those in the low-risk group, patients with high-risk scores exhibited poor survival probability, higher immune scores, decreased benefit from immunotherapy and poor drug sensitivity.
CONCLUSIONS: In summary, this study established a prognostic risk model for HCC based on GSH metabolism-related genes, which could predict the prognosis and characterize immune infiltration status of HCC. This study may contribute to the identification of potential prognostic targets and the development of new clinical management strategies for HCC.

Keywords:  Glutathione metabolism; Hepatocellular carcinoma; Immune infiltration; Prognostic model

DOI:  https://doi.org/10.1186/s40001-025-03403-8