bims-glucam 2026-11-08 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–11–08
twelve papers selected by
Sreeparna Banerjee, Middle East Technical University

TTK Promotes Hepatic Fibrosis Through PKM2/H3T11-Mediated GLS1-Dependent Glutamine Catabolism.
Glutaminolysis inhibition boosts cuproptosis to eliminate breast cancer stem cells.
Impact of Autoclaving and Long-Term Storage on Bacterially Available Glutamine Sources in Complex Media.
Correction to: Glutamine Metabolism: a Metabolic Hub Linking Vascular Remodeling and Plaque Stability in Atherosclerosis.
Hepatocyte IRE1α-XBP1s axis prevents pro-metastatic niche formation through metabolic rewiring of inflammatory monocytes.
Hepatic Stellate Cells: Fibrogenic Effectors to Central Regulators of Metabolism, Liver Disease Signaling, and Systemic Crosstalk.
Folding without glutamine: Proteome-scale removal of a canonical amino acid.
18F-FGln PET/CT Imaging of Glutamine Uptake Has Potential for Predicting Immunotherapy Response in Hepatocellular Carcinoma.
Orchestrating Tumor-Immune Interface and Microenvironment Remodeling via a Tumor-Preferential DNA Nano-Regulator for Metabolic-Immunotherapy.
Exercise-induced metabolic reprogramming in lung cancer and its translational implications for therapeutic advancement.
Extracellular Matrix Stiffness Regulates Mechanical-Metabolic Coupling in Tumors: Mechanisms and Therapeutic Opportunities.
SLC25A1/CIC supports osteoclastogenesis by coordinating mitochondrial bioenergetics and redox homeostasis.

Liver Int. 2026 Dec;pii: e70893. [Epub ahead of print]46(12):

TTK Promotes Hepatic Fibrosis Through PKM2/H3T11-Mediated GLS1-Dependent Glutamine Catabolism.

Linying Lai, Zeyu Wang, Jianbin Zhang, Shiyi Chang, Jieru Chen, Cheng Guo, Jiangfeng Hu, Lingnan He, Bensong Duan.

   BACKGROUND: Hepatic fibrosis represents a critical pathological process associated with substantial morbidity and mortality. Despite significant advances in understanding fibrogenesis, the molecular mechanisms driving fibrosis progression remain incompletely defined, and effective anti-fibrotic therapies are still limited. This study aims to investigate the role of threonine tyrosine kinase (TTK) in hepatic fibrosis and uncover the underlying mechanisms involved.
METHODS: Murine fibrosis models, HSC-specific TTK knockout mice, and TTK inhibitors were employed to investigate the role of TTK in hepatic fibrosis. Fibrosis was evaluated by histological and biochemical assessments. Mix1 homeobox-like 1 (MIXL1) was screened from RNA-seq analysis and analysed by dual-luciferase reporter assay. Mass spectrometry and Co-immunoprecipitation identified TTK binding proteins. Metabolomics analysis and Seahorse analyser were performed to characterize glutamate metabolism and ATP production in HSC.
RESULTS: TTK expression was elevated in patients with fibrosis and in CCl4-and TAA-induced fibrosis models. TTK silencing attenuated liver fibrosis in vitro and in vivo. Whereas TTK overexpression markedly exacerbated TGFβ-induced fibrotic responses. Mechanistic investigations revealed TTK modulated glutamine catabolism in HSC. TTK inhibition impaired the integration of glutamate into the tricarboxylic acid cycle, thereby reducing ATP production required for HSC activation. Specifically, TTK upregulated transcription factor MIXL1 and transcriptionally activated GLS1, which was ultimately involved in HSC glutamine catabolism. Furthermore, TTK-phosphorylated PKM2 translocated into the nucleus and phosphorylated histone H3 at threonine 11 (H3T11), facilitating MIXL1-mediated transcriptional activation of GLS1.
CONCLUSIONS: These findings revealed a novel mechanism underlying the upregulation of GLS1 mediated by transcriptional control and highlighted TTK as a critical metabolic regulator in HSC activation and hepatic fibrosis.

Keywords:  H3T11; glutaminase 1 (GLS1); glutamine metabolism; hepatic fibrosis; pyruvate kinase isozyme type M2 (PKM2); threonine tyrosine kinase (TTK)

DOI:  https://doi.org/10.1111/liv.70893
Acta Pharm Sin B. 2026 Nov;16(11): 7614-7630

Glutaminolysis inhibition boosts cuproptosis to eliminate breast cancer stem cells.

Zitao Fan, Shiyou Li, Chen Xiao, Qiang Wang, Zhijie Zhang, Ao Hua, Qingqing Xu, Tian Yang, Jiayuan Li, Yue Pan, Baizhu Chen, Xiangliang Yang, Zhenwei Zou, Zifu Li.

  The metabolic plasticity of cancer stem cells (CSCs) enables them to adaptively switch between glycolysis, oxidative phosphorylation, and alternative fuels such as glutamine and fatty acids, promoting tumorigenesis and progression by ensuring survival under diverse environmental stresses. However, current therapeutic approaches targeting CSCs remain limited, particularly those relying on single metabolic interventions. By leveraging concurrent metabolic modulation and redox disruption to sensitize CSCs to cuproptosis, we prepared a polydopamine/hydroxyethyl starch-based nanoplatform (CH@PHF) for co-delivering copper-diethyldithiocarbamate (CuET) and HYL001. Specifically, HYL001 suppresses glutaminase (GLS) activity, thereby blocking glutamine metabolism and inhibiting glutathione (GSH) biosynthesis. This effect synergizes with CuET to collectively amplify oxidative stress in CSCs. Furthermore, the combination of HYL001 and CuET significantly elevates intracellular copper levels, particularly the cuprous form (Cu+), thereby sensitizing CSCs to cuproptosis. This combined treatment effectively inhibits tumor growth and metastasis by targeting and eradicating breast cancer stem cells (BCSCs), offering a promising avenue for tumor therapy.

Keywords:  Cancer stem cells; Cancer therapy; Cuproptosis; Glutaminolysis; Hydroxyethyl starch; Metabolic therapy; Nano drug delivery system; Redox

DOI:  https://doi.org/10.1016/j.apsb.2026.06.008
Microbiol Immunol. 2026 Nov 03.

Impact of Autoclaving and Long-Term Storage on Bacterially Available Glutamine Sources in Complex Media.

Koichiro Yamada, Kazuya Ishikawa, Kazuyuki Furuta, Shin-Ichi Miyoshi, Makoto Tsunoda, Chikara Kaito.

  Free glutamine is unstable in aqueous solution and rapidly degrades at elevated temperatures. In complex microbiological media, glutamine may exist in free and peptide-bound forms; however, how autoclaving and prolonged storage affect bacterially available glutamine sources remains unclear. Here, we used an Escherichia coli glutamine synthetase-deficient mutant (ΔglnA) as a biological indicator to assess glutamine availability in complex media. The ΔglnA mutant exhibited reduced but detectable growth in autoclaved LB compared with non-autoclaved LB, indicating the presence of both heat-labile and heat-stable glutamine sources. Prolonged storage of autoclaved LB at room temperature further reduced ΔglnA growth. Brain heart infusion, tryptic soy broth, and M17 contained both heat-labile and heat-stable glutamine sources, whereas Mueller-Hinton broth (MHB) and nutrient broth contained neither. Furthermore, supplementation of MHB, which appeared to lack bacterially available glutamine sources, with glutamine resulted in a greater reduction in viable Staphylococcus aureus cells in the presence of gentamicin than gentamicin treatment alone. These findings demonstrate that medium processing, storage, and composition influence the availability of glutamine sources and can affect bacterial growth and antibiotic susceptibility.

Keywords:  Escherichia coli; autoclaving; complex medium; glutamine; long‐term storage

DOI:  https://doi.org/10.1111/1348-0421.70103
Curr Atheroscler Rep. 2026 Nov 05. pii: 110. [Epub ahead of print]28(1):

Correction to: Glutamine Metabolism: a Metabolic Hub Linking Vascular Remodeling and Plaque Stability in Atherosclerosis.

Jiangqin Wang, Jingwen Wang, Jie Tian, Peng Gao.

DOI: https://doi.org/10.1007/s11883-026-01479-z
Nat Commun. 2026 11 03. pii: 10961. [Epub ahead of print]17(1):

Hepatocyte IRE1α-XBP1s axis prevents pro-metastatic niche formation through metabolic rewiring of inflammatory monocytes.

Haiyan Zhang, Peibin Liang, Wei Yang, Xiaocong Chen, Yizhen Fu, Chonghao Chen, Zeren Yin, Xiaolin Li, Xin Pei, Josh Haipeng Lei, Xiangpeng Chu, Zhi-Bin Zhao, Hai Hu, Minshan Chen, Hong Pan, Zhe-Xiong Lian, Xiaofan Ding, Nils Halberg, Grant A Ramm, Jiajie Hou.

Inositol-requiring enzyme 1α (IRE1α) and the downstream spliced form of X-Box Binding Protein 1 (XBP1s) have been identified as tumor promotors. However, how IRE1α-XBP1s signaling affects tumor progression in a non-cell autonomous manner remains unclear. Here we show that the hepatocyte IRE1α-XBP1s axis unexpectedly inhibits liver metastasis by confining local metainflammation. Genetic ablation of IRE1α or XBP1 in mouse hepatocytes exacerbates liver metastasis due to the accumulation of inflammatory monocytes (IMs). Mechanistically, a non-canonical Forkhead box O1 (FoxO1)-glutamine synthetase (GS) pathway endows the IRE1α- or XBP1-null hepatocytes with the metabolic activity to secrete glutamine, which is necessary and sufficient for IM fitness. Reintroduction of hepatocyte XBP1s or blockade of glutamine metabolism effectively reduces IMs and mitigates disease progression. Importantly, clinical patient survival with liver metastases positively correlates with hepatocyte XBP1s expression. Our study defines a paradigm of hepatocyte-IM interaction that can be leveraged to treat liver metastasis.

DOI: https://doi.org/10.1038/s41467-026-78812-2
Gut Liver. 2026 Nov 02.

Hepatic Stellate Cells: Fibrogenic Effectors to Central Regulators of Metabolism, Liver Disease Signaling, and Systemic Crosstalk.

Xiang Li, Hao Chen, Wenguang Fu.

  Hepatic stellate cells (HSCs) have long been regarded as the core effector cells in liver fibrosis. The advent of single-cell omics and metabolomics has led to a paradigm shift in our understanding of these cells. Notably, they are not only implicated in local fibrosis but are being increasingly recognized as a hub integrating metabolic and immune signaling. Located at the interface between hepatic vasculature and parenchyma, HSCs have the capacity to modulate intestinal barrier function, neurotransmitter circulation, myocardial energy metabolism, and bone remodeling through metabolic reprogramming (enhanced glycolysis, vitamin A consumption, glutamine metabolism remodeling) and receptor signaling (TLR4, TGF-β, CXCR4, etc.), as well as by secreting metabolites, exosomal miRNAs, and cytokines. Concurrently, HSCs perceive feedback signals from these organs, forming a dynamic cross-organ feedback network. This review systematically integrates the metabolic characteristics of HSCs in diseases such as metabolic dysfunction-associated steatotic liver disease, alcohol-related liver disease, chronic viral hepatitis, and hepatocellular carcinoma, along with their cross-organ interactive effects. We further discuss intervention strategies targeting metabolic pathways, exosomal cargo, and the microbiota-metabolism axis, and propose a three-tier translational framework stratifying HSC-targeted therapeutic approaches by developmental stage, offering novel insights for shifting liver disease treatment from single antifibrotic approaches toward systemic, multi-organ precision interventions.

Keywords:  Fibrosis; Hepatic stellate cells; Metabolic reprogramming; MicroRNAs; Microbiota

DOI:  https://doi.org/10.5009/gnl260010
PLoS Comput Biol. 2026 Nov;22(11): e1014931

Folding without glutamine: Proteome-scale removal of a canonical amino acid.

Alejandro Garciarrubio, Blanca Ramos-Cerrillo, Enrique Morett, Lorenzo Segovia.

All known life uses a canonical alphabet of 20 amino acids, yet which residues are structurally essential remains untested at proteome scale. Isoleucine was recently eliminated from ribosomal proteins in Escherichia coli, establishing that amino acid alphabet reduction is feasible. Here we ask whether an entire amino acid can be eliminated from a proteome, and develop a computational framework to identify the best target. Using two independent approaches - ProteinMPNN structure-based probabilities and multiple sequence alignment conservation - we define "keep-score" as the fraction of positions where the native residue is optimal. Both methods converge on an unexpected candidate: glutamine has the lowest keep-score, with proline and glycine the highest - counter to substitution-matrix intuition. Glutamine's low keep-score is not explained by a single obvious substitute; glutamate is preferred in only 14% of replacements. Removing this target proteome-wide, we replaced every glutamine across 4,148 proteins with ProteinMPNN-optimal alternatives and modeled the resulting sequences with AlphaFold2. The recoded proteome maintained native-like structures: 85.5% of models exceeded a TMscore of 0.8, indistinguishable from the 85.9% baseline for rebuilt native sequences. Orthogonal validation - ESMFold predictions, Rosetta energy calculations, and conformational ensemble comparisons - revealed no evidence of systematic misfolding attributable to glutamine removal. As a consistency check, a glutamine-free TEM-1 β-lactamase designed with ProteinMPNN conferred ampicillin resistance in E. coli, indicating fold preservation can extend to biological function. Evolutionary evidence further supports these findings: 24% of E. coli proteins have glutamine-free orthologs in prokaryotic genomes, and glutamine ranks lowest in keep-score in Saccharomyces cerevisiae. These results show that an entire amino acid can be removed from a proteome with folds broadly preserved, establishing keep-score as a general framework and glutamine as the primary candidate for recoding. Crucially, this reflects a computational analysis of structural replaceability, not a demonstration of biological dispensability.

DOI: https://doi.org/10.1371/journal.pcbi.1014931
Adv Sci (Weinh). 2026 Nov 03. pii: e78622. [Epub ahead of print]

18F-FGln PET/CT Imaging of Glutamine Uptake Has Potential for Predicting Immunotherapy Response in Hepatocellular Carcinoma.

Yi Liu, Jindian Li, Xiaoyu Pan, Xiaoping Xu, Xuan Huang, Simin He, Jianping Zhang, Fei Liu, Shaoli Song.

  We investigated whether glutamine (Gln) uptake, imaged by 18F-(2S,4R)-4-fluoroglutamine (18F-FGln) PET/CT, could predict and modulate immunotherapy response in hepatocellular carcinoma (HCC). Analysis of the Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma (LIHC) dataset revealed that SLC1A5 expression-which encodes a primary Gln uptake channel in HCC cells-was significantly associated with poor prognosis, higher tumor grade, and an immunosuppressive tumor microenvironment. In murine HCC models, tumors with high 18F-FGln uptake exhibited elevated Slc1a5 expression and poor response to anti-PD-1 therapy, whereas low-uptake tumors were more sensitive to immunotherapy. Genetic knockdown of Slc1a5 reduced 18F-FGln uptake, enhanced anti-PD-1 efficacy, increased cytotoxic T lymphocyte infiltration, and decreased regulatory T cell abundance. Transcriptomic and single-cell analyses revealed activation of antitumor immune pathways and reprogramming toward an immune-inflamed phenotype after Slc1a5 suppression. V-9302 decreased tumor Gln uptake, as measured by 18F-FGln PET/CT, and sensitized HCC to PD-1 blockade. In patient-derived organoid-T cell co-culture systems, low-SLC1A5 organoids were susceptible to PD-1 blockade, whereas high-SLC1A5 organoids were resistant, consistent with 18F-FGln PET/CT findings. These results identify Gln uptake as a checkpoint of immune evasion in HCC and support that 18F-FGln PET/CT has the potential to predict and monitor immunotherapy response.

Keywords:  18F‐FGln PET/CT; glutamine uptake; hepatocellular carcinoma; immunotherapy

DOI:  https://doi.org/10.1002/advs.78622
Angew Chem Int Ed Engl. 2026 Nov 05. pii: e9465567. [Epub ahead of print]

Orchestrating Tumor-Immune Interface and Microenvironment Remodeling via a Tumor-Preferential DNA Nano-Regulator for Metabolic-Immunotherapy.

Chao-Qiang Li, Wen-Jia Shi, Yi-Shan Liu, Hua-Dong Li, Yan Zhang, Bin-Cheng Yin, Pei-Qiang Ma, Bang-Ce Ye.

  Metabolic reprogramming in malignant cells drives tumor progression and impairs immunotherapy efficacy, highlighting the urgent need for synergistic metabolic-immunotherapy. However, the pharmacokinetic disparity and systemic toxicities pose significant challenges on this synergy. We develop a tumor-preferential, multifunctional DNA nano-regulator assembled on a DNA origami-based framework with two functional layers for the integration of immune cues and metabolic modulation at the tumor-immune interface. The inner layer is precisely functionalized with anti-CD3/CD28/PD-L1 antibodies and glutamine synthetase, enabling in situ T-cell engagement, PD-L1 blockade, and metabolic environment improvement. The outer layer combines albumin-binding domains with pH-responsive i-motif switches to form a pH-sensitive albumin coating in vivo, which shields the inner antibodies during systemic circulation and specifically exposes them within the tumoral acidic microenvironment. In the xenograft and syngeneic mouse models, the regulator-mediated broad remodeling of the intratumoral immune and metabolic landscapes results in enhanced T‑cell infiltration and activation, potent tumor-growth suppression, and a favorable safety profile. This study combines metabolic intervention with immunotherapy by integrating the synergism and tumor preference of therapies.

Keywords:  DNA origami; glutamine metabolism; metabolic immunotherapy; nano‐regulator; tumor‐immune interface

DOI:  https://doi.org/10.1002/anie.9465567
J Transl Med. 2026 Aug 06. pii: 1389. [Epub ahead of print]24(1):

Exercise-induced metabolic reprogramming in lung cancer and its translational implications for therapeutic advancement.

Yonghua Zheng, Yisheng Chen, Hanyang Zhao, Guanghui Wu, Chen Hua, Fu Gao, Yue Liu, Lei Jiang, Lihua Dai.

  Lung cancer remains one of the leading causes of cancer-related mortality worldwide, characterized by profound metabolic reprogramming that sustains malignant growth, immune evasion, and therapeutic resistance. Aberrant activation of glycolysis, increased fatty acid synthesis and uptake, and dysregulated glutamine metabolism provide energy and biosynthetic substrates while reshaping the tumor microenvironment through lactate accumulation, acidosis, and angiogenic signaling. Experimental and clinical evidence indicates that exercise may modulate aspects of these oncogenic metabolic pathways, enhance mitochondrial oxidative capacity, improve oxygen delivery, and restore systemic metabolic homeostasis. By modulating glycolytic flux, lipid turnover, and amino acid metabolism, exercise exerts comprehensive effects on both tumor cells and the host, alleviating cancer-associated cachexia, improving insulin sensitivity, and suppressing systemic inflammation. Exercise may also enhance immune competence and vascular function, thereby potentially promoting antitumor surveillance and supporting the therapeutic response.Integrated with conventional treatments such as chemotherapy, radiotherapy, and immunotherapy, exercise may serve as a non-pharmacological metabolic adjuvant that increases treatment tolerance, mitigates adverse effects, and improves quality of life. Furthermore, exercise-related metabolic, molecular, and physiological biomarkers, including glucose and lipid indices, insulin sensitivity parameters, irisin, cardiopulmonary performance indicators, and serum glycosylation profiles, offer promising tools for evaluating metabolic states and guiding personalized interventions. Collectively, these findings underscore exercise as a powerful modulator of tumor and host metabolism, aligning with the translational paradigm that bridges mechanistic discovery and clinical application. Future research should focus on defining standardized exercise prescriptions, validating predictive biomarkers, and elucidating subtype-specific responses to facilitate the integration of precision exercise therapy into lung cancer management.

Keywords:  Exercise therapy; Fatty acid metabolism; Glycolysis; Lung cancer; Metabolic reprogramming; Translational medicine; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-026-08665-2
Technol Cancer Res Treat. 2026 Jan-Dec;25:25 15330338261500555

Extracellular Matrix Stiffness Regulates Mechanical-Metabolic Coupling in Tumors: Mechanisms and Therapeutic Opportunities.

Xiaolin Liu, Yingjie Wang, Fei Qi, Xiaomi Li, Peng Jiang, Yixuan Wang, Sen Li, Tongmei Zhang.

  The extracellular matrix (ECM) stiffening in the tumor microenvironment (TME) is an important physical characteristic of solid tumors and can serve as an active signaling hub that regulates the biological behavior of tumors. Abnormal deposition, cross-linking, and remodeling of collagen not only alter the mechanical properties and structure of tissues but also convert mechanical stimuli into intracellular signals through mechanosensitive ion channels such as integrin-FAK, Hippo-YAP/TAZ, Piezo1/2, and Transient receptor potential vanilloid subtype 4 (TRPV4), thereby reprogramming tumor cell metabolism, including enhancing the Warburg effect, lipid synthesis, and glutamine catabolism, forming a malignant cycle of "matrix stiffening - metabolic reprogramming" that promotes tumor progression and treatment tolerance. Mechanical signals can also create an immunosuppressive TME by restricting CD8+ T-cell infiltration and promoting tumor-associated macrophage polarization toward an M2-like state. Metabolites generated by reprogrammed cells, including lactate, can further remodel and stiffen the ECM, creating a positive-feedback loop. Genetic and epigenetic heterogeneity, hypoxia, nutrient availability, and oncogenic signaling may uncouple mechanical regulation from metabolic output and complicate therapeutic targeting. Non-coding RNAs (ncRNAs) add a regulatory layer that may connect mechanotransduction with metabolic plasticity and immune remodeling, although their effects remain context dependent. This review integrates the existing evidence on the regulation of tumor metabolism and immune microenvironment by ECM mechanical signals, focuses on summarizing the key mechanical sensing pathways, feedback mechanisms, and therapeutic targets, and proposes research directions for precisely identifying key regulatory nodes of the mechanical-metabolic axis by combining spatial omics, metabolic flux analysis, and mechanical imaging techniques, providing a conceptual framework for developing novel therapeutic strategies targeting the biomechanical processes of tumors.

Keywords:  Matrix stiffness; immunotherapy; metabolic reprogramming; signal pathway; tumor microenvironment

DOI:  https://doi.org/10.1177/15330338261500555
Cell Death Differ. 2026 Nov 06.

SLC25A1/CIC supports osteoclastogenesis by coordinating mitochondrial bioenergetics and redox homeostasis.

Chen Tu, Meng-Xuan Dai, Zhi-Wei Huang, Yi Tang, Si-Qi Lai, Jie Zhang, Shi-Yong Le, Min-Ye He, Wen-Sheng Zhang, Jia-Wen Gao, Liang Wang.

Osteoclastogenesis requires precise coordination between mitochondrial bioenergetics and anabolic programs, yet the underlying mechanisms remain unclear. Here, we identify the mitochondrial citrate carrier (CIC, encoded by SLC25A1) as a crucial link that couples mitochondrial bioenergetics to glutathione (GSH)-dependent redox regulation during osteoclastogenesis. CIC expression was elevated in the osteoclast-lineage cells from postmenopausal osteoporosis (PMOP) patients and ovariectomized (OVX) mice, and was positively correlated with classical osteoclast markers. During osteoclastogenesis, CIC was progressively upregulated. Pharmacologic inhibition of CIC with CTPI-2 not only suppressed osteoclastogenesis but also disrupted core metabolic processes, including tricarboxylic acid cycle engagement, amino acid biosynthesis, and mitochondrial respiration. Integrative transcriptomic and metabolomic profiling further revealed a compensatory shift toward enhanced GSH synthesis. Mechanistically, CIC associated with the glutamate-cysteine ligase modifier subunit (GCLM), linking mitochondrial metabolic regulation to the GSH synthetic machinery. CIC inhibition increased GCL activity, intracellular GSH content, and the GSH/GSSG ratio, accompanied by reduced reactive oxygen species accumulation. The functional importance of the GSH axis was evident, as GCL inhibition by buthionine sulfoximine partially reversed the anti-osteoclastogenic effects of CIC inhibition. Consistently, osteoclast-targeted silencing of CIC in OVX mice mitigated bone loss. Collectively, these findings support a role for CIC as a metabolic integrator of energy and redox metabolism in osteoclasts, and highlight its potential as a candidate target for limiting excessive bone resorption in PMOP.

DOI: https://doi.org/10.1038/s41418-026-01903-6