bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2026–04–26
twenty-one papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Targeting glutamine metabolism to modulate macrophage functions in the tumor microenvironment.
  2. [Glutamine metabolic reprogramming in regulating the occurrence and development of osteosarcoma].
  3. SPC25 promotes gastric cancer cells G1/S cell cycle transition and tumorigenesis by enhancing SLC1A5-mediated glutamine metabolism.
  4. NAT10 promotes lung cancer progression by enhancing glutamine metabolism through increasing ac4C modification on NIT2.
  5. E3 ubiquitin ligase RBX1 inhibits glutamine metabolism and attenuates cardiomyocyte hypertrophy.
  6. A Deep-Red-Absorbing Osmium(II)-Based Photosensitizer Evokes Pyroptosis by Targeting Glutamine Metabolism and Impairing Cell Redox Homeostasis.
  7. A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.
  8. TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis.
  9. Integration of a glutamine metabolism-based prognostic signature and a synergistic nanotherapeutic strategy targeting metabolic vulnerabilities in prostate cancer.
  10. Polyploid cancer cells surviving cisplatin reallocate central carbon sources to fuel antioxidant metabolism for survival.
  11. Significance of SLC1A5 expression in head and neck squamous cell carcinoma: A bioinformatics and in-vitro analysis.
  12. Mitochondrial inhibition enhances the sensitivity of pancreatic ductal adenocarcinoma cells to oncolytic adenovirus.
  13. Glutamine metabolic stress induces SLC25A6-dependent mitofission via MIC60-MIC19 complex disassembly in colorectal cancer.
  14. Glutaminase-mediated glutamate metabolism is critical for maintaining Th17/Treg balance.
  15. Stress Tested: Aging Rewires Tumors for Metastatic Spread Through Activation of the Integrated Stress Response.
  16. B cell deficiency limits exercise capacity by remodeling liver glutamate metabolism.
  17. Amino Acid Metabolism in Chronic Liver Disease: from Pathogenic Driver to Therapeutic Target.
  18. GLUL deficiency causes sperm acrosome defects and male infertility via influencing redox balance in mice.
  19. GLS1 governs vascular smooth muscle cell phenotypic switching and aortic dissection via glutamate metabolism.
  20. The role of dietary components in upper gastrointestinal cancers: A narrative review.
  21. Brain imaging as a prognostic biomarker in urea cycle disorders.
  1. Discov Oncol. 2026 Apr 24.
    Targeting glutamine metabolism to modulate macrophage functions in the tumor microenvironment.
    Shuyan Wu, Yuwei Peng, Qian Wang, Zhaorong Li, Kewei Ge, Lihong Ye.
      
    Keywords:  Cancer therapy; Glutamine metabolism; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s12672-026-04999-x
  2. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2025 Dec 28. pii: 1672-7347(2025)12-2425-13. [Epub ahead of print]50(12): 2425-2437
    [Glutamine metabolic reprogramming in regulating the occurrence and development of osteosarcoma].
    Yaxuan Xu, Xinyu Zhao, Yuyu Gao, Yujun Lian, Yingchun He, Huai Tao.
      Excessive cellular proliferation and metabolic reprogramming are important characteristics of cancer cells. Cancer cells promote excessive proliferation and growth by altering coordinated metabolic pathways. In terms of glucose metabolism, most cancer cells exhibit increased glucose uptake and lactate production even under aerobic conditions, known as the Warburg effect. Increased glucose uptake not only provides energy but also supplies essential carbon sources for the biosynthesis of nucleotides, lipids, and proteins. During this process, decreased pyruvate dehydrogenase activity leads to disruption of the tricarboxylic acid cycle (TCA), thereby increasing tumor cell dependence on other nutrients. In addition to glucose, glutamine (Gln) is also a key metabolic substrate required for cancer cell growth and proliferation. It provides both carbon and nitrogen sources to support the synthesis of ribose, non-essential amino acids, citrate, and glycerol, and compensates for the reduced oxidative phosphorylation caused by the Warburg effect. In human plasma, Gln is one of the most abundant amino acids. Normal cells synthesize Gln through glutaminase (GLS), but the Gln synthesized by tumor cells is insufficient to meet the demands of rapid proliferation, resulting in "Gln dependence". Most cancers, including osteosarcoma, show significantly increased demand for Gln. Metabolic reprogramming enables tumor cells to gain survival advantages in maintaining redox homeostasis and biosynthesis while forming unique metabolic phenotypes. Focusing on key enzymes and transporters involved in Gln metabolism in osteosarcoma and identifying potential targets may provide new ideas and directions for drug development.
    Keywords:  amino acid transporters; glutaminase; glutamine metabolism; metabolic reprogramming; osteosarcoma
    DOI:  https://doi.org/10.11817/j.issn.1672-7347.2025.250321
  3. J Bioenerg Biomembr. 2026 Apr 20. pii: 8. [Epub ahead of print]58(1):
    SPC25 promotes gastric cancer cells G1/S cell cycle transition and tumorigenesis by enhancing SLC1A5-mediated glutamine metabolism.
    Xinqi Yao, Jie Wu, Yu Song, Hao Shen.
      
    Keywords:  IGF2BP2; SLC1A5; SPC25; gastric cancer; glutamine metabolism; m6A
    DOI:  https://doi.org/10.1007/s10863-026-10108-y
  4. Mol Immunol. 2026 Apr 23. pii: S0161-5890(26)00088-X. [Epub ahead of print]194 104-113
    NAT10 promotes lung cancer progression by enhancing glutamine metabolism through increasing ac4C modification on NIT2.
    Dafu Yang, Yue Zhu, Yang Liu, Zhaoxia Dai.
      Glutamine metabolism plays a critical role in lung cancer progression due to its substantial contribution to energy supply. NAT10 is currently the only known ac4C transferase and regulates gene expression and mRNA stability through ac4C modification, thereby influencing tumor progression. This study aimed to investigate the mechanisms by which NAT10 mediates glutamine metabolism in lung cancer. The UALCAN database was used to perform pan-cancer analysis and assess NAT10 expression in lung cancer. Cell viability, proliferation, and migration were evaluated to characterize malignant behaviors in lung cancer cells. Glutamine metabolism was assessed by measuring glutamine consumption, as well as α-ketoglutarate (α-KG) and ATP production. NAT10-associated genes were identified from the GSE3141 dataset and subjected to pathway enrichment analysis. The underlying mechanism was explored using methylated RNA immunoprecipitation and dual-luciferase reporter assays. The role of NAT10 in lung cancer progression in vivo was assessed using a xenograft model. Results showed that NAT10 was upregulated in lung cancer cells and promoted cell viability, proliferation, migration, and glutamine metabolism in A549 and H460 cells, whereas NAT10 inhibition reversed these effects. Mechanistically, NAT10 enhanced ac4C modification of NIT2 and increased NIT2 mRNA stability. Overexpression of NIT2 restored cell viability, proliferation, migration, and glutamine metabolism that were suppressed by NAT10 knockdown in A549 and H460 cells. Furthermore, inhibition of NAT10 reduced tumor growth and glutamine metabolism in nude mice. Collectively, our findings demonstrate that NAT10 promotes glutamine metabolism in lung cancer by enhancing ac4C modification of NIT2, providing new insights into the mechanisms underlying lung cancer progression.
    Keywords:  Ac4C; Glutamine metabolism; Lung cancer; NAT10; NIT2
    DOI:  https://doi.org/10.1016/j.molimm.2026.04.010
  5. Int Immunopharmacol. 2026 Apr 17. pii: S1567-5769(26)00499-6. [Epub ahead of print]180 116654
    E3 ubiquitin ligase RBX1 inhibits glutamine metabolism and attenuates cardiomyocyte hypertrophy.
    Yu-Ting Yang, Zheng Xu, Yao Yao, Yan Gong, Jun Shao.
      Cardiac hypertrophy is an independent risk factor for cardiovascular disease, and with the progress of research, metabolic reprogramming has been recognized as a key mechanism in the development of several cardiac diseases. Recently, increased glutamine metabolism has been found to be strongly associated with cardiomyocyte hypertrophy, but the exact mechanism has not been elucidated. Our investigation confirmed that inhibition of glutamine metabolism reversed cardiomyocyte hypertrophy and that this metabolic alteration was associated with c-Myc. Meanwhile, the role of ubiquitination modification in maintaining protein homeostasis and cardiac function has been a hot research topic, we found that the E3 ubiquitin ligase RBX1 was significantly decreased in cardiomyocyte hypertrophy model and was accompanied by an increase in c-Myc mediated glutamine metabolism. However, RBX1 did not bind directly to c-Myc. Subsequently, we found that RBX1 interacts with the transcription factor FoxO1 by prediction, and the latter showed elevated protein expression without significant changes in mRNA levels in the cardiac hypertrophy model, suggesting a post-translational modification process. We found that RBX1 plays a protective role in cardiomyocyte hypertrophy by degrading FoxO1 through ubiquitination and thereby affecting c-Myc mediated glutamine metabolism. Collectively, these findings suggest that strategies based on inhibition of the RBX1/FoxO1 axis may hold promise for the treatment of cardiomyocyte hypertrophy.
    Keywords:  Cardiomyocyte hypertrophy; FoxO1; Glutamine metabolism; RBX1; Ubiquitination
    DOI:  https://doi.org/10.1016/j.intimp.2026.116654
  6. J Am Chem Soc. 2026 Apr 21.
    A Deep-Red-Absorbing Osmium(II)-Based Photosensitizer Evokes Pyroptosis by Targeting Glutamine Metabolism and Impairing Cell Redox Homeostasis.
    Yiyi Zhang, Zhimei Xiao, James W Southwell, Ruonan Gao, Bruno Saubaméa, Morgane Moinard, Philippe Arnoux, Céline Frochot, Pierre Mesdom, Gilles Gasser.
      Pyroptosis plays an emerging role in cancer immunotherapy, however, most currently known compounds that activate this cell death mechanism were discovered serendipitously. Here, we report a pyroptosis-inducing strategy that works through metabolic reprogramming of cancer cells to enhance antitumor immunity. Specifically, an osmium-based photosensitizer (Os) was covalently attached to a small-molecule glutamine carrier protein inhibitor (IMD-0354), to construct the conjugate Os-IMD. This conjugate significantly enhanced the photosensitizer's uptake into cancer cells via the glutamine metabolic pathway, inhibited glutamine uptake, and promoted mitochondrial targeting. As a result, upon light irradiation, Os-IMD induced mitochondrial damage and impaired electron transport chain function as well as intracellular redox homeostasis, leading to a switch in the mode of cell death from the apoptosis typically observed with Os to gasdermin D (GSDMD)-mediated pyroptosis. Our study offers a new avenue for the development of scalable pyroptosis-inducing agents.
    DOI:  https://doi.org/10.1021/jacs.6c04446
  7. Cell Rep Med. 2026 Apr 23. pii: S2666-3791(26)00187-4. [Epub ahead of print] 102770
    A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.
    Omid Hajihassani, Asael Roichman, Jacob A Boyer, Michal MacArthur, Ricardo Cordova, Alexander Loftus, Christina S Boutros, Jonathan J Hue, Parnian Naji, Soubhi Tahhan, Peter Gallagher, William Beegan, Danyal Shah, James Choi, Nimat Manzoor, Shihong Lei, Christine Kim, Moeez Rathore, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Craig Hunter, Mehrdad Zarei, Sydney Alibeckoff, Karen Ji, Hallie Graor, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengraber, Rui Wang, Peder J Lund, Luke D Rothermel, Joshua D Rabinowitz, Jordan M Winter.
      Pancreatic cancer is the third leading cause of cancer-related death in the United States. Current chemotherapy options provide limited benefits. Emerging evidence suggests that a ketogenic diet (KD) exerts anti-tumor effects by reprogramming tumor metabolism and revealing therapeutic vulnerabilities. Efforts to target glutamine metabolism-an essential pathway in many cancers-have shown promise in preclinical models, but clinical efficacy has remained limited. Here, we show that a KD increases tricarboxylic acid (TCA) cycle activity and elevates reliance on glutamine-related metabolites in murine pancreatic cancer models and in vitro under KD-mimicking conditions. This metabolic adaptation occurs in response to reduced glucose availability. We demonstrate that combining glutamine metabolism inhibitors, such as CB-839 or 6-diazo-5-oxo-L-norleucine (DON), with a KD leads to robust anti-tumor effects in preclinical models of pancreatic cancer. Thus, metabolic vulnerability induced by dietary intervention provides a rationale for combining glutamine-targeted therapies with a ketogenic diet in future clinical studies.
    Keywords:  PDAC nutrient flux; chemotherapy; combination therapy; glutamine metabolism; glutamine tracing; ketogenic diet; ketogenic diet media; pancreatic cancer; targeted therapy
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102770
  8. JCI Insight. 2026 Apr 23. pii: e199449. [Epub ahead of print]
    TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis.
    Fei Li, Niv Vigder, David R Ziehr, Mari Kamiya, Hung N Nguyen, Diana E Ferreyra Faustino, Aseel H Khalil, Hilaire C Lam, Matthew L Steinhauser, Edy Y Kim, William M Oldham.
      Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease driven by aberrant fibroblast-to-myofibroblast differentiation, which requires metabolic reprogramming. Here, we identify alanine as an essential metabolite for myofibroblast differentiation. Transforming growth factor-β1 (TGF-β) increases intracellular alanine levels through enhanced synthesis and import in both normal and IPF lung fibroblasts. Alanine synthesis is primarily mediated by glutamate-pyruvate transaminase 2 (GPT2), whose expression is regulated by the glutamine-glutamate-α-ketoglutarate axis. Inhibition of GPT2 depletes alanine and suppresses TGF-β-induced α-SMA and COL1A1 expression, which are rescued by exogenous alanine. We also identify solute carrier family 38 member 2 (SLC38A2) as a transporter for both alanine and glutamine, upregulated by TGF-β or alanine deprivation. SLC38A2 and GPT2 form a coordinated regulatory axis sustaining intracellular alanine levels to support myofibroblast differentiation. Mechanistically, alanine deficiency impairs glycolytic flux and depletes tricarboxylic acid cycle intermediates, while alanine supplementation provides carbon and nitrogen for intracellular glutamate and proline biosynthesis, particularly under glutamine deprivation. Combined inhibition of alanine synthesis and uptake suppresses fibrogenic responses in fibroblasts and human precision-cut lung slices, highlighting dual metabolic targeting as a potential therapeutic strategy for fibrotic lung disease. .
    Keywords:  Amino acid metabolism; Cell biology; Fibrosis; Metabolism; Metabolomics; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.199449
  9. Discov Oncol. 2026 Apr 18.
    Integration of a glutamine metabolism-based prognostic signature and a synergistic nanotherapeutic strategy targeting metabolic vulnerabilities in prostate cancer.
    Wenya Li, Weiying Ge, Wenjie Ni, Hao Zhang, Yangyang Guo, Yuxin Xie, Zhen Zhou, Yiming Li, Zhe Zheng, Jianmin Li, Yang Zhao.
      
    Keywords:  ASNS; Cisplatin; Glutamine metabolism; Nanomedicine; Prognostic signature; Prostate cancer
    DOI:  https://doi.org/10.1007/s12672-026-04969-3
  10. Mol Metab. 2026 Apr 18. pii: S2212-8778(26)00054-2. [Epub ahead of print] 102370
    Polyploid cancer cells surviving cisplatin reallocate central carbon sources to fuel antioxidant metabolism for survival.
    Melvin Li, Bradley Priem, Luke V Loftus, Michael J Betenbaugh, Kenneth J Pienta, Sarah R Amend.
      Therapy resistance is the leading cause of cancer-related deaths. Polyploid cancer cells mediate resistance through adaptive cell states transitions that promote survival and tumor recurrence. Here, we investigate metabolic differences between cisplatin-surviving polyploid cells and parental cancer cells using integrated fluxomics. Transcriptomic and proteomic profiling and extracellular flux analyses revealed that surviving cells upregulate glycolysis and gluconeogenesis while reducing oxidative phosphorylation, indicating a shift in central carbon metabolism. Isotope tracing and metabolic modeling demonstrate that surviving cells utilize glucose to fuel the pentose phosphate pathway (PPP) for NADPH generation and metabolize glutamine to provide carbons for the PPP via gluconeogenesis. Integrating our multi-omic datasets into a genome-scale model identified that surviving cells sustain antioxidant metabolism by decreasing fluxes of other NADPH-consuming reactions upon in silico PPP knockout. In addition, pathway-centric transcriptomic analysis revealed that high PPP and antioxidant gene expression correlated with poor survival outcomes in patients across multiple cancer types, demonstrating the clinical prognostic value of PPP and antioxidant metabolism. These findings reveal a systems-level shift in metabolism that maintains antioxidant activity for cell survival, highlighting potential targets and treatment paradigms to overcome therapy resistance.
    Keywords:  (13)C-metabolic flux analysis; Cancer metabolism; Chemotherapy resistance; Genome scale metabolic modeling; Integrated fluxomics
    DOI:  https://doi.org/10.1016/j.molmet.2026.102370
  11. J Oral Biol Craniofac Res. 2026 May-Jun;16(3):16(3): 101448
    Significance of SLC1A5 expression in head and neck squamous cell carcinoma: A bioinformatics and in-vitro analysis.
    S Kaarunya, Palati Sinduja, Monal Yuwanati, Senthilmurugan Mullainathan.
       Introduction: Head and Neck Squamous Cell Carcinoma (HNSCC) is associated with high mortality due to tumor proliferation and metastasis. Altered function of metabolic transporters such as glutamine transporter SLC1A5 in tumor cells and their microenvironment plays a crucial role in proliferation and metastasis. The aim of this study was to assess the expression of SLC1A5 in HNSCC and evaluate its prognostic significance using computational analysis.
    Materials and methods: SLC1A5 expression in tumor and normal tissue was analyzed followed by computational prognosis analysis in The Cancer Genome Atlas (TCGA)-HNSCC cohort. Survival analyses were performed using Kaplan-Meier analysis. Differences between the groups were statistically evaluated using the log-rank test, and hazard ratios (HR) with 95% confidence intervals (CI) were calculated. SLC1A5 expression was validated on separate HNSCC tumor and normal tissue samples using qPCR.
    Results: Differential expression studies showed that SLC1A5 was significantly overexpressed in HNSCC tumors as compared to normal tissues in TCGA cohort, which was confirmed with qPCR analysis in separate HNSCC cohort (p < 0.05). High SLC1A5 was associated with low overall survival in TCGA cohort. While STRING analysis does not confer great significance to prognosis, it accentuates SLC1A5 as a hub in amino acid metabolism and tumor progression pathways in HNSC.
    Conclusion: The overexpression of SLC1A5 is linked with unfavorable survival in HNSCC, highlighting its value to the metabolic reprogramming in HNSCC.
    Keywords:  Epigenetics; Glutamine metabolism; Head and neck cancer; Neoplasm; Prognostic marker; SLC1A5
    DOI:  https://doi.org/10.1016/j.jobcr.2026.101448
  12. Mol Ther Oncol. 2026 Jun 18. 34(2): 201180
    Mitochondrial inhibition enhances the sensitivity of pancreatic ductal adenocarcinoma cells to oncolytic adenovirus.
    Ryohei Shoji, Hiroshi Tazawa, Shinji Kuroda, Takeyoshi Nishiyama, Yoshinori Kajiwara, Motohiko Yamada, Yasuo Nagai, Hiroaki Inoue, Naoyuki Hashimoto, Satoru Kikuchi, Ryuichi Yoshida, Yuzo Umeda, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara.
      The metabolism of cancer cells is associated with resistance to anticancer therapies. Pancreatic ductal adenocarcinoma (PDAC) cells exhibit glycolytic and non-glycolytic subtypes. Although oncolytic virotherapy is a novel antitumor modality, the relationship between metabolism and virus sensitivity remains unclear. We demonstrated the cytopathic activity of telomerase-specific, replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 against PDAC cells. Here, we show the role of metabolism in the virus sensitivity of PDAC cells. The virus sensitivity of human PDAC cells of glycolytic (MIA PaCa-2, PK-45H) and non-glycolytic (PK-59, Capan-2) subtypes was assessed by evaluating replication, glycolysis, and glutamine metabolism through exposure to hypoxia and glucose deprivation or treatment with the mitochondrial metabolism inhibitor CPI-613. Glycolytic PDAC cells were sensitive, and non-glycolytic cells were resistant to oncolytic adenoviruses, which was improved by hypoxia and glucose deprivation or CPI-613 treatment to induce glycolytic activation. OBP-702-mediated p53 activation modulated glutamine metabolism to promote virus sensitivity. In vivo experiments demonstrated the antitumor efficacy of combination therapy with CPI-613 and OBP-702, and the utility of positron emission tomography/computed tomography metabolic parameters for assessing glycolytic activity. Our results suggest that non-glycolytic PDAC cells are refractory to oncolytic adenoviruses. CPI-613 is a promising reagent for overcoming virotherapy resistance in PDAC tumors.
    Keywords:  CPI-613; MT: Regular Issue; PET/CT; glycolysis; oncolytic virotherapy; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.omton.2026.201180
  13. Cell Death Dis. 2026 Apr 23.
    Glutamine metabolic stress induces SLC25A6-dependent mitofission via MIC60-MIC19 complex disassembly in colorectal cancer.
    Yinong Wang, Bingzhi Wang, Yu Liu, Cheng Zhou, Junhu Yuan, Fanyu Zhang, Ling Ma, Yiming Ma, Hongying Wang.
      Glutamine addiction is a key metabolic vulnerability in cancer. However, the mechanisms governing the limited efficacy of glutamine metabolism inhibitor (GMI) monotherapy require further investigation. Via single-cell monitoring using a caspase-3 activity indicator, we identified SLC25A6 as a key mediator of GMI-induced apoptosis in colorectal cancer cells. SLC25A6 overexpression enhanced apoptosis both in vitro and in vivo. SLC25A6 promoted mitochondrial fragmentation and dysfunction and upregulated the expression of mitochondrial fission markers. Notably, mitofission inhibitors largely abolished SLC25A6-related mitochondrial dysfunction and intrinsic apoptosis. Mechanistically, SLC25A6 directly interacted with MIC60, competitively inhibiting MIC19 binding; both MIC60 and MIC19 are key components of the mitochondrial contact site and cristae organizing system (MICOS). The SLC25A6 T126A mutant failed to bind MIC60 and lost its ability to destabilize the MICOS complex and facilitate mitofission. Upregulation of SLC25A6 expression induced by the glutaminase inhibitor CB-839 sensitized cancer cells to the Bcl-2 inhibitor ABT-199. Combined CB-839 and ABT-199 treatment showed strong synergistic antitumor effects in colorectal cancer xenograft models. Our findings reveal a novel function of SLC25A6 that links metabolic stress to mitochondrial apoptosis via disruption of the MICOS complex. Combination treatments with mitochondrial apoptotic inducers represent a promising avenue for maximizing the efficacy of GMIs in cancer treatment.
    DOI:  https://doi.org/10.1038/s41419-026-08754-6
  14. Cent Eur J Immunol. 2025 ;50(4): 341-352
    Glutaminase-mediated glutamate metabolism is critical for maintaining Th17/Treg balance.
    Xiaohan Jin, Jinglong Tao.
      Autoimmune diseases are severe disorders that affect populations worldwide. Their occurrence is considered to be multifactorial: genetic, hormonal and immunological factors all contribute to the development of autoimmune diseases. CD4 T cells differentiate into different subtypes, among which Th17 and Treg cells are the two most important in regulation of immune response balance. The Th17/Treg equilibrium is crucial in the pathogenesis of autoimmune diseases. Glutamate, an excitatory neurotransmitter in the nervous system, induces multiple effects. It activates normal T cells, enhancing cell adhesion, migration, secretion and gene expression. However, the effect of glutamate on T cell fate remains unclear. Here, we found that glutamate promotes Treg differentiation but suppresses Th17 differentiation. Further results showed that the rate-limiting enzyme of glutamate metabolism, glutaminase (GLS), is the key regulator for Treg cell generation. These findings suggest that GLS-mediated glutamate metabolism is critical for Treg cell differentiation, and may represent a potential therapeutic target for autoimmune disease.
    Keywords:  Th17; Treg; autoimmune; glutaminase; glutamine
    DOI:  https://doi.org/10.5114/ceji.2025.155429
  15. Cancer Res. 2026 Apr 21.
    Stress Tested: Aging Rewires Tumors for Metastatic Spread Through Activation of the Integrated Stress Response.
    Mitchell E Fane, Daniel J Zabransky.
      Aging is a major risk factor for cancer incidence and mortality, but its effect on tumor evolution and metastatic progression remains incompletely understood. A recent study by Patel and colleagues published in Nature reveals a paradoxical role for aging in cancer biology: while aging constrains primary tumor growth, it simultaneously enhances metastatic spread. Using genetically engineered mouse models and patient-derived data, the authors demonstrate that aging epigenetically reprograms mutant KRAS-driven lung adenocarcinoma through activation of the integrated stress response (ISR). Central to this process is the transcription factor ATF4, which promotes epithelial plasticity and metabolic adaptations, thereby enabling metastasis. This work provides a mechanistic framework linking host aging to tumor cell state transitions that favor distant spread of cancer cells. Importantly, it challenges a long-held assumption that tumor aggressiveness is primarily reflected by primary tumor growth kinetics and properties, and instead, it highlights metastasis as a distinct, age-influenced evolutionary trajectory. The identification of ATF4-driven ISR signaling as a mediator of metastasis highlights new therapeutic vulnerabilities, such as an acquired dependence on glutamine, particularly for older patients who comprise the majority of lung cancer cases. More broadly, this study underscores the need to incorporate aging biology into cancer models and therapeutic strategies, redefining how we conceptualize tumor progression across the lifespan.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1612
  16. Cell. 2026 Apr 17. pii: S0092-8674(26)00340-5. [Epub ahead of print]
    B cell deficiency limits exercise capacity by remodeling liver glutamate metabolism.
    Youxiang Mao, Ziyan Xia, Xu Pan, Wenjun Xia, Peng Jiang.
      B cells are an essential component of humoral immunity, and B cell depletion therapies have clinically succeeded in eliminating cancerous B cells and treating autoimmune diseases. Here, we report an immune-independent function of B cells that spatially and metabolically drives exercise capacity. During exercise, B cell deficiency reduces transforming growth factor (TGF)-β1 production, which alters hepatic glutamate metabolism and decreases blood and muscle glutamate. Mechanistically, B cell-derived TGF-β1 transcriptionally upregulates hepatic glutaminase 2 (GLS2) and solute carrier family 7 member 5 (SLC7A5) expression, increasing glutamine catabolism and thus glutamate production in the liver. The resulting increase in glutamate fosters skeletal muscle calcium oscillations, calmodulin-dependent protein kinase (CaMK) kinase activity, and mitochondrial biogenesis, thereby improving exercise performance. Thus, we identify a metabolite-driven liver-muscle connection that regulates exercise capacity, linking B cell function to skeletal muscle calcium signaling via alteration of hepatic glutamate metabolism.
    Keywords:  B cells; TGF-β1; exercise capacity; hepatic glutamate metabolism; immune-independent regulation; immunoexercise; skeletal muscle function; transforming growth factor
    DOI:  https://doi.org/10.1016/j.cell.2026.03.039
  17. Int J Biol Sci. 2026 ;22(7): 3544-3563
    Amino Acid Metabolism in Chronic Liver Disease: from Pathogenic Driver to Therapeutic Target.
    Yingchen Huang, Yao Jiang, Wenkai Ye, Xin Hu, Nuerbiye Abudurexiti, Jiarui Li, Chuang Li, Ronggao Chen, Xiao Xu.
      Amino acid metabolism is central to the liver's multifaceted physiology, serving as the cornerstone for protein homeostasis, metabolic integration, and tissue repair and regeneration. In addition, the dysregulation of amino acid metabolism is intricately linked to the pathogenesis and progression of a wide spectrum of liver diseases, acting as a central pathological driver beyond a passive metabolic consequence. In metabolic dysfunction-associated steatotic liver disease (MASLD), characteristic alterations in circulating branched-chain amino acids (BCAAs) and glycine levels directly promote hepatic steatosis, oxidative stress, and inflammation. The progression to hepatocellular carcinoma (HCC) is fueled by a profound metabolic reprogramming that creates a dependency on amino acids like glutamine and aspartate for energy and biomass, while methionine and tryptophan metabolism foster an immunosuppressive microenvironment and epigenetic dysregulation to facilitate immune evasion and tumor growth. Furthermore, in liver fibrosis and cirrhosis, metabolic adaptations support disease progression, whereas in hepatic encephalopathy, the hallmark imbalance between BCAAs and aromatic amino acids, coupled with ammonia neurotoxicity, disrupts neurotransmitter balance. These disease-specific alterations not only provide robust biomarkers for diagnosis and prognosis but, more importantly, reveal critical therapeutic vulnerabilities. Consequently, targeting amino acid metabolism emerges as a promising strategic avenue, encompassing dietary interventions, targeted supplementation, and pharmacological inhibition for the development of novel therapeutics across the landscape of liver diseases. This review aims to systematically expound on these dual physiological and pathological roles, arguing that such disease-specific metabolic alterations not only provide biomarkers but, more importantly, unveil targetable vulnerabilities, thereby positioning amino acid metabolism as a strategic frontier for developing novel therapeutics across liver diseases.
    Keywords:  HCC; MASLD/MASH; amino acid metabolism; chronic liver disease
    DOI:  https://doi.org/10.7150/ijbs.128644
  18. Free Radic Biol Med. 2026 Apr 21. pii: S0891-5849(26)00320-5. [Epub ahead of print]
    GLUL deficiency causes sperm acrosome defects and male infertility via influencing redox balance in mice.
    Mengyuan Lin, Yangkun Feng, Yun Zhang, Honghua Wang, Yan Wang, Ninghan Feng, Qingwen He.
      Glutamate-ammonia ligase (GLUL) catalyzes the syntheses of glutamine, as the antioxidant that has been shown to influence sperm quality in mammals. Research on the precise functions of the GLUL gene during spermatogenesis has been constrained by the structural complexity of the testis. In this study, we established a mouse model with postnatal, germ cell-specific deletion of GLUL. Conditional knockout (cKO) of GLUL led to reduced male fertility. Epididymal sperm from cKO mice exhibited acrosomal malformation, diminished acrosin activity, and redox imbalance. Moreover, GLUL deficiency was found to alter protein levels of Spam1 and Tssk3 in epididymal sperm. These functional deficits could be partially rescued by intraperitoneal glutathione (GSH) administration or by intracytoplasmic sperm injection (ICSI). Collectively, our results demonstrate that GLUL in germ cells is essential for combating oxidative stress during spermatogenesis in mice. These findings enhance the understanding of GLUL's role in male germ cell development and propose GSH supplementation as a potential therapeutic strategy for conditions associated with low acrosin activity.
    Keywords:  GLUL; GSH; ICSI; redox imbalance; reduced male fertility
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.030
  19. JCI Insight. 2026 Apr 23. pii: e203575. [Epub ahead of print]
    GLS1 governs vascular smooth muscle cell phenotypic switching and aortic dissection via glutamate metabolism.
    Wei Xie, Chen Ning, Chen Lu, Dongjin Wang, Shuang Zhao, Tianyu Song, Hailong Cao.
      Aortic dissection (AD) is a catastrophic vascular emergency with high mortality, and current pharmacologic interventions to prevent its progression are limited. Vascular smooth muscle cells (VSMCs) undergo a pathological phenotypic switch from a contractile to a synthetic state during AD, compromising aortic wall integrity; however, the underlying metabolic mechanisms remain poorly understood. In this study, we performed integrative transcriptomic analyses and identified glutaminase 1 (GLS1) as a key regulator of VSMC phenotypic switching in AD. GLS1 expression was significantly downregulated in VSMCs from both human AD aortic tissues and mouse models. Functionally, GLS1 deficiency promoted PDGF-BB-induced VSMC dedifferentiation in vitro. Smooth muscle cells specific Gls1 knockout (Gls1SMKO) mice exhibited aggravated AD upon BAPN treatment, whereas VSMCs specific GLS1 overexpression improved the contractile phenotype and reduced AD incidence. Mechanistically, GLS1 downregulation impaired glutamate metabolism, leading to reduced levels of glutathione and α-ketoglutarate. This metabolic disruption promoted reactive oxygen species accumulation and mitochondrial dysfunction, ultimately triggering VSMC phenotypic switching. Furthermore, we found that GLS1 transcription was repressed by retinoic acid receptor-α (RARα). Pharmacologic inhibition of RARα with AR7 restored GLS1 expression, ameliorated VSMC phenotypic switching, and conferred protection against AD. These findings reveal a critical role of GLS1-mediated glutamate metabolism in VSMC phenotypic switching and suggest a promising therapeutic strategy for AD.
    Keywords:  Cardiology; Molecular pathology; Muscle; Therapeutics; Vascular biology
    DOI:  https://doi.org/10.1172/jci.insight.203575
  20. Cancer Treat Res Commun. 2026 Apr 08. pii: S2468-2942(26)00119-X. [Epub ahead of print]47 101208
    The role of dietary components in upper gastrointestinal cancers: A narrative review.
    Ziba Asheri, Ahmadreza Kolahi, Mahdi Amirpour, Mohammad Gholizadeh.
       BACKGROUND: Esophageal and gastric cancers together account for approximately 17% of global cancer deaths. The main modifiable risk factors are Helicobacter pylori infection, gastroesophageal reflux disease (GERD), and dietary patterns.
    OBJECTIVE: This narrative review synthesizes evidence on the roles of dietary components- Phytochemicals, probiotics, carotenoids, cysteine/taurine/homocysteine, arginine/citrulline/NO, glutamine, and carnitine-in UGI cancer epidemiology, etiology, prevention, and treatment.
    METHODS: A narrative synthesis of literature from 2010 to 2025 was conducted using PubMed and Google Scholar, focusing on mechanistic and clinical insights.
    RESULTS: Phytochemicals found in vegetables inhibit cancer cell proliferation and metastasis, although their efficacy is limited by poor bioavailability. Probiotics enhance Helicobacter pylori eradication and attenuate inflammation, potentially reducing gastric cancer risk. Carotenoids, including α-carotene and β-carotene, have shown promise in lowering the risk of esophageal and gastric cancers, though evidence remains inconsistent. Certain amino acids-namely cysteine, taurine, homocysteine, arginine, and glutamine-play dual roles in regulating redox balance and tumor metabolism. In contrast, carnitine intake has been associated with an elevated risk of gastric cancer, particularly in men.
    CONCLUSIONS: Nutritional interventions have the potential to modulate UGI carcinogenesis; however, fragmented evidence, variable study designs, and regional dietary differences highlight the need for large-scale clinical trials to develop standardized guidelines.
    Keywords:  Amino acids; Cancer Prevention; Carotenoids; Phytochemicals; Probiotics; Upper gastrointestinal cancer
    DOI:  https://doi.org/10.1016/j.ctarc.2026.101208
  21. Mol Genet Metab. 2026 Apr 08. pii: S1096-7192(26)00399-9. [Epub ahead of print]148(2): 110116
    Brain imaging as a prognostic biomarker in urea cycle disorders.
    Andrea Gropman, Kosar Khaksari, Puneet Bagga.
      The Urea cycle disorders (UCDs) represent a group of rare inborn errors of metabolism that have impaired nitrogen handling from the breakdown of protein, with ensuing acute episodic or chronic hyperammonemia and neurotoxicity. Although advances in newborn screening, molecular diagnosis, and therapeutic interventions have improved survival, neurocognitive, behavioral, and psychiatric sequelae remain prevalent in those with both neonatal onset as well as later onset partial deficiencies. The mechanisms of brain injury in UCDs are complex and multifactorial, and in some cases are not fully known. Common themes include astrocytic dysfunction, altered neurotransmitter cycling, oxidative stress, and energy failure. Neuromonitoring including EEG and Neuroimaging has become a cornerstone in elucidating these mechanisms in UCD patients, offering objective biomarkers to detect subclinical injury, guide management, and evaluate treatment efficacy. This review synthesizes current neuroimaging therapies used in routine clinical practice (structural MRI, Diffusion imaging), as well as research focused and emerging imaging modalities including magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), functional MRI (fMRI), and functional near-infrared spectroscopy (fNIRS) and discusses their translational potential beyond diagnostic entities as prognostic and therapeutic biomarkers in UCDs. Novel approaches such as glutamine chemical exchange saturation transfer (GlnCEST) imaging and multimodal integration with omics data may offer a framework for predictive modeling and precision-guided care. The validation of imaging biomarkers across multicenter studies and across field strengths represents a critical next step in the evolution of neuroimaging from descriptive to quantitative, prognostic, and regulatory endpoints in metabolic disorders. Important issues in multicenter harmonization will be addressed but not discussed in detail.
    Keywords:  Biomarkers; Diffusion tensor imaging (DTI); GlnCEST; Glutamine; Hyperammonemia; Magnetic resonance spectroscopy (MRS); Neuroimaging; Precision medicine; ammonia, urea cycle disorders (UCD); fMRI; fNIRS
    DOI:  https://doi.org/10.1016/j.ymgme.2026.110116
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