bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2026–03–29
thirty-six papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Targeting the Glutamine Transporter SLC1A5 Enhances Sensitivity of Acute Myeloid Leukemia to MLN4924.
  2. Metabolic orchestration driven by GGCT: diverting glutamine to glutathione biosynthesis while enhancing glucose anaplerosis for tumor proliferation.
  3. Host Cell Central Carbon Metabolism and Cellular NAD+ Pool Regulate Efficient Replication of Vesicular Stomatitis Virus.
  4. Functional cooperation between the B-cell receptor and NOTCH1 in regulating metabolic reprogramming in chronic lymphocytic leukemia.
  5. The Glucose and Glutamine Requirements of Cancer and Normal Cells Do Not Distinguish Them, in Contrast to Their Methionine Requirement, Suggesting the Warburg Effect Is Not a Cancer Paradigm.
  6. Glutamine fructose 6-phosphate transaminase-2 as a marker of mesothelial proliferations.
  7. Cancer Metabolism and Its Historical & Molecular Foundations: An Overview.
  8. Comprehensive In Silico Investigation of L-Glutamine Transporters and Metabolism in Glioblastoma.
  9. Stress Responses Tied to Metastasis and Immune Evasion.
  10. Targeting Glutaminase Isoforms GLS and GLS2 in Luminal Breast Cancer.
  11. Α-Ketoglutarate ameliorates appendicitis by modulating Gln metabolism and inhibiting NF - κB signaling pathway.
  12. Hypoxia and aspirin additively increase intracellular glutamine accumulation in PIK3CA-mutated colorectal cancer cells.
  13. Tissue and CD4 T cell subset dependence on the amino acid transporter SLC38A1.
  14. Methionine metabolism is linked with phospholipid and glutamine metabolism to drive ferroptosis.
  15. Glutamine-dependent changes in fibroblast-derived extracellular matrix dictate cancer cell behavior.
  16. [Experience of glutamine in parenteral nutrition in patients undergoing hematopoietic stem cell transplantation].
  17. Co-Exposure to PS-NPs and HFPO-TA Potentiates Reproductive Toxicity via Ferroptosis and SLC1A5-Mediated Glutamine Deprivation in Male Mice.
  18. Metabolic Landscape and Emerging Therapeutic Potential in Pediatric and Adult Gliomas.
  19. Inhibition of Glutamate Dehydrogenase as a Potential Strategy to Modulate Intrahepatic Cholangiocarcinoma Cell Metabolism.
  20. AKT1 phosphorylates PRMT7 to promote GLUD1 methylation and gastric cancer progression.
  21. Circular and Long Non-Coding RNAs in Cancer Metabolism: Dual Perspective of Biomarkers and Therapeutic Targets.
  22. Effect of Perioperative Glutamine-Enhanced Parenteral Nutrition on Short-Term Outcomes in Colorectal Cancer Patients Undergoing Radical Resection: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
  23. Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity.
  24. Crosstalk Between Cis-Regulatory Elements and Metabolism Reprogramming in Hepatocellular Carcinoma.
  25. Comparative and immunohistochemical analyses on hepatic zonation in vertebrates with a special reference to evolution.
  26. Sex differences in congenital hereditary endothelial dystrophy (CHED) and Slc4a11-/- mouse model of CHED.
  27. Autophagy inhibition potentiates the antileukemic effect of FLT3 inhibitors and overcomes resistance in FLT3-ITD acute myeloid leukemia.
  28. Ultrasound-Potentiated Targeting of GLS1 by an Oridonin Derivative (R13) in Multiple Myeloma: Therapeutic Efficacy and Safety Considerations.
  29. 1H NMR-Based Metabolomics in Pediatric Acute Lymphoblastic Leukemia: A Pilot Study of Plasma and Cerebrospinal Fluid Profiles.
  30. The osteoclast intracellular environment fosters bacterial growth during Staphylococcus aureus infection.
  31. Mitochondria in sarcoma and carcinoma: Achilles' heel or Hercules' strength?
  32. CISAT, a CoPP-Induced lncRNA, Improves Cardiac Mesenchymal Progenitor Cell Survival and Myocardial Repair via SFPQ/NRF2/p38 Redox Regulation.
  33. Expression of Hexokinase-2 (HK2), Glutaminase-1 (GLS1) and Fatty Acid Synthase (FASN) in Gastric Cancer and Their Prognostic Significance.
  34. mTOR signaling regulates demand-adapted hematopoiesis and metabolic reprogramming required for an effective cellular immune response in Drosophila melanogaster larvae.
  35. Systematic evaluation of transposon vector elements to establish high-producing stable CHO cell pools achieving >10g/L monoclonal antibody titers.
  36. Tumor-associated epilepsy and high expression of xCT shape the proteome of IDH-wildtype glioblastoma.
  1. Biomedicines. 2026 Mar 14. pii: 667. [Epub ahead of print]14(3):
    Targeting the Glutamine Transporter SLC1A5 Enhances Sensitivity of Acute Myeloid Leukemia to MLN4924.
    Yin Wang, Yuancheng Guo, Xiao Tang, Yu Zhu, Haiping Liang, Yali Zhang, Bei Liu.
      Background/Objectives: Acute myeloid leukemia (AML) remains a hematologic malignancy with poor prognosis. The neddylation inhibitor MLN4924 has demonstrated potent anti-leukemic activity in preclinical models, yet its clinical translation faces significant challenges. The aim of this study was to explore combination therapy strategies that could further enhance MLN4924's anti-leukemia potential. Methods: AML cell lines used in this study were Kasumi-1 and MOLM-13. Cell viability was assessed using CCK-8 assays. mRNA and protein expression levels were determined through RT-qPCR and Western blot, respectively. Flow cytometry was employed to analyze surface markers (SLC1A5, CD11b, CD14, CD16), mitochondrial membrane potential (JC-1), and apoptosis (Annexin V-FITC/PI). In vivo efficacy was validated using an NCG mouse xenograft model. Transcriptomic profiling was performed to explore the potential mechanism by which MLN4924 in combination with V9302 inhibits leukemia. Results: Treatment with MLN4924 significantly upregulated key glutamine metabolic proteins, GLUL and the glutamine transporter SLC1A5, in AML cells. Knockdown of SLC1A5 significantly enhanced AML cell sensitivity to MLN4924. The combination of MLN4924 and the SLC1A5 inhibitor V9302 synergistically inhibited AML cell proliferation, induced monocytic differentiation, and promoted apoptosis. Transcriptomic analysis revealed that this combination therapy prominently suppressed the tricarboxylic acid (TCA) cycle. Conclusions: Neddylation inhibition induces compensatory upregulation of glutamine metabolism in AML. Co-targeting neddylation and glutamine transporter SLC1A5 synergistically exerts anti-leukemic effects, at least in part through disruption of the TCA cycle. This combination represents a novel and effective therapeutic strategy against AML.
    Keywords:  GLUL; MLN4924; SLC1A5; V9302; acute myeloid leukemia; glutamine metabolism; neddylation
    DOI:  https://doi.org/10.3390/biomedicines14030667
  2. Cell Death Dis. 2026 Mar 24.
    Metabolic orchestration driven by GGCT: diverting glutamine to glutathione biosynthesis while enhancing glucose anaplerosis for tumor proliferation.
    Lijun Yang, Handi Sun, Ruonan Wang, Depeng Yang, Qi Gu, Guiping Zhao, Liping Sun, Xinghe Chen, Jianxin Lv, Xiaoyu Lin, Jiahui Cheng, Muhammad Luqman Akhtar, Mengmeng Zhang, Jingyu Zang, Xinyue Shi, Zihao Zhang, Lijun Deng, Lixing Xiao, Lei Yue, Wei Dong, Qinghua Jiang, Fang Han, Yu Li, Huan Nie.
      Glutamine (Gln) metabolism serves dual metabolic roles: it fuels the tricarboxylic acid (TCA) cycle, while concurrently sustaining redox balance through glutathione (GSH) synthesis. γ-Glutamylcyclotransferase (GGCT), a key metabolic enzyme frequently overexpressed in various cancers, has an undefined role in directing glutamine metabolic flux during tumorigenesis. This study demonstrated that glutamine promotes cancer cell growth by regulating GSH and reactive oxygen species (ROS) levels, with this process being closely associated with GGCT expression. Knockdown of GGCT significantly inhibited tumor growth, depleted GSH, and elevated ROS levels, whereas overexpression of GGCT exerted the opposite effects. Furthermore, we refined and established the Gln/c-Myc/miR-29b-3p/GGCT regulatory axis. Notably, GGCT knockdown markedly altered mitochondrial morphology and impaired oxidative phosphorylation and glycolysis capacity. Targeted metabolomics analysis revealed that GGCT knockdown significantly reduced the abundance of TCA cycle intermediates, while GGCT overexpression substantially increased their levels. [U-13C]glutamine isotope tracing experiments showed that GGCT overexpression reduced Gln contribution to the TCA cycle and diverted it preferentially to the GSH synthesis pathway for ROS regulation. In contrast, [U-13C]glucose isotope tracing results demonstrated a significant increase in TCA cycle intermediates derived from glucose when GGCT was overexpressed. Additional, supplementation of sodium pyruvate and JX06 in GGCT-knockdown cells confirmed that this regulatory effect of GGCT-mediated changes in ROS was independent of energy metabolism pathways. Collectively, this study identifies GGCT as a metabolic switch that diverts Gln flux toward GSH synthesis to maintain redox homeostasis, while enhancing glucose-fueled anaplerosis into the TCA cycle to sustain cell proliferation. These findings highlight GGCT as a potential therapeutic target for disrupting cancer redox adaptation and metabolic plasticity.
    DOI:  https://doi.org/10.1038/s41419-026-08619-y
  3. Viruses. 2026 Mar 06. pii: 326. [Epub ahead of print]18(3):
    Host Cell Central Carbon Metabolism and Cellular NAD+ Pool Regulate Efficient Replication of Vesicular Stomatitis Virus.
    Kush K Pandey, Bikash R Sahoo, D S McVey, Asit K Pattnaik.
      Vesicular stomatitis virus (VSV) is a promising oncolytic virus whose replication efficiency and tumor selectivity are strongly influenced by host cell metabolism. Cancer cells, including glioblastoma, exhibit profound rewiring of central carbon metabolism to sustain proliferation, redox balance, and biosynthetic demand, yet how these metabolic states regulate VSV replication remains incompletely defined. Here, we investigated the dependency of VSV replication on glycolysis, the pentose phosphate pathway (PPP), and glutamine metabolism in A172 human glioblastoma cells. Pharmacologic inhibition of glycolysis using 2-DG strongly suppressed VSV replication in a dose-dependent manner, highlighting a robust requirement for glycolytic flux and downstream intermediates. While inhibiting the PPP with 6-AN, a nicotinamide adenine dinucleotide (NAD) analog, markedly impaired viral replication, D-ribose was unable to rescue the inhibition, indicating that nucleotide precursor limitation alone was insufficient to explain this effect. Interestingly, depletion of glucose 6-phosphate dehydrogenase (G6PD), a key enzyme in the PPP, resulted in significant enhancement of VSV replication. Restoration of viral replication by NAD+ precursors in the presence of 6-AN or suppression of replication by the NAMPT inhibitor FK866 suggested NAD+ availability as a critical determinant of VSV replication. Additionally, blockade of glutaminase activity with BPTES reduced viral replication, underscoring the importance of anaplerotic pathways in glioblastoma cells. Collectively, these findings demonstrate that VSV replication is tightly coupled to metabolic programs, particularly those governing energy production and NAD(P)H balance. This work provides a metabolic framework for optimizing oncolytic VSV therapies and suggests that metabolic interventions in cancer treatment may influence oncolytic virus efficacy.
    Keywords:  2-DG; NAD+ metabolism; glutaminolysis; glycolysis; pentose phosphate pathway; siRNA-mediated depletion; vesicular stomatitis virus
    DOI:  https://doi.org/10.3390/v18030326
  4. Leukemia. 2026 Mar 23.
    Functional cooperation between the B-cell receptor and NOTCH1 in regulating metabolic reprogramming in chronic lymphocytic leukemia.
    Amelia Fascì, Francesco Edoardo Vallone, Nahal Nabelsi, Elodie Viry, Ilenia Sana, Alessia Morabito, Silvia Seghezzi, Noemi Anna Pesce, Matteo Rovere, Nadia Bertola, Chloé Duculty, Silvia Ravera, Samir Mouhssine, Marta Muzio, Paolo Ghia, Candida Vitale, Marta Coscia, Etienne Moussay, Gianluca Gaidano, John Allan, Richard R Furman, Jerome Paggetti, Tiziana Vaisitti, Silvia Deaglio.
      Mutations in NOTCH1, which occur in ~10% of Chronic Lymphocytic Leukemia (CLL) patients at diagnosis, are typically associated with unmutated (UM) B-cell receptor (BCR) subsets and define patients with earlier treatment need. Using primary CLL cells classified as NOTCH1 wild-type (CLL/NWT) or mutated (CLL/NM), both with UM-BCR, we show that BCR stimulation activates the NOTCH1 pathway, upregulating metabolic programs and mitochondrial biogenesis, selectively in CLL/NM. These cells display enhanced basal respiration and glycolysis, driven by higher mitochondrial mass, and further increase metabolic activity upon BCR triggering. To directly implicate NOTCH1 mutations, we engineered an MEC-1 model to generate wild-type (MEC-1/NWT) or mutated (MEC-1/NM) clones in a UM-BCR background. Here, NOTCH1 hyperactivation promoted mitochondrial metabolism through TFAM-dependent transcriptional control. Gene expression profiling, metabolic assays, and stable isotope tracing confirmed that MEC-1/NM cells rely on oxidative metabolism, with increased glutamine dependency and strengthened anabolic pathways, leading to augmented proliferation compared to MEC-1/NWT. Importantly, CLL/NM cells exhibit a marked vulnerability to glutamine deprivation. Combined inhibition of glutamine utilization and BCL2 triggered rapid apoptosis, providing a rationale for tailored therapeutic strategies in NOTCH1-mutated CLL. Representation of the molecular mechanism behind the metabolic reprogramming. BCR and NOTCH1 drive a dual metabolic reprogramming of glucose and glutamine pathways. In NOTCH1-mutated cells, both glucose and glutamine uptake are positively increased and even more upon BCR stimulation. Glucose is preferentially used to fuel the pentose phosphate pathway, and glutamine the TCA cycle. Concurrently, NICD accumulation, driven by BCR signaling, promotes TFAM expression and mitochondrial biogenesis. The resulting increase in mitochondrial mass underpins enhanced ATP production, oxygen consumption, and ROS generation, establishing a glutamine-dependent mitochondrial phenotype. This dependency sensitizes NOTCH1-mutated cells to glutamine blockade, which selectively induces apoptosis, further enhanced by combination with BCL-2 inhibition.
    DOI:  https://doi.org/10.1038/s41375-026-02912-7
  5. Anticancer Res. 2026 Apr;46(4): 1875-1882
    The Glucose and Glutamine Requirements of Cancer and Normal Cells Do Not Distinguish Them, in Contrast to Their Methionine Requirement, Suggesting the Warburg Effect Is Not a Cancer Paradigm.
    Yuta Miyashi, Kohei Mizuta, Tomoyuki Ishiguro, Qinghong Han, Shukuan Li, Byung Mo Kang, Jin Soo Kim, Michael Bouvet, Yasunori Tome, Kotaro Nishida, Robert M Hoffman.
       BACKGROUND/AIM: In the present study we compared the glucose and glutamine requirements of cancer and normal cells to determine if the Warburg effect is cancer specific.
    MATERIALS AND METHODS: 143B human osteosarcoma, HT1080 human fibrosarcoma, HCT116 human colon cancer and normal Hs27 human fibroblasts were cultured in Dulbecco's modified Eagle's medium (DMEM) with and without glucose; with and without glutamine; or with and without methionine. The EC50 of glucose, glutamine and methionine was compared in cancer and normal cells. Co-culture of Hs27 normal fibroblast with each cancer cell line was performed by using 12-well plates with and without glucose or methionine. Cell viability was determined with the WST-8 viability reagent, by phase-contrast microscopy or fluorescence microscopy.
    RESULTS: The EC50 of glucose for the three cancer cell lines ranged from 0.54 to 4.88 mM. The EC50 of glucose for Hs27 normal fibroblasts was 0.35 mM, which was not significantly lower than in HCT116 cells (p=0.2225). The EC50 for glutamine ranged from 0.15 to 0.54 mM for the cancer-cell lines and 0.24 mM for normal fibroblasts, which did not distinguish normal from cancer cells. For comparison the EC50 of cancer cells for methionine ranged from 3.8 μM to 21.4 μM while for normal fibroblasts the EC50 for methionine was 2.3 μM, which was significantly lower than in all the cancer cell lines (p<0.0167). In co-culture of cancer and normal fibroblasts, glucose-free or glutamine-free medium resulted in loss of cell viability by day 7 for both the cancer and normal cells. In contrast, in methionine-free medium, the normal fibroblasts were alive and healthy at day 7.
    CONCLUSION: The Warburg effect of glucose and glutamine addiction is not cancer specific in comparison to methionine addiction (Hoffman effect), which is cancer specific, suggesting the Warburg effect is not a cancer paradigm.
    Keywords:  Glucose; Hoffman effect; Warburg effect; cancer cells; cancer-specific; co-culture; glutamine; methionine; normal fibroblasts; paradigm; requirement; vulnerability
    DOI:  https://doi.org/10.21873/anticanres.18080
  6. Histopathology. 2026 Mar 17.
    Glutamine fructose 6-phosphate transaminase-2 as a marker of mesothelial proliferations.
    Andrew Churg, Simon Cheung.
      
    Keywords:  HEG1; Uroplakin IIIb; adenocarcinoma of lung; glutamine fructose 6‐phosphate transaminase‐2; high grade serous carcinoma; mesothelioma
    DOI:  https://doi.org/10.1111/his.70132
  7. Drugs Drug Candidates. 2026 Mar;5(1):
    Cancer Metabolism and Its Historical & Molecular Foundations: An Overview.
    Rami A Al-Horani.
      Cancer metabolism is a cornerstone of tumor biology, characterized by profound alterations in cellular energy production and biosynthetic pathways that drive malignancy. The seminal discovery of the "Warburg effect", the preference of cancer cells for aerobic glycolysis even under oxygen-rich conditions, provided the first major insight into this field. Historically, this observation was attributed to defective mitochondria, but modern research has revealed a far more complex picture of metabolic reprogramming that is actively driven by oncogenes, tumor suppressor genes, and the tumor microenvironment (TME). This review advances a unifying framework for understanding cancer metabolism as a dynamic ecosystem defined by three interconnected adaptations: metabolic plasticity, oncometabolite-driven epigenetic remodeling, and immune-metabolic crosstalk. These adaptations extend beyond glycolysis to encompass glutamine metabolism, lipid synthesis, amino acid utilization, and mitochondrial dynamics, all coordinated to fuel rapid proliferation, promote survival, and enable metastasis. By examining the drivers, consequences, and therapeutic barriers within this framework, we highlight emerging strategies for precision intervention. Although understanding the mechanistic basis of these pathways has unveiled new therapeutic avenues, clinical translation has been limited by metabolic redundancy, microenvironmental buffering, and patient heterogeneity. Strategies such as metabolic inhibitors, dietary interventions, and immuno-metabolic combinations offer promising prospects for disrupting tumor growth when guided by biomarker-driven patient selection and emerging technologies, including spatial metabolomics and AI-driven network modeling.
    Keywords:  TME; Warburg effect; aerobic glycolysis; epigenetic regulation; metabolic reprogramming; mitochondrial dynamics; targeted therapy
    DOI:  https://doi.org/10.3390/ddc5010017
  8. Pharmaceuticals (Basel). 2026 Mar 11. pii: 455. [Epub ahead of print]19(3):
    Comprehensive In Silico Investigation of L-Glutamine Transporters and Metabolism in Glioblastoma.
    Sachin Kumar, Chih-Yang Wang, Helena Kishore Lalwani, Juan Lorell Ngadio, Fitria Sari Wulandari, Daniel Dahlak Solomon, Hui-Pu Liu.
      Background/Objectives: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains associated with poor prognosis despite multimodal therapy. Metabolic reprogramming, particularly increased dependence on glutamine, supports GBM bioenergetic, biosynthetic, and redox demands. This study aimed to systematically identify glutamine-associated metabolic regulators with prognostic relevance and biological plausibility in GBM. Methods: Transcriptomic data from TCGA and GTEx were analyzed using GEPIA2, with survival validation performed using the CGGA. Functional pathway enrichment, protein expression assessment, protein-protein interaction network analysis, tumor microenvironment evaluation, epigenetic profiling, and single-cell RNA sequencing validation were integrated to contextualize candidate genes. Pharmacogenomic correlation analysis and structure-based molecular docking were applied as supportive validation layers. Results: Ceruloplasmin (CP), Solute Carrier Family 25 Member 13 (SLC25A13), and Solute Carrier Family 38 Member 2 (SLC38A2) were selectively dysregulated and associated with poor clinical outcomes in GBM. CP was linked to redox regulation and stress-adaptive survival programs, SLC25A13 to mitochondrial metabolite exchange and glutamine-coupled nucleotide biosynthesis, and SLC38A2 to glutamine uptake, nutrient sensing, and mTORC1-MYC-associated growth signaling. Conclusions:CP, SLC25A13, and SLC38A2 emerge as clinically relevant glutamine-associated metabolic regulators in GBM, linking redox regulation, mitochondrial metabolite exchange, and glutamine-driven growth signaling. These findings highlight transport- and exchange-centered metabolic nodes as potential biomarkers and candidates for future metabolic targeting in GBM.
    Keywords:  SLC25A13; SLC38A2; cancer metabolism; ceruloplasmin; glioblastoma; glutamine metabolism
    DOI:  https://doi.org/10.3390/ph19030455
  9. Cancer Discov. 2026 Mar 27. OF1
    Stress Responses Tied to Metastasis and Immune Evasion.
      Two studies show that cancer cells co-opt the integrated stress response, via the transcription factor ATF4, to drive both metastasis and immune evasion. Targeting this pathway or its downstream effectors, such as glutamine metabolism and the secreted protein LCN2, may offer a way to limit tumor spread and restore antitumor immunity.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NW2026-0029
  10. Int J Mol Sci. 2026 Mar 19. pii: 2780. [Epub ahead of print]27(6):
    Targeting Glutaminase Isoforms GLS and GLS2 in Luminal Breast Cancer.
    Brendah K Masisi, Rokaya El Ansari, Ali Fakroun, Büsra Erkan, Emad A Rakha, Andrew R Green.
      Upregulation of glutaminase enzymatic activity promotes tumour cell proliferation. Its overexpression correlates with poor disease outcome in patients, including those with breast cancer. A selective glutaminase inhibitor, CB-839, which targets cancer cells by blocking glutamine conversion to glutamate, has shown promising preclinical results as a therapeutic target in triple-negative breast cancer treatment. The current study aimed to determine the importance of glutaminase in Oestrogen Receptor positive/luminal breast cancer to potentially identify therapeutic targets to treat this subtype. In vitro studies using luminal breast cancer cells were performed to investigate the effects of siRNA knockdown of glutaminase genes (GLS and GLS2) and inhibition using CB-839 on functional assays. Silencing GLS in luminal breast cancer cells significantly reduced cell proliferation whilst inducing apoptosis. A similar impact on cell proliferation was observed when silencing GLS2 in luminal B cells, but there was no observed effect on cell apoptosis and cell cycle. There was little effect of GLS inhibition using CB-839 in luminal breast cancer. This study demonstrates that glutaminase is necessary for luminal breast cancer growth and survival. Co-targeting GLS and GLS2 might be a novel approach for the treatment of this subclass. Further functional studies to evaluate the underlying molecular mechanisms of this process are warranted.
    Keywords:  breast cancer; glutaminase; luminal cell lines; metabolism
    DOI:  https://doi.org/10.3390/ijms27062780
  11. Int Immunopharmacol. 2026 Mar 21. pii: S1567-5769(26)00395-4. [Epub ahead of print]177 116550
    Α-Ketoglutarate ameliorates appendicitis by modulating Gln metabolism and inhibiting NF - κB signaling pathway.
    Yuxiang Wang, Yishu Lu, Shilin Wang, Jiahao Luo, Zihao Hu, Yingying Zhuang, Hao Li, Linxiao Li, Liesheng Lu, Chenzhang Shi.
       BACKGROUND: Acute appendicitis, a prevalent surgical emergency, is characterized by dysregulated immune responses and metabolic disturbances. Current therapeutic strategies, including surgical intervention and antibiotic therapy, remain limited by complications and recurrence risks. This study investigates the role of Glutamine (Gln) metabolism and its downstream metabolite α-Ketoglutarate (α-KG) in modulating inflammation and intestinal barrier dysfunction during appendicitis.
    METHODS: Transcriptomic profiling of human appendiceal tissues and murine cecal ligation and puncture (CLP) models were employed. Clinical specimens from acute appendicitis patients and murine sepsis models were analyzed via RNA sequencing, RT-qPCR, immunofluorescence, and biochemical assays. The therapeutic effects of exogenous α-KG supplementation were evaluated through survival analysis, cytokine profiling, and NF-κB pathway modulation.
    RESULTS: Inflamed appendiceal tissues exhibited marked downregulation of Gln catabolic genes (GLS1, GLUD1) and reduced α-KG levels, correlating with NF-κB hyperactivation and cytokine storms. Murine CLP models confirmed impaired Gln-α-KG axis activity, exacerbating systemic inflammation. Exogenous α-KG supplementation suppressed p65 phosphorylation, stabilized IκBα, and attenuated pro-inflammatory cytokines (IL-6, TNF-α), significantly improving survival rates. Combined α-KG and antibiotic therapy demonstrated synergistic efficacy, while Gln alone showed limited benefits.
    CONCLUSIONS: Dysfunctional Gln metabolism drives appendicitis pathogenesis through NF-κB-mediated inflammation. In our preclinical models, α-KG demonstrated potent therapeutic effects, alleviating disease progression via both metabolic and anti-inflammatory mechanisms. These results from animal studies and human tissue analysis highlight α-KG as a potential adjunctive therapy for acute appendicitis, laying the groundwork for further clinical exploration.
    Keywords:  Acute appendicitis; Cecal ligation and puncture; Cytokine storm; Glutamine metabolism; NF-κB signaling; Α-Ketoglutarate
    DOI:  https://doi.org/10.1016/j.intimp.2026.116550
  12. Sci Rep. 2026 Mar 24. pii: 9202. [Epub ahead of print]16(1):
    Hypoxia and aspirin additively increase intracellular glutamine accumulation in PIK3CA-mutated colorectal cancer cells.
    Nodoka Umezaki, Shogen Boku, Yoshiyuki Matsuo, Tetsushi Yamamoto, Hironaga Satake, Motoki Watanabe, Kiichi Hirota, Tomoharu Sugie, Mitsugu Sekimoto.
      
    Keywords:   PIK3CA ; aspirin; colorectal cancer; glutaminolysis; hypoxia
    DOI:  https://doi.org/10.1038/s41598-026-42753-z
  13. Cell Metab. 2026 Mar 23. pii: S1550-4131(26)00085-9. [Epub ahead of print]
    Tissue and CD4 T cell subset dependence on the amino acid transporter SLC38A1.
    Ayaka Sugiura, Katherine L Beier, Channing Chi, Darren R Heintzman, Xiang Ye, Melissa M Wolf, Andrew R Patterson, Jacqueline-Yvonne Cephus, Hanna S Hong, Jeffrey M Perera, Costas A Lyssiotis, Dawn C Newcomb, Jeffrey C Rathmell.
      Amino acid (AA) uptake is essential for T cell metabolism and function, but how tissue sites and inflammation affect CD4+ T cell subset requirements for specific AAs remains uncertain. Here, we tested CD4+ T cell AA demands with in vitro and in vivo CRISPR screens and identified subset- and tissue-specific dependencies on the AA transporter SLC38A1 (SNAT1). While dispensable for T cell persistence and expansion in vivo in lung inflammation, SLC38A1 was critical for Th1, but not Th17, cell-driven experimental autoimmune encephalomyelitis (EAE) and contributed to Th1 cell-driven inflammatory bowel disease. SLC38A1 deficiency reduced mTORC1 signaling and glycolytic activity in Th1 cells, in part by reducing glutamine uptake and disrupting hexosamine biosynthesis and redox regulation. Pharmacological inhibition of SLC38 transporters also delayed Th1-mediated EAE but did not affect lung inflammation. CD4+ T cells thus have subset- and tissue-specific nutrient transporter dependencies that may guide new metabolic approaches for selective immunotherapies.
    Keywords:  Slc38a1; T cell; amino acid transport; glutaminolysis
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.016
  14. Cell Rep. 2026 Mar 26. pii: S2211-1247(26)00235-4. [Epub ahead of print]45(4): 117157
    Methionine metabolism is linked with phospholipid and glutamine metabolism to drive ferroptosis.
    Jong Woo Kim, Seo Young Jang, Yeon Jin Roh, Yeajin Ju, Ju-Bin Kang, Byung-Sun Park, Ji-Yoon Lee, Min Wook Kim, Byung Jun Jeong, Woosung Jung, Kyoung-Jin Oh, Won Kon Kim, Baek-Soo Han, Kwang-Hee Bae, Tackhoon Kim, Yun Pyo Kang, Hee Min Yoo, Chuna Kim, Scott J Dixon, Dong Wook Choi, Geum-Sook Hwang, Eun-Woo Lee.
      Ferroptosis is a lipid peroxidation-induced cell death mechanism that is regulated by amino acid metabolism. Cystine deprivation induces ferroptosis, but ferroptosis execution requires other amino acids. While methionine contributes to several metabolic pathways, including transsulfuration (TS), its role in ferroptosis remains controversial. Here, we report that methionine is required for ferroptosis triggered by cysteine deprivation. Notably, the TS pathway and methionine cycle in lung cancer cells are largely inactive, and methionine is instead funneled into polyamine synthesis via the methionine salvage route. Methionine depletion provokes metabolic shifts that dampen glutamine catabolism via the glutamine-methionine bi-cycle. Furthermore, methionine depletion alters phospholipid metabolism by promoting ACSL4 degradation, limiting polyunsaturated fatty acid (PUFA) incorporation into phospholipids. The methionine cycle intermediate S-adenosylmethionine (SAM) supplementation is sufficient to restore the perturbed metabolic state and ferroptosis sensitivity. Taken together, the results of this study highlight methionine as a key coordinator of ferroptosis through dynamic metabolic remodeling.
    Keywords:  ACSL4; CP: metabolism; CP: molecular biology; ferroptosis; glutaminolysis; methionine; methionine salvage pathway; phospholipid metabolism; transsulfuration pathway
    DOI:  https://doi.org/10.1016/j.celrep.2026.117157
  15. Matrix Biol. 2026 Mar 25. pii: S0945-053X(26)00025-9. [Epub ahead of print]
    Glutamine-dependent changes in fibroblast-derived extracellular matrix dictate cancer cell behavior.
    Julien Guillard, Jessica Stradley, Kristof Turan, Marta R Storl-Desmond, Shan Lin, Yi-Chia Huang, Kevin Muñoz Forti, Christopher R Weber, Simon Schwӧrer.
      The extracellular matrix (ECM) provides key biochemical and biomechanical cues that govern fundamental cellular processes, including growth and migration. ECM dysregulation and altered cell-matrix interactions are drivers of cancer progression, exemplified by pancreatic ductal adenocarcinoma (PDAC), where an abnormally dense, collagen-rich, and stiff ECM correlates with poor patient outcomes. The PDAC microenvironment is poorly perfused, resulting in altered nutrient availability, yet how this metabolic stress shapes the ECM and its biological activity remains largely unknown. Herein, using murine and patient-derived fibroblasts, we demonstrate that glutamine, a key amino acid depleted in poorly perfused PDAC regions, regulates the biochemical composition, mechanical properties, and biological activity of fibroblast-derived ECM. As glutamine availability decreases, fibroblasts shift from producing an interstitial, mature ECM enriched in fibrillar collagens toward a basement membrane-like ECM. Consistent with these observations, glutamine stress inversely correlates with fibrillar collagen expression in CAFs in patients with PDAC. ECM produced under low glutamine conditions is depleted in collagen I, more elastic, and promotes PDAC cell growth compared to ECM generated under glutamine-rich conditions. Reducing the stiffness of such matrices is sufficient to increase PDAC cell growth. Glutamine-dependent changes in ECM composition, stiffness, and biological activity are driven in part by glutamine-regulated alpha-ketoglutarate availability in fibroblasts. These findings establish nutrient availability as a key regulator of ECM biology and suggest the nutrient-dictated ECM as a novel mechanism by which glutamine stress in the tumor microenvironment shapes cancer cell behavior.
    Keywords:  ECM; Glutamine; PDAC; collagen; fibroblast; stiffness
    DOI:  https://doi.org/10.1016/j.matbio.2026.03.004
  16. Nutr Hosp. 2026 Mar 11.
    [Experience of glutamine in parenteral nutrition in patients undergoing hematopoietic stem cell transplantation].
    M ª Teresa Alonso Domínguez, Emilio Sánchez Navarro, Maria Josefa López López, Elena Arjonilla Sampedro, Pedro Sánchez Sequero, Fátima Illán Gómez.
       INTRODUCTION: hematopoietic stem cell transplantation (HSCT) is an aggressive and toxic procedure that can lead to malnutrition in patients. It has been proposed that these conditions may worsen under conditions of glutamine deficiency.
    AIM: the aim of this study is to analyze the effect of glutamine supplementation in parenteral nutrition (PN) for patients undergoing HSCT.
    MATERIAL AND METHODS: a retrospective observational study was conducted on patients who received PN following HSCT (both autologous and allo-HSCT) at our hospital between 2015 and 2020. The patients were divided into two groups: those who received glutamine and those who did not. Nutritional status, duration of PN, associated complications, hospital stay, mortality, and progression-free survival (PFS) at day +100 were analyzed. Data analysis was performed using the SPSS statistical software package.
    RESULTS: a total of 117 patients were included, 41.9 % of whom received glutamine supplementation in their PN. There were no significant differences in nutritional status or duration of PN between the two groups. Infections were more frequent in the glutamine group (p = 0.05). There were no significant differences between groups for other complications, although a subgroup analysis based on the type of conditioning showed a higher prevalence of diarrhea in the non-glutamine group of patients receiving reduced-intensity conditioning (p = 0.02). There were no significant differences in mortality, PFS, or duration of PN. Hospital stays were longer in the glutamine group (p = 0.026).
    CONCLUSIONS: in our study, patients receiving glutamine did not show an improvement in their nutritional status; they experienced more infections and had longer hospital stays. We suggest that glutamine supplementation should not be routinely recommended for PN in these patients.
    DOI:  https://doi.org/10.20960/nh.06172
  17. Chem Biol Interact. 2026 Mar 24. pii: S0009-2797(26)00167-5. [Epub ahead of print] 112059
    Co-Exposure to PS-NPs and HFPO-TA Potentiates Reproductive Toxicity via Ferroptosis and SLC1A5-Mediated Glutamine Deprivation in Male Mice.
    Lihai Wu, Jing Ding, Jiayu Xue, Meiling Le, Yiqi Wan, Wanting Zhao, Yangyang Yuan, Xiaodong Kuang, Xinyuan Zhao, Liping Zheng, Dalei Zhang.
      The pervasive co-contamination of ecosystems by nanoplastics (NPs) and per- and polyfluoroalkyl substances causes a synergistic harm to environmental and human health. In this study, murine and TM3 Leydig cell models were employed to explore the combined toxicities of polystyrene (PS)-NPs and hexafluoropropylene oxide trimer acid (HFPO-TA) to male reproduction and the potential mechanisms. Our results revealed that PS-NPs significantly exacerbated HFPO-TA-induced testicular histopathological damage, testosterone synthesis decline and spermatogenesis impairment. Mechanistically, HFPO-TA exposure triggered iron dyshomeostasis, mitochondrial dysfunction, oxidative stress and lipid peroxidation, culminating in ferroptosis evidenced by glutathione peroxidase 4 (GPX4) downregulation and acyl-CoA synthetase long chain family member 4 (ACSL4) upregulation. Additionally, HFPO-TA directly bound to the glutamine transporter solute carrier family 1 member 5 (SLC1A5), suppressing glutamine uptake and glutathione biosynthesis. Crucially, co-treatment with PS-NPs synergistically amplified these alterations induced by HFPO-TA. Notably, both ferroptosis inhibitor ferrostatin-1 and glutathione supplementation markedly attenuated the toxicity caused by PS-NPs and HFPO-TA co-exposure in Leydig cells, confirming ferroptosis as the pivotal toxicological mechanism. Overall, PS-NPs aggravated ferroptosis, glutathione deprivation and mitochondrial impairment upon HFPO-TA co-exposure in mouse testes and Leydig cells, indicating their synergy in inducing male reproductive toxicity. Our findings contribute to a deeper understanding regarding reproductive health risks from environmental co-exposure to NPs and HFPO-TA, and highlight ferroptosis as a critical target pathway for intervention.
    Keywords:  ferroptosis; hexafluoropropylene oxide trimer acid; mitochondria; oxidative stress; polystyrene nanoplastics; testis
    DOI:  https://doi.org/10.1016/j.cbi.2026.112059
  18. Int J Mol Sci. 2026 Mar 17. pii: 2720. [Epub ahead of print]27(6):
    Metabolic Landscape and Emerging Therapeutic Potential in Pediatric and Adult Gliomas.
    Cayley S Brock, Lam Nguyen, Curtis Pattillo, Cheyenne J Ahamed, Keisaku Sato, Kevin K Kumar.
      The underlying metabolism of tumor cells in gliomas has become an area of focus secondary to the difficulties in diagnosis and treatment of these tumors. Heterogeneity in both molecular and phenotypic features of tumor cells in pediatric and adult gliomas presents a significant barrier to traditional treatment options such as radiotherapy and chemotherapy. Low-grade gliomas in pediatric and adult populations have relatively high survival rates, while high-grade gliomas have no effective treatments. Recent advancements in metabolomic techniques have uncovered key metabolic abnormalities, such as increased glutamine and creatinine in invasive edge cells and increased purines in viable tumor cells, distinguishing tumor cells in gliomas. Spatial metabolic heterogeneity and metabolic plasticity enable gliomas to adapt to diverse microenvironments and oxidative stress, necessitating precision medicine approaches that target subtype-specific metabolic vulnerabilities. Further, gliomas are characterized by high intratumoral heterogeneity, with metabolic distinctions between core, edge, viable, and necrotic regions. Altered metabolism of tumor cells has an impact on cells within the tumor microenvironment, resulting in a dysfunctional phenotypic state in resident cells. These metabolic abnormalities differentiate tumor cells from the surrounding microenvironment. Enhanced understanding of the metabolic abnormalities in gliomas could inform targeted therapies, increasing therapeutic response in patients. This review synthesizes emerging evidence on intratumoral and intertumoral heterogeneity in gliomas, highlights the role of tumor-immune cell crosstalk in shaping the metabolic landscape, and discusses how these vulnerabilities may be exploited to develop novel therapies.
    Keywords:  cancer metabolism; glioma metabolism; metabolic dysregulation; metabolic heterogeneity; metabolomics
    DOI:  https://doi.org/10.3390/ijms27062720
  19. Biomolecules. 2026 03 17. pii: 449. [Epub ahead of print]16(3):
    Inhibition of Glutamate Dehydrogenase as a Potential Strategy to Modulate Intrahepatic Cholangiocarcinoma Cell Metabolism.
    Anna Santarsiero, Ilaria Pappalardo, Alessandro Santarsiere, Ernesto Santoro, Marisabel Mecca, Antonio Evidente, Pierluigi Reveglia, Lucia Lecce, Federica De Carlo, Carlo Calabrese, Vittoria Infantino, Stefano Superchi, Simona Todisco.
      Cholangiocarcinoma (CCA) is a rare malignancy of the biliary tree with increasing global incidence and mortality and limited therapeutic options. Intrahepatic cholangiocarcinoma (iCCA) metabolism exhibits enhanced glycolysis, oxidative phosphorylation, and glutamine utilization. In this study, we investigated the therapeutic potential of targeting glutaminolysis in iCCA, identifying glutamate dehydrogenase (GDH)-which converts glutamate to α-ketoglutarate-as a key metabolic hub. We evaluated the effects of pomegranate waste extract (PWE), a by-product of industrial pomegranate juice production, on cell viability, proliferation, migration, ATP production, and extracellular acidification in CCLP1 cells, an established iCCA model. Our results are consistent with an altered cellular energy metabolism. We further assessed GDH enzymatic activity, expression, and transcriptional regulation in the presence or absence of PWE and its major components, punicalagin and ellagic acid. GDH expression was downregulated by PWE in a dose-dependent manner through inhibition of NF-κB signaling, revealing a new mechanistic link between NF-κB and GDH. In addition, GDH enzymatic activity was dose-dependently inhibited by PWE, as well as punicalagin and ellagic acid. Notably, punicalagin was identified as a novel competitive inhibitor of GDH. Overall, these findings provide the first evidence that modulation of glutaminolysis through GDH targeting impairs iCCA cell growth and metabolism, supporting GDH as a promising metabolic target. This study highlights pomegranate-derived compounds as potential leads for the development of adjunctive or preventive strategies in intrahepatic cholangiocarcinoma.
    Keywords:  NF-κB; ellagic acid; glutamate dehydrogenase; intrahepatic cholangiocarcinoma; pomegranate waste extract; punicalagin
    DOI:  https://doi.org/10.3390/biom16030449
  20. Cell Death Dis. 2026 Mar 24.
    AKT1 phosphorylates PRMT7 to promote GLUD1 methylation and gastric cancer progression.
    Ziyi Cui, Hongchen Li, Xiaoben Liang, Xinyu Zhao, Kai Xu, Yao Lu, Yan Zhang, Xia Li, Siyao Wu, Zhen Wang, Lei Lv, Yanping Xu.
      Glutamine metabolism has emerged as an essential metabolic driver of tumor progression. Glutamate dehydrogenase 1 (GLUD1), a key enzyme in glutaminolysis, is frequently overexpressed in malignancies. Post-translational modifications (PTMs) are crucial for regulating protein function and tumor progression. However, the PTMs of GLUD1, particularly arginine methylation, remain unexplored. Here we report that protein arginine methyltransferase 7 (PRMT7) mediates monomethylation of GLUD1 at arginine 76 (R76), enhancing its protein stability by antagonizing ubiquitin-dependent degradation. Moreover, high glucose destabilizes GLUD1 via the PI3K/Akt pathway. Mechanistically, AKT1 phosphorylates PRMT7 at threonine 73 (T73) and promotes its activity to stabilize GLUD1 by increasing its methylation and reducing ubiquitination. Clinical analysis reveals that elevated GLUD1, PRMT7, and meGLUD1(R76) levels correlate with tumor progression in gastric cancer. In xenograft models, PRMT7 inhibitor SGC3027 combined with chemotherapeutic drugs docetaxel (DTX) synergistically suppresses tumor growth. Collectively, this study identifies the AKT1-PRMT7-GLUD1 axis as a key regulatory pathway in gastric cancer, and highlights its potential as a therapeutic target.
    DOI:  https://doi.org/10.1038/s41419-026-08601-8
  21. Noncoding RNA. 2026 Mar 19. pii: 11. [Epub ahead of print]12(2):
    Circular and Long Non-Coding RNAs in Cancer Metabolism: Dual Perspective of Biomarkers and Therapeutic Targets.
    Francesca Pia Carbone, Stefania Hanau, Nicoletta Bianchi.
      Background/Objectives: Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to sustain proliferation, survive under metabolic stress, and develop therapeutic resistance. While oncogenic signaling pathways regulating cancer metabolism have been extensively studied, increasing evidence indicates that non-coding RNAs (ncRNAs) play essential roles in coordinating metabolic adaptation. This review aims to synthesize current knowledge on long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) as important but relatively less characterized regulators of cancer metabolic adaptation and discuss their potential as biomarkers and therapeutic targets. Methods: We analyzed their roles across multiple types of cancer, prioritizing studies that integrate ncRNA profiling with metabolomics and mechanistic investigations, with particular attention to their diagnostic, prognostic, and predictive value. Results: LncRNAs and circRNAs regulate major metabolic pathways, including glycolysis, mitochondrial function, glutaminolysis, lipid metabolism, and redox balance. They act through transcriptional and epigenetic mechanisms, protein scaffolding, peptide encoding, and miRNA sponging, frequently converging on key regulators such as HIF-1α, c-Myc, p53, AMPK, and mTOR. However, many reported associations remain largely correlative, with limited integration of quantitative metabolic flux analyses and insufficient validation in physiologically relevant models. Conclusions: Although lncRNAs and circRNAs constitute an important context-dependent regulatory layer linking oncogenic signaling to metabolic reprogramming, future studies should combine ncRNA perturbation with stable isotope tracing, fluxomics, spatial metabolomics, long-read sequencing, and single-cell approaches to define causal and spatially resolved metabolic functions. Such integrative strategies may improve biomarker development and support ncRNA-informed, metabolism-oriented therapeutic interventions.
    Keywords:  cancer; circular RNA; metabolites; non-coding RNAs
    DOI:  https://doi.org/10.3390/ncrna12020011
  22. Technol Cancer Res Treat. 2026 Jan-Dec;25:25 15330338261438204
    Effect of Perioperative Glutamine-Enhanced Parenteral Nutrition on Short-Term Outcomes in Colorectal Cancer Patients Undergoing Radical Resection: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
    Yong Huang, Xiuzhi Yang, Songhan Qin, Tao Zhang, Ming Xie, Jiwei Wang.
      BackgroundParenteral glutamine (Gln) supplementation can enhance the immune function of patients with colorectal cancer(CRC), regulate inflammatory response, nitrogen balance and protein synthesis, reduce the morbidity of postoperative complications and shorten the length of hospitalization. However, some guidelines and clinical studies have questioned the rationality of using glutamine-containing immunonutrition support in the perioperative period of CRC. Therefore, we conducted a meta-analysis of the effects of perioperative glutamine-enriched parenteral nutrition on short-term postoperative clinical outcomes in patients with CRC.MethodsA comprehensive search of all relevant literature from the default date to June 2025 was performed using the following databases: PubMed, Embase, Web of Science, Cochrane Library, China Biology Medicine Database (CBM), China National Knowledge Infrastructure (CNKI), VIP Medical Information System (VIP), and Wanfang electronic database. RevMan 5.3 software was used for the meta-analysis. We calculated the outcomes using random- and fixed-effects models.ResultsSeventeen single-center randomized controlled trials (RCTs) involving 950 patients with CRC were included. The control group consisted of 470 patients who received traditional parenteral nutrition therapy and the experimental group consisted of 480 patients who received parenteral nutrition with Gln. The analyses showed that perioperative Gln-enhanced parenteral nutrition reduced the morbidity of infectious complications (Relative Risk [RR]=0.36,95% Confidence Interval [CI]:0.23-0.58) and non-infectious complications (RR=0.27, 95% CI: 0.13-0.55). The length of hospitalization was reduced by 2.18 days (mean difference [MD] = -2.18, 95% CI: -2.59--1.78).ConclusionParenteral Gln supplementation may potentially reduced the morbidity of postoperative complications, shortened postoperative hospitalization, improved some aspects of nutritional status, immune and inflammation function in patients with CRC, based on current evidence of low-to-moderate certainty.
    Keywords:  colorectal cancer; complications; length of hospitalization; meta-analysis; nutritional status
    DOI:  https://doi.org/10.1177/15330338261438204
  23. Mol Genet Metab. 2026 Mar 17. pii: S1096-7192(26)00189-7. [Epub ahead of print]148(2): 109906
    Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity.
    André B P van Kuilenburg, Hanna Mandel, Tameemi Abdalla Moady, Ronen Sloma, Ayalla Fedida, René Leen, Judith Jansen-Meijer, Tamar Paperna, Vered Fleisher Sheffer, Doreen Dobritzsch, Ori Hochwald, Nicole N van der Wel, Anita E Grootemaat, Semyon Chulsky, Mika S Rootman, Ayelet Eran, Maha A Yousef, April Dinwiddie, Joshua Manor, Clara D M Van Karnebeek, Limor Kalfon, Tova Hershkovitz, Galit Tal, Tzipora C Falik Zaccai.
      Glutaminase deficiency has recently been identified as a novel inherited metabolic disorder with a broad phenotypic spectrum ranging from early-onset global developmental delay to lethal early neonatal encephalopathy. We describe three infants from two unrelated families who presented clinically with neonatal onset refractory burst-suppression epileptic encephalopathy and respiratory failure, progressing to either a persistent vegetative state or early death. One patient remains alive at the age of six years. Metabolic investigations demonstrated elevated glutamine concentrations in cerebrospinal fluid and increased serum alanine and glutamine levels, biochemical features characteristic of urea cycle disorders, while ammonia levels remained within the normal range. Notably, brain magnetic resonance imaging revealed cystic lesions resembling the neuroimaging findings typically observed in patients with urea cycle defects. Exome sequencing identified a homozygous, unreported missense variant in GLS (NM_014905.5:c.1174G > A; p.Gly392Arg) in both siblings from family 1, and a novel homozygous missense variant (NM_014905.5:c.1031 T > C; p.Leu344Pro) in the proband from family 2. Functional studies of patient fibroblasts and recombinantly expressed mutant glutaminase protein, demonstrated a complete glutaminase deficiency. In addition, patient-derived fibroblasts exhibited pronounced ultrastructural abnormalities, including nuclear dysmorphisms, lysosomal dysfunction with glycogen accumulation, ER stress, Golgi disruption, and mitochondrial fragmentation, along with altered cellular bioenergetics characterized by impaired mitochondrial respiratory function. The biochemical and clinical findings in our patients support a key role for elevated glutamine in the neuropathogenesis of both glutaminase-deficient patients and individuals with hepatic encephalopathy and/or urea cycle defects.
    Keywords:  Encephalopathy; GLS; Glutaminase deficiency; Glutamine; Hyperammonemia
    DOI:  https://doi.org/10.1016/j.ymgme.2026.109906
  24. Cancers (Basel). 2026 Mar 19. pii: 1002. [Epub ahead of print]18(6):
    Crosstalk Between Cis-Regulatory Elements and Metabolism Reprogramming in Hepatocellular Carcinoma.
    Yuqing Ren, Di Tang, Xiaofan Ding, Mian He.
      Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, arising from profound metabolic reprogramming and widespread epigenetic dysregulation. However, the role of epigenetic aberrations in modulating metabolic reprogramming and the interplay between cis-regulatory elements (CREs), such as promoters, enhancers and super-enhancers, and metabolic adaptation have not been systematically summarized. Therefore, this review aims to integrate current evidence to elucidate the mechanisms of how cis-regulatory elements (CREs) drive oncogenic and metabolic signals in HCC progression. For instance, enhancers and super-enhancers transcriptionally activate key metabolic genes involved in aerobic glycolysis (GLUT1, HK2, PKM2, LDHA), de novo lipogenesis (ACLY, FASN, ACC), glutaminolysis (SLC1A5, GLS), and nucleotide synthesis. Meanwhile, many metabolic intermediates, including acetyl-CoA, succinyl-CoA and lactate, act as cofactors or substrates for epigenetic modifiers, creating bidirectional feedback loops that reinforce CRE-driven malignant phenotypes. Therefore, aberrant CREs acts as "metabolic switches" that sense and respond to various metabolic conditions to sustain HCC growth. Consequently, targeted intervention against oncogenic CREs, such as super-enhancers or their co-activators, to disrupt CRE-mediated metabolic vulnerabilities, has emerged as a highly promising new paradigm for precision therapy in HCC.
    Keywords:  Cis-regulatory elements; hepatocellular carcinoma; metabolic reprogramming
    DOI:  https://doi.org/10.3390/cancers18061002
  25. Cell Tissue Res. 2026 Mar 25. pii: 3. [Epub ahead of print]404(1):
    Comparative and immunohistochemical analyses on hepatic zonation in vertebrates with a special reference to evolution.
    Nobuyoshi Shiojiri, Noriaki Ota, Haruka Hirose, Tatsuya Fukuda, Hideaki Kato, Hikari Maeda, Shuji Takabayashi, Takahiko Kawasaki, Kazuho Ikeo.
      The mammalian liver lobules have zonation for various hepatic functions. It remains to be precisely determined which vertebrate taxa exhibit the hepatic zonation. There are two types of liver architectures in vertebrates: the portal triad type (roughly vertebrates except teleosts) and the non-portal triad type (teleosts). The aim of the present study is to determine histochemically and immunohistochemically how the hepatic zonation is established in vertebrates with a reference to the liver architectures and evolution. As a result, the typical hepatic zonation of metabolic enzymes, such as phosphoenolpyruvate carboxykinase and Cyp1a2, was detectable in mammals, including the opossums, pigs, dolphins, guinea pigs, mice, and marmosets. They also consistently exhibited pericentral expression of glutamine synthase, one of ammonia-metabolizing enzymes, which was undetectable in other vertebrates. Murine livers had a more remarkable zonation of cell adhesion molecules and carbamoyl-phosphate synthase I, which other mammals did not exhibit. Chicken and Japanese quail livers showed zonation of alkaline phosphatase (ALP) activity in sinusoidal cells, but no zonation of metabolic enzymes. The amphibian and reptilian livers showed poor zonation. Although many actinopterygians did not exhibit hepatic zonation, some teleost livers showed zonation for the accumulation of periodic acid-Schiff-positive substances and sinusoidal ALP activity. Grass puffer exhibited zonation of transcription factors and cell adhesion molecules. These data indicated that hepatic zonation was not associated with the two types of liver architectures. Mammals and some teleosts may have acquired remarkable hepatic zonation during evolution. Zonation of pericentral glutamine synthase expression is unique to mammalian species among vertebrates.
    Keywords:  Carbamoyl-phosphate synthase I; Evolution; Glutamine synthase; Liver; Zonation
    DOI:  https://doi.org/10.1007/s00441-026-04063-8
  26. Biol Sex Differ. 2026 Mar 28.
    Sex differences in congenital hereditary endothelial dystrophy (CHED) and Slc4a11-/- mouse model of CHED.
    Wenlin Zhang, Divya Sree Ramya, Eduardo Araujo, Jhuwala Venkatakrishnan, Saloni Gupta, Isa Matsubayashi, Marco Morselli, Ananya Kaginalkar, Sunita Chaurasia, Matteo Pellegrini, Radhika Tandon, Muralidhar Ramappa, Arthur Arnold, Anthony J Aldave.
       BACKGROUND: Sex differences have been described in several corneal diseases such as Fuchs endothelial corneal dystrophy and keratoconus, with estrogens implicated in the induction of these differences. Here, we report the identification of sex differences in a cohort of 177 individuals with Corneal Hereditary Endothelial Dystrophy (CHED), a rare corneal endothelial dystrophy associated with biallelic SLC4A11 gene mutations, and in a Slc4a11-/- mouse model of CHED.
    METHODS: Central corneal thickness (CCT) was measured in individuals with CHED and in Slc4a11-/- and Slc4a11+/+ mice to identify a correlation between sex and the degree of corneal edema. To investigate potential causes of such a correlation, RNAseq analysis and mitochondrial superoxide measurement were performed on corneal endothelium from male and female Slc4a11-/- and Slc4a11+/+ mice, for which body composition analysis was also performed. Gonadectomy or sham surgery was performed in Slc4a11-/- and Slc4a11+/+ mice at 4 weeks of age with subsequent longitudinal CCT and body weight monitoring, followed by an analysis of the interaction effect of surgery type, sex and genotype on CCT.
    RESULTS: Male sex is associated with increased CCT, and thus more severe corneal edema, the characteristic clinical feature of CHED, in affected individuals and Slc4a11-/- mice. The corneal endothelium in male Slc4a11-/- mice demonstrates increased levels of oxidative stress compared to Slc4a11-/- female mice, as evidenced by higher levels of glucose- and glutamine-derived mitochondrial superoxide, controlling for age. Removal of gonadal hormones in Slc4a11-/- mice increases corneal edema in female mice, suggesting a protective role for ovarian hormones. Transcriptomic analysis of corneal endothelium and body composition analysis in Slc4a11+/+ and Slc4a11-/- mice suggest that estrogens play a role in promoting corneal endothelial utilization of lipids via β-oxidation as an alternative energy source in the absence of SLC4A11-mediated NH3:H transport function, thereby reducing oxidative stress from glucose and glutamine metabolism.
    CONCLUSIONS: Male sex is associated with a more severe corneal phenotype in individuals with CHED and a Slc4a11-/- mouse model of the disease. Increased corneal edema in female Slc4a11-/- mice following gonadectomy suggests ovarian hormones play a protective role in maintaining corneal deturgescence in the setting of loss of SLC4A11 function.
    Keywords:   Slc4a11 -/- mouse model; CHED (Congenital Hereditary Endothelial Dystrophy); Corneal edema; Estrogen; Gene therapy; Lipid β-oxidation; Oxidative stress; Sex differences; Solute carrier family 4 member 11 gene (SLC4A11); Transcriptomic analysis
    DOI:  https://doi.org/10.1186/s13293-026-00879-9
  27. Cell Death Discov. 2026 Mar 24.
    Autophagy inhibition potentiates the antileukemic effect of FLT3 inhibitors and overcomes resistance in FLT3-ITD acute myeloid leukemia.
    Manuela Albuquerque de Melo, Brunno Gilberto Santos de Macedo, Diego A Pereira-Martins, Antônio Bruno Alves-Silva, Natasha Peixoto Fonseca, Livia Bassani Lins de Miranda, Cleide Lucia Araújo Silva, Priscila Santos Scheucher, Jan Jacob Schuringa, João Agostinho Machado-Neto, Fabiola Traina.
      Autophagy induction has recently emerged as a mechanism of resistance to FLT3 inhibitors (FLT3i) in patients with FLT3-ITD mutant acute myeloid leukemia (AML). Here, we assessed the molecular mechanisms of autophagy inhibition associated with FLT3i and its impact on cell survival and pharmacological resistance. In FLT3-ITD AML cell lines (MOLM13 and MV4-11), treatment with first- and second-generation FLT3i (midostaurin and quizartinib, respectively) induced autophagy. Combining FLT3i with autophagy inhibitors further decreased cell viability and increased cell apoptosis in both cell lines and in primary patient samples. Label-free quantification proteomics of MOLM13 cells revealed that RFC4 (Replication Factor C Subunit 4), an autophagy regulator linked to increased chemosensitivity, and GATD3/C21orf33 (Glutamine Amidotransferase Class 1 Domain Containing 3) proteins were upregulated only in the combined group, while 11 proteins mostly associated with chemoresistance were downregulated. In vivo, the combination of midostaurin and autophagy inhibition improved overall survival in MOLM13-transplanted mice. ATG5- (Autophagy Related 5) and ATG7-knockdown (Autophagy Related 7) increased sensitivity to first- and second-generation FLT3i in MOLM13 cells. To investigate the potential of autophagy inhibition in overcoming FLT3i resistance, we generated MV4-11 cells resistant to quizartinib (MV4-11QR). The resistant cell line exhibited higher basal levels of autophagy compared to the parental cell line. The combination of quizartinib and chloroquine demonstrated a synergistic effect in MV4-11QR cells and this effect was associated with greater inhibition of the FLT3 receptor compared to the monotherapies. Therefore, combining FLT3i with autophagy inhibition enhances the FLT3i antileukemic efficacy and overcomes pharmacological resistance.
    DOI:  https://doi.org/10.1038/s41420-026-03037-7
  28. Cancer Biother Radiopharm. 2026 Mar 25. 10849785261422297
    Ultrasound-Potentiated Targeting of GLS1 by an Oridonin Derivative (R13) in Multiple Myeloma: Therapeutic Efficacy and Safety Considerations.
    Xi Xu, Yan Zhuang, Yu Zhang, Dongmei Tian, Kang Yu.
       OBJECTIVE: To create a structurally optimized oridonin derivative (R13) and study its safety profile, molecular mechanism, and ultrasound-enhanced antitumor activity in multiple myeloma (MM), with an emphasis on glutamine metabolism-driven oncogenic signaling.
    MATERIALS AND METHODS: Using oridonin as the parent nucleus, photocatalytic double-bond addition and esterification processes were used to create R13. Using CCK-8, colony formation, and Transwell assays, the antiproliferative, anticlonogenic, and anti-invasive effects of R13 were assessed in MM cell lines (U266 and KMS-11) both on its own and in response to low-intensity ultrasonic exposure. Key elements of the glutaminase 1-protein kinase B (GLS1-AKT) signaling axis were evaluated for modification using quantitative reverse transcription-polymerase chain reaction (RT-PCR). Stable cell lines with GLS1 knockdown and overexpression were created to confirm target reliance and ultrasound-mediated sensitization. To assess systemic toxicity, organ safety, and in vivo antitumor activity under combination treatment settings, a nude mouse xenograft model was created.
    RESULTS: In a dose- and time-dependent way, R13 dramatically reduced MM cell proliferation, and colony formation, invasion, and migration; these effects were further enhanced by exposure to ultrasound. Mechanistically, R13 specifically targeted and downregulated GLS1, leading to inhibition of the GLS1-AKT signaling pathway, which is characterized by overexpression of the tumor suppressor PTEN and lower expression of AKT2, AKT3, and GSK-3β without changing the expression of AKT1. The biological benefits of R13 and its ultrasound-enhanced pathway regulation were partially reversed by GLS1 overexpression, indicating GLS1-dependent therapeutic action. R13 therapy significantly slowed the growth of xenograft tumors in vivo, while coadministration with ultrasound increased the anticancer activity. Major organs showed no discernible histopathological damage, suggesting a good safety profile.
    CONCLUSIONS: Through ultrasound-potentiated suppression of GLS1-driven metabolic and AKT signaling pathways, R13, a new oridonin derivative, exhibits strong anti-MM action with little systemic toxicity. These results support the combination of drugs originating from Traditional Chinese Medicine with noninvasive ultrasound techniques to enhance treatment efficacy while preserving safety, and they show R13 as a good option for ultrasound-augmented biotherapy in MM.
    Keywords:  GLS1-AKT pathway; antitumor activity; glutaminase 1; multiple myeloma; oridonin derivative; targeted therapy
    DOI:  https://doi.org/10.1177/10849785261422297
  29. Metabolites. 2026 Feb 28. pii: 160. [Epub ahead of print]16(3):
    1H NMR-Based Metabolomics in Pediatric Acute Lymphoblastic Leukemia: A Pilot Study of Plasma and Cerebrospinal Fluid Profiles.
    Agata Serrafi, Małgorzata Pupek, Łukasz Lewandowski, Anna Janicka-Kłos, Andrzej Wasilewski, Adrian Kasprzak, Agnieszka Matera-Witkiewicz, Tomasz Zatoński, Katarzyna Połtyn-Zaradna, Milena Ściskalska, Tomasz Brutkowski, Bernarda Kazanowska.
       BACKGROUND/OBJECTIVES: This pilot study aimed to evaluate the metabolic profiles in plasma and cerebrospinal fluid (CSF) of 14 patients with acute lymphoblastic leukemia (ALL) and plasma of a control group, using proton magnetic resonance spectroscopy (1H NMR).
    METHODS: Multivariate analysis, including orthogonal partial least-squares discriminant analysis (OPLS-DA), was used to analyze the metabolome composition.
    RESULTS: Significant differences in plasma metabolic profiles were found between the ALL and control groups. We detected elevated levels of formate, citrate, and glycerophosphocholine (GPC), along with decreased concentrations of glutamine and myo-inositol. The OPLS-DA model showed stability, with R2Y = 69.7% and Q2 = 45.15%. Additionally, we observed differences in chemical shifts for leucine, myo-inositol, alanine, phenylalanine, and valine between CSF and plasma in patients with ALL.
    CONCLUSIONS: Our findings suggest that metabolomic analysis with 1H NMR is a promising tool for identifying potential molecular biomarkers and for deepening our understanding of metabolic reprogramming in pediatric ALL. The observed metabolic differences highlight the potential involvement of the central nervous system in the disease's pathophysiology.
    Keywords:  acute lymphoblastic leukemia; metabolomics; nuclear magnetic resonance; pilot study
    DOI:  https://doi.org/10.3390/metabo16030160
  30. bioRxiv. 2026 Mar 18. pii: 2026.03.18.712565. [Epub ahead of print]
    The osteoclast intracellular environment fosters bacterial growth during Staphylococcus aureus infection.
    Luke D O'Connor, Saumya Bhagat, Nidhi Roghati, Gabriel Mbalaviele, James E Cassat, Deborah J Veis.
      Bone infections, which are predominantly caused by Staphylococcus (S.) aureus , can be difficult to treat and have high rates of chronicity and reoccurrence. We previously identified that osteoclasts, the cells that break down bone matrix, may contribute to disease progression by allowing S. aureus to replicate intracellularly. There we identified that this bacterium's ability to grow intracellularly is tied to the maturation of osteoclasts. In this study we addressed whether osteoclast differentiation supports intracellular growth by changing the host cell's response to infection or by altering the host cell environment to better support S. aureus . Using dual species RNA-sequencing we analyzed host and bacterial transcripts of infected osteoclast and precursor bone marrow macrophage (BMM) cultures. Host transcript analysis suggests that infected osteoclasts are slow to upregulate bacterial response genes compared to BMMs. We also identify that the S. aureus transcriptional response is primarily determined by the host cell type, and that bacteria in osteoclasts upregulate carbon metabolism genes compared to those inside BMMs. By utilizing intracellular survival assays on S. aureus mutants deficient in carbon metabolism and related pathways we determine that S. aureus require glycolysis, acetyl-CoA synthesis, and aspartate biosynthesis for proliferation inside osteoclasts, although bacteria can survive without them. With differentiation, osteoclasts increase glutamine uptake, and this metabolite is required for S. aureus intracellular growth. Taken together, these findings suggest that osteoclasts support S. aureus intracellular growth by providing nutrients required to replicate in the context of a blunted antimicrobial response.
    IMPORTANCE: Infectious osteomyelitis, bone infection, is frequently caused by the bacterium Staphylococcus aureus . Intracellular infection of cells that build bone, osteoblasts, and cells that resorb bone, osteoclasts, have been implicated in disease progression by providing a niche for immune evasion. While S. aureus in osteoblasts are largely quiescent, bacteria in osteoclasts proliferate and therefore may be a source of reemergent infection. Factors that promote this growth in osteoclasts are poorly characterized. In this study we find that osteoclasts have a diminished transcriptional response to infection and show that S. aureus acquire glucose and glutamine, which have high flux in osteoclasts, to support intracellular growth. We further observe that S. aureus in osteoclasts require aspartate synthesis to grow intracellularly. This work highlights the importance of host cellular metabolism for the intracellular fate of S. aureus as an added factor beyond the direct antimicrobial response.
    DOI:  https://doi.org/10.64898/2026.03.18.712565
  31. Semin Cancer Biol. 2026 Mar 21. pii: S1044-579X(26)00033-7. [Epub ahead of print]121 49-60
    Mitochondria in sarcoma and carcinoma: Achilles' heel or Hercules' strength?
    Mohammad Reza Ashrafi, Laure Cayrefourcq, Sadegh Rajabi, Catherine Alix-Panabières.
      Sarcomas and carcinomas represent approximately 1% and 80% of all cancer diagnoses, respectively. Despite their very different prevalence, both tumor types share a critical dependence on mitochondrial functions for metabolic adaptation, survival and progression. Mitochondria act as cellular powerhouses by generating ATP through oxidative phosphorylation; however, their roles extend far beyond energy production. These organelles are central hubs of biosynthetic and catabolic pathways, including the tricarboxylic acid cycle, glutaminolysis, lipid metabolism, branched-chain amino acid catabolism and gluconeogenesis. Moreover, they play a key role in regulating various forms of programmed cell death, such as apoptosis, necroptosis, ferroptosis and pyroptosis. In this review, we provide a comprehensive overview on the contribution of mitochondria to tumor cell metabolism specifically in sarcomas and carcinomas. We describe how mitochondrial DNA-encoded proteins influence tumorigenesis and how mitochondria support cancer stem cell maintenance. We also discuss the therapeutic potential of targeting mitochondrial pathways, highlighting clinical trials and emerging strategies. The available evidence suggests that sarcoma cells might be more responsive to mitochondrial-targeted therapies due to their higher mitochondrial content and activity compared with carcinomas. Lastly, we bring some evidence of the involvement of mitochondria in the tumor microenvironment and discuss the implication of this finding for cancer immunotherapy. Altogether, these insights emphasize the importance of mitochondria as central regulators of cancer cell fate and promising therapeutic targets.
    Keywords:  Carcinoma; Mitochondria; Sarcoma; Therapeutic target
    DOI:  https://doi.org/10.1016/j.semcancer.2026.03.004
  32. Cells. 2026 Mar 20. pii: 557. [Epub ahead of print]15(6):
    CISAT, a CoPP-Induced lncRNA, Improves Cardiac Mesenchymal Progenitor Cell Survival and Myocardial Repair via SFPQ/NRF2/p38 Redox Regulation.
    Xiuchun Li, Xiao-Liang Wang, Sofia Lopez, Jill Wang, Chuanxi Cai.
      Cellular therapy using human cardiac mesenchymal progenitor cells (hMPCs) for regenerative medicine is hindered by poor cell survival and senescence. Long non-coding RNAs (lncRNAs) are critical regulators of cellular processes, yet their role in cardiac aging remains underexplored. Here, lncRNA microarray profiling identified a novel lncRNA, XLOC_002543, upregulated in hMPCs preconditioned with cobalt protoporphyrin (CoPP), which was named CoPP-Induced and SFPQ-Associated RNA Transcript (CISAT) due to its interaction with splicing factor proline and glutamine rich (SFPQ), confirmed via RNA pull-down and immunoprecipitation. CISAT was the only highly expressed transcript among seven lnc-ANKMY1-5 variants in hMPCs, as shown by RT-PCR. Notably, CISAT expression decreased in aging/senescent hMPCs, correlating with elevated p16INK4A, a senescence marker. Overexpression of CISAT reduced p16INK4A levels; enhanced hMPC survival, proliferation, and migration; and increased antioxidant and anti-apoptotic protein expression, while CISAT knockdown reduced resistance to H2O2-induced oxidative stress. In vivo, intramyocardial transplantation of CISAT-overexpressed hMPCs in an immune-deficient murine myocardial infarction model reduced fibrosis, promoted angiogenesis, and preserved cardiac function. Mechanistically, CISAT interacts with SFPQ to regulate NRF2-mediated redox homeostasis and inhibits p38 MAPK phosphorylation, mitigating senescence and enhancing cell survival. These findings suggest that targeting CISAT to modulate redox signaling and p38 MAPK pathways in aging hMPCs could improve their therapeutic efficacy for myocardial repair in heart disease.
    Keywords:  NRF2 signaling; cardiac progenitor cells; cellular senescence; lncRNA CISAT; myocardial repair
    DOI:  https://doi.org/10.3390/cells15060557
  33. Med Sci (Basel). 2026 Mar 19. pii: 148. [Epub ahead of print]14(1):
    Expression of Hexokinase-2 (HK2), Glutaminase-1 (GLS1) and Fatty Acid Synthase (FASN) in Gastric Cancer and Their Prognostic Significance.
    Elisa García-Martínez, Leonardo S Lino-Silva, Adriana Romo-Pérez, Leticia Bornstein-Quevedo, Alma Chavez-Blanco, Guadalupe Dominguez-Gomez, Horacio N Lopez-Basave, Alejandro Padilla-Rosciano, Consuelo Diaz-Romero, Aurora Gonzalez-Fierro, Alfonso Duenas-Gonzalez.
      Background/Objectives: To evaluate the immunohistochemical expression of hexokinase-2 (HK2), glutaminase-1 (GLS1), and fatty acid synthase (FASN) and its prognostic significance in diffuse gastric adenocarcinoma. Materials and Methods: Formalin-fixed paraffin-embedded tissue samples from 92 patients with diffuse gastric adenocarcinoma were analyzed. Immunohistochemistry (IHC) was performed to assess the expression of HK2, GLS1 and FASN. Expression levels were evaluated semi-quantitatively based on staining intensity and the percentage of positive cells. Associations between enzyme expression and clinicopathological features were assessed using the Chi-square test. Kaplan-Meier survival analysis was employed to evaluate progression-free survival (PFS) and overall survival (OS) and the log-rank test and Cox proportional hazards models were used for statistical analysis. Results: HK2 and FASN were overexpressed in 20.7% and 22.8% of patients, respectively, and were significantly associated with advanced tumor stage. In contrast, GLS1 expression, found in 30.4% of patients, did not independently correlate with clinicopathological characteristics. Furthermore, HK2 expression and co-expression of HK2/FASN (10.9%) and HK2/GLS1/FASN (8.7%) were associated with progressive disease. In the univariate analysis, stage, HK2 overexpression, and co-expression of HK2/FASN and HK2/GLS1/FASN were associated with shorter survival. However, only stage retained prognostic value in the multivariate analysis. Conclusions: Co-expression of these key metabolic enzymes remains a promising candidate as prognostic markers and therapeutic targets. Concurrent targeting of these metabolic pathways may offer novel therapeutic opportunities for patients with advanced-stage gastric cancer.
    Keywords:  fatty acid synthase; gastric cancer; glutaminase-1; hexokinase-2
    DOI:  https://doi.org/10.3390/medsci14010148
  34. PLoS Genet. 2026 Mar 24. 22(3): e1012094
    mTOR signaling regulates demand-adapted hematopoiesis and metabolic reprogramming required for an effective cellular immune response in Drosophila melanogaster larvae.
    Ines Anderl, Jens-Ola Ekström, Tea Tuomela, Mika Rämet, Tiina Susanna Salminen, Laura Vesala.
      The evolutionarily conserved mechanistic Target of Rapamycin (mTOR) pathway connects energy and nutrient availability to growth, proliferation, differentiation, immunity and survival. Here, we investigated the role of the mTOR pathway in Drosophila hematopoiesis and immunity using genetic and transcriptomic analyses of peripheral larval blood cells (hemocytes). We show that blood cell-directed mTor expression induced lamellocyte differentiation as seen after parasitoid wasp infection. Genetic epistasis revealed that lamellocyte hematopoiesis downstream of mTor is mediated by the JNK and p38 pathways. Transcriptomic profiling showed largely similar changes in gene expression patterns of wasp infected and mTor overexpressing hemocytes. While mTOR signaling is necessary for proper lamellocyte differentiation, mTOR Complex 1 (mTORC1) activity is suppressed in mature lamellocytes. Our transcriptome data indicated that hemocyte activation is accompanied by a shift in metabolism towards aerobic glycolysis for energy production, the oxidative pentose phosphate pathway for NADPH recycling, ROS production and detoxification as well as glutaminolysis for glutathione production. Our data highlight the key role of mTOR in controlling blood cell fate in Drosophila.
    DOI:  https://doi.org/10.1371/journal.pgen.1012094
  35. N Biotechnol. 2026 Mar 23. pii: S1871-6784(26)00041-5. [Epub ahead of print]
    Systematic evaluation of transposon vector elements to establish high-producing stable CHO cell pools achieving >10g/L monoclonal antibody titers.
    Maria Tsachaki, Mégane Peltret, Timothee Brunstein Laplace, Emilie Vaxelaire-Hily, Farid Mosbaoui, Céline Aillerie, Angelique Schmid, Anna Galea, Francesca Contarin, Lionel Duarte, Roberto Giovannini, Martin Bertschinger.
      Rapid generation of cell populations capable of producing industrially relevant levels of complex biologics remains challenging. Using wild-type PiggyBac transposase and a CHO-K1 glutamine synthetase (GS) knockout cell line, we screened known and novel vector elements in a multi-gene vector (containing two expression cassettes and one resistance marker) for their impact on accumulated titer in stable fed-batch pools. The optimal combination included the Cricetulus griseus polyubiquitin gene UbC (CHUB2) enhancer, a fusion promoter combining the murine cytomegalovirus (CMV) enhancer with the TATA box, transcription start site (TSS), and 5' UTR of the human β-hemoglobin gene, human SV40 and CMV enhancers placed between cassettes, and the WPRE element (Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element) in the 3' UTR. Expression remained stable over 30 population doubling levels (PDLs). This enabled the generation of pools producing >10g/L of trastuzumab in a standardized fed-batch process within 5 weeks post-transfection, with product quality comparable to the commercial reference. Clonal populations reached up to 15g/L with low variability in expression between clones. To further increase titers, we engineered a PiggyBac variant with additional nuclear localization signals and expressed it under a strong promoter. The improved transposase increased pool performance by 10-30%. Suitability of the vector for complex molecules was demonstrated by achieving up to 2.5g/L in pools expressing a difficult-to-express multispecific antibody format.
    Keywords:  Chinese hamster ovary; Multigene vector; Stable cell line; antibody; difficult to express; plasmid; promoter; transposase; vector architecture
    DOI:  https://doi.org/10.1016/j.nbt.2026.03.008
  36. Cell Death Discov. 2026 Mar 25.
    Tumor-associated epilepsy and high expression of xCT shape the proteome of IDH-wildtype glioblastoma.
    Iris Divé, Jasmin A Schäfer, Katharina J Weber, Ali Yavuz Çakır, Nikita A Verheyden, Nadja I Lorenz, Seon-Ah Chong, Pia S Zeiner, Carmen Franiczek, Benedikt Sauer, Martin Adrian-Allgood, Hans Urban, Anna-Luisa Luger, Katharina J Wenger, Adam Strzelczyk, Felix Rosenow, Johannes Streffer, Vincent Prinz, Daniel P Brucker, Stefanie Dedeurwaerdere, Véronique M André, Joachim P Steinbach, Florian Buettner, Christian Münch, Michael W Ronellenfitsch.
      Given the role of glutamate signaling in glioma-associated epilepsy (GAE) and glioma cell growth, amino acid transporters have gained attention as therapeutic targets. Here, we conducted a comparative analysis of four key transporters-xCT, CD98, EAAT2, and ASCT1-with particular emphasis on xCT, due to the availability of clinically established inhibitors. Protein expression was quantified by immunoblot in snap-frozen tissue of tumor treatment-naïve IDH-mutant and IDH-wildtype gliomas (n = 87) with and without GAE. Quantitative whole-cell proteomics was performed on glioblastoma (GB) from 16 patients stratified for GAE and xCT expression levels. Gliomas from patients with GAE showed significantly higher EAAT2 and ASCT1 levels. In IDH-mutant versus IDH-wildtype glioma, xCT, EAAT2 and ASCT1 were significantly upregulated. Quantitative proteomics revealed 214 significantly regulated proteins in GB with GAE. Upregulated proteins showed enrichment for Gene Ontology (GO) terms involving neurotransmitter and amino acid turnover as well as lipid metabolism. Within the epilepsy group, xCT high-expressing tumors had distinct enrichment patterns. The 231 upregulated proteins partially overlapped with proteins upregulated in the epilepsy cohort, but additionally showed enrichment in pathways related to myelination and synaptic plasticity. In the survival analysis (n = 87), xCT expression and epilepsy did not affect patient survival in either IDH-mutant or IDH-wildtype tumors. Our findings highlight the role of amino acid transporters in GAE. The proteome analysis reveals distinct patterns in GB with epilepsy and also underscores the influence of xCT expression on the tumor proteome, which could inform the development of targeted anti-seizure medication.
    DOI:  https://doi.org/10.1038/s41420-026-03029-7
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