bims-glucam 2026-03-01 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–03–01
24 papers selected by
Sreeparna Banerjee, Middle East Technical University

ASCT2 palmitoylation regulated by JNK1-ZDHHC14 axis orchestrates glutamine metabolism and NSCLC progression.
Functional nutrient-genetic profiling reveals biotin and FBXW7 are essential to bypass glutamine addiction.
Metabolic Vulnerabilities as a Therapeutic Target in Breast Cancer.
Design, synthesis and biological evaluation of symmetric thiadiazole carboxamide derivative as glutaminase inhibitor.
Mitochondrial targets in IDH1-mutated cholangiocarcinoma.
Blocking glutamine transport normalizes lymphatic vessels in hypoxic environments by attenuating glycolysis.
The application prospects of amino acid deprivation for cancer therapy.
Glutamine Supplementation and Exercise: A Narrative Review of Biochemical Mechanisms and Timing Strategies.
Sequential, chromosome-specific glutamine synthetase double knockout with Cas-CLOVER establishes enhanced CHO platforms for cell line development.
Acteoside targeting glutamine synthetase ameliorates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis.
A phenotype-based cell culture model of melanoma cells that persist as residual disease after therapies leading to recurrence.
Machine learning derived proliferating T cell-related signature: a novel biomarker for prognosis and treatment efficacy in clear cell renal cell carcinoma.
Lower serum threonine and glutamine levels could be a predictor for multiple sclerosis in pregnancy.
Neonatal Hyperoxia Induces Metabolic Reprogramming in Senescent Alveolar Macrophages, Leading to Persistent Lung Injury.
Metabolic Portrait of Breast Cancer in Mixed Saliva.
WTAP-Mediated Glutaminase Splicing Bias Suppresses Ferroptosis in Hepatocellular Carcinoma.
The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy.
Glutathione is critical for NK cell-mediated immunity.
Injury Causes Altered Metabolism including O 2 Consumption in Bovine and Human Chondrocytes.
Multi-Omics Analyses Reveal Metabolic Alterations Regulated by Orf Virus in Primary Ovine Fetal Turbinate Cells.
Untargeted metabolomic profiling reveals mTORC1-dependent regulation of amino acid utilization in lymphatic endothelial cells.
Lactate metabolism and protein lactylation in cancer.
Alpha-ketoglutarate dehydrogenase: more than just a TCA cycle enzyme.
Evaluation of SLC38A1 in Pediatric and Adult Acute Leukemias; A Potential New Prognostic Factor.

Cell Discov. 2026 Feb 24. pii: 13. [Epub ahead of print]12(1):

ASCT2 palmitoylation regulated by JNK1-ZDHHC14 axis orchestrates glutamine metabolism and NSCLC progression.

Xingyu Chen, Zihao Ke, Shihui Wei, Jiajin Chen, Ke Zhu, Jiaqi Xu, Yun Zhao, Mengyuan Cen, Yan Jin, Zhilei Pan, Juan Xiong, Ying Chen, Chenfang Dong, Qianhua Cao, Chao Cao.

S-palmitoylation, a reversible post-translational modification regulates protein stability and cellular functions, yet its role in glutamine metabolism remains unclear. Here, we show that ZDHHC14 as the key palmitoyltransferase catalyzing ASCT2 palmitoylation at conserved Cys39 and Cys48 residues, promoting lysosomal degradation of this glutamine transporter, whereas ABHD17B functions as a depalmitoylase to stabilize ASCT2. Mechanistically, glutamine deprivation activates JNK1, which directly phosphorylates ZDHHC14 at Thr440 residue, triggering its degradation and thereby enhancing ASCT2 stability. Importantly, combination of JNK and ASCT2 inhibitors synergistically inhibits glutamine metabolism and tumor growth in vivo. These findings reveal a phosphorylation-palmitoylation axis linking JNK-mediated ASCT2 palmitoylation and glutamine metabolism, offering a potential therapeutic strategy for non-small cell lung cancer.

DOI: https://doi.org/10.1038/s41421-026-00870-z
Mol Cell. 2026 Feb 25. pii: S1097-2765(26)00097-3. [Epub ahead of print]

Functional nutrient-genetic profiling reveals biotin and FBXW7 are essential to bypass glutamine addiction.

Miriam Lisci, Fanny Vericel, Yifan Liu, Hector Gallart-Ayala, Julijana Ivanisevic, Owen S Skinner, Alexis A Jourdain.

  Metabolic flexibility is key to survival and growth in all living organisms. In mammals, the pathways supporting cell proliferation in nutrient-limiting conditions have not been fully elucidated, although certain tumors display metabolic dependencies that can be targeted for therapy. Here, we combine metabolic tracers, nutrient supplementation, and genome-wide CRISPR-Cas9 screening to investigate the pathways mediating glutamine addiction, a hallmark of several cancers. We report that the vitamin biotin allows the bypassing of glutamine dependence by activating pyruvate carboxylase (PC), and we discover a mechanism by which the tumor suppressor FBXW7 promotes pyruvate anaplerosis. Mechanistically, we show that FBXW7 prevents c-MYC accumulation and recruitment of a cluster of transcriptional repressors, including MAX, MNT, and SIN3A, to the PC promoter, thereby maintaining PC expression and avoiding glutamine addiction. Our work sheds light on the molecular mechanisms that support metabolic flexibility and prevent glutamine addiction in cancer, with high relevance for FBXW7-associated cancer mutations.

Keywords:  FBXW7; MYC; PC; biotin; glutamine; glutamine addiction; malate-aspartate shuttle; nutrient screen; pyruvate; pyruvate carboxylase

DOI:  https://doi.org/10.1016/j.molcel.2026.02.002
Curr Oncol. 2026 Feb 23. pii: 129. [Epub ahead of print]33(2):

Metabolic Vulnerabilities as a Therapeutic Target in Breast Cancer.

Sabrina Guo, Christina L Addison.

  Metabolic reprogramming is a defining feature of breast cancer, enabling tumor cells to sustain rapid proliferation, survive under stress, and resist therapy. Key pathways including glycolysis, glutaminolysis, lipid metabolism, and one-carbon metabolism, play central roles in meeting the energetic and biosynthetic demands of malignant cells. Enhanced glycolytic flux supports ATP generation and lactate production, while glutamine metabolism fuels the tricarboxylic acid cycle and provides nitrogen for nucleotide synthesis. Lipid metabolic pathways, particularly fatty acid synthesis, contribute to membrane biogenesis and signaling, and one-carbon metabolism driven by serine and glycine supplies methyl groups for epigenetic regulation and nucleotide production. These metabolic adaptations not only promote tumor growth but also create vulnerabilities that can be exploited therapeutically. Inhibiting these pathways has shown promise in preclinical models; however, challenges such as metabolic plasticity, tumor heterogeneity, and potential toxicity in normal tissues underscore the need for biomarker-driven strategies and rational combination therapies. Herein, we describe current knowledge of the role of these pathways in breast cancer progression, highlighting the role of key enzymes in promoting breast cancer tumor cell growth and in breast cancer prognoses.

Keywords:  TCA cycle; breast cancer; fatty acids; glutaminolysis; glycolysis; metabolism; pentose phosphate pathway; prognosis; serine biosynthesis; tumor growth

DOI:  https://doi.org/10.3390/curroncol33020129
Bioorg Med Chem Lett. 2026 Feb 21. pii: S0960-894X(26)00062-4. [Epub ahead of print]136 130595

Design, synthesis and biological evaluation of symmetric thiadiazole carboxamide derivative as glutaminase inhibitor.

Rajath Cyriac, Eun Ji Lee, Yeongju Kwon, Mi Ran Yun, Myoung Eun Jung, Sunjoo Ahn, Chang Hak Chae, Gildon Choi, Byoung Chul Cho, Kwangho Lee.

  Metabolic reprogramming toward glutamine anaplerosis is a well-established vulnerability in tumors harboring co-occurring KRAS and KEAP1 mutations, creating a dependency on glutaminase (GLS)-mediated glutaminolysis for survival and growth. Although allosteric GLS inhibitors such as BPTES (Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide) and later-generation analogs such as CB-839 (Telaglenastat) have pharmacologically validated this target, their clinical utility has been constrained by suboptimal drug-like properties, including poor solubility and bioavailability. To overcome these limitations, we developed TRG-192, a novel symmetric amidothiadiazole derivative engineered with a distinct chemical scaffold to enhance physicochemical and pharmacokinetic profiles. In vitro characterization revealed that TRG-192 is a potent GLS inhibitor (IC₅₀ = 68 nM). This biochemical potency translated to a functional effect in a cellular model of glutamine dependence, as evidenced by a significant depletion of intracellular glutamate pools in LDK378-resistant (LR) cells. Furthermore, TRG-192 demonstrated a favorable preclinical safety profile in initial toxicological assessments. Collectively, these data-encompassing potent target engagement, functional on-target activity, and preliminary safety-provide a compelling rationale for the advancement of TRG-192 into in vivo efficacy studies.

Keywords:  Anticancer; BPTES; Cancer metabolism; GLS1; Glutaminase 1

DOI:  https://doi.org/10.1016/j.bmcl.2026.130595
Hepatol Commun. 2026 Mar 01. pii: e00909. [Epub ahead of print]10(3):

Mitochondrial targets in IDH1-mutated cholangiocarcinoma.

Camila Carvalho, Fulei Wuchu, Nicole Peterson, Deepak Nagrath, Arathi Mohan, Vaibhav Sahai.

  Cholangiocarcinoma (CCA), a subset of biliary tract cancers, remains a therapeutically challenging malignancy with poor long-term survival despite recent advances in targeted therapies. Recent data suggest that IDH1-mutated CCA exhibits unique mitochondrial vulnerabilities. In this report, we discuss the emerging role of mitochondrial metabolism as a target in IDH1-mutated CCA, including preclinical evidence supporting the inhibition of the tricarboxylic acid (TCA) cycle, glutamine metabolism, and potential combination approaches. We aim to highlight the growing need to integrate mitochondrial-targeted strategies into future clinical investigations.

Keywords:  cholangiocarcinoma; ivosidenib; mutant isocitrate dehydrogenase; targeted therapy

DOI:  https://doi.org/10.1097/HC9.0000000000000909
bioRxiv. 2026 Feb 17. pii: 2025.12.18.695240. [Epub ahead of print]

Blocking glutamine transport normalizes lymphatic vessels in hypoxic environments by attenuating glycolysis.

Ellie Johandes, Eva Hall, Tomas Harbut, Kaden Priebe, Margaret Schwarz, Donny Hanjaya-Putra.

Dysfunctional lymphangiogenesis is a component of several diseases with hypoxic microenvironments, including secondary lymphedema and solid malignancies. These vessels are ineffective at draining interstitial fluid, resulting in complications such as increased inflammation, slowed wound healing, and, for cancer patients, increased risk of metastasis. Current treatments to normalize vasculature have negative effects on healthy vessels and do not specifically target lymphatic endothelial cells (LECs). As hypoxia is known to change endothelial cell metabolism, exploiting LEC-specific metabolic pathways may provide a focused approach to restoring lymphatic function in patients. However, outside of glycolysis, changes to LEC metabolism in hypoxic conditions are understudied. To address this gap in knowledge, we examined the impact of glutamine availability on factors critical to lymphangiogenesis, including glycolysis, cell proliferation, and migration. We found that increasing glutamine availability results in increased lactate production as well as a hypoxia-specific increase in glycolytic genes HK2, GLUT1, and GLUT3. The presence of glutamine also encouraged LEC proliferation, while blocking glutamine transport reduced lactate production, HK2 expression, and slowed collective LEC migration. In a vessel formation assay, we found that glutamine increased vessel formation in normoxic conditions, but lowered vessel connectivity in hypoxic conditions, reflecting the dysfunction seen in hypoxic diseases. However, attenuating glycolysis by blocking glutamine transport caused LECs to form longer, interconnected vascular networks. This study reveals that glutamine availability can modulate LEC glycolysis, and therefore lymphangiogenesis, in a hypoxia-dependent manner. Collectively, our study identifies glutamine availability as a potential target for lymphatic vessel normalization in chronic and hypoxic diseases.

DOI: https://doi.org/10.64898/2025.12.18.695240
Eur J Med Chem. 2026 Feb 18. pii: S0223-5234(26)00150-9. [Epub ahead of print]308 118705

The application prospects of amino acid deprivation for cancer therapy.

Meng Wei, Renbing Wang, Jingxuan Peng, Zhiyu Li, Ahmed R Ali, Jinlei Bian, Huidan Huang, Yucheng Tian.

  Metabolic reprogramming, a hallmark of cancer that alters nutrient utilization, enhances tumor dependence on specific amino acids. This addiction-like dependence offers a compelling rationale for employing amino acid antagonism in cancer therapy. It is well-established that efficacy is inextricably linked to immunomodulation. Although substantial evidence from early-stage and human research indicates this approach holds therapeutic value, the broader clinical application faces significant challenges. This review systematically explores the roles of ten key amino acids in tumor progression, including glutamine, asparagine, leucine, isoleucine, valine, methionine, cysteine, arginine, serine, and glycine. The current blockade strategies and relevant drugs were also summarized to offer future research directions.

Keywords:  Amino acids; Blocking therapies; Cancer; Drug design; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.ejmech.2026.118705
Medicina (Kaunas). 2026 Feb 06. pii: 329. [Epub ahead of print]62(2):

Glutamine Supplementation and Exercise: A Narrative Review of Biochemical Mechanisms and Timing Strategies.

Branka Djordjevic, Vladana Stojiljkovic, Aleksandra Velickov, Jana Kocic, Jelena Milenkovic, Andrej Veljkovic, Jelena Basic, Tatjana Cvetkovic.

  Intense physical activity imposes substantial oxidative, metabolic, and immunological stress on the human body. It is often accompanied by reductions in plasma glutamine levels, making this amino acid conditionally essential. Glutamine plays a vital role in energy production, nitrogen transport, acid-base balance, antioxidant defense, and immune function. It is required in the biosynthesis of neurotransmitters, nucleotides, nicotinamide-derived coenzymes, glutathione, and hexosamines, making it a candidate for supporting exercise recovery. In addition, glutamine may support key mechanisms involved in muscle adaptation and recovery during exercise-induced stress by contributing to redox balance, energy sensing, anabolic signaling, intestinal barrier integrity, and immune function. This narrative review aims to synthesize biochemical mechanisms underlying glutamine effects relevant to exercise and evaluate preclinical and clinical findings on supplementation outcomes, with emphasis on timing strategies. Preclinical findings demonstrate that glutamine can modulate protein synthesis, reduce oxidative stress, improve intestinal integrity, and attenuate immune and inflammatory disturbances. Limited preclinical data suggest that post-exercise supplementation may better resolve muscle and organ damage. Clinical trials, however, report heterogeneous outcomes: several studies show improvements in markers of intestinal permeability and intestinal epithelial damage, oxidative stress, muscle damage, and inflammation, whereas others report minimal or no effect, including limited influence on performance outcomes. Variability in timing protocols, participant characteristics, and measured endpoints contributes to inconsistent findings. Overall, glutamine demonstrates several biologically plausible mechanisms that could support recovery and overall health in active individuals, athletes, and specific clinical populations. However, current evidence remains insufficient to determine clear supplementation benefits or define an optimal timing strategy. Future research using standardized protocols and integrated biochemical and functional endpoints is needed to clarify timing effects. Until such evidence emerges, recommendations should remain individualized, considering athlete-specific needs.

Keywords:  athletes; exercise; glutamine; muscle recovery; supplementation timing

DOI:  https://doi.org/10.3390/medicina62020329
Biotechnol Prog. 2026 Feb 22. e70113

Sequential, chromosome-specific glutamine synthetase double knockout with Cas-CLOVER establishes enhanced CHO platforms for cell line development.

Cintia Gomez Limia, Valeriya Steffey, Hsueh Che Cheng, Daniel Machado, Thomas Hart, Mark Cameron McHargue, Corey Brizzee, Jack Crawford.

  Cas-CLOVER is an emerging high-fidelity genome editing system that enables precise and efficient cell engineering. In this study, we applied Cas-CLOVER to establish a robust, gene-edited platform in suspension-adapted CHO-K1 cells supporting cell line development (CLD) for biopharmaceutical production. An attractive strategy for high-yield clone selection is the use of glutamine synthetase (GS) knockout CHO cells. The primary GS gene resides on chromosome 5 (GS5), while a recently identified GS pseudogene is located on chromosome 1 (GS1). To compare editing efficiency, we evaluated Cas-CLOVER and Cas9 at both GS loci using the Neon™ Transfection System. Cas-CLOVER achieved 84% editing at GS5 and 74% at GS1, markedly higher than Cas9. Leveraging Cas-CLOVER's dual-guide RNA design, we generated a GS5 single knockout (GS5-SKO) and subsequently a double knockout (GS-DKO) line at both the GS5 and GS1 loci, both with none detected off-target mutations analyzed in 40 predictably off-target sites. For functional validation, these cell lines were engineered with the proprietary Harbor-IN transposase system to stably express trastuzumab. Using an optimized protocol, the resulting GS-DKO platform, termed CleanCut GS CHO, enabled stringent selection and yielded high-producing clones with cell-specific productivity exceeding 100 pg/cell/day and antibody titers greater than 5 g/L in 24 deep well-plate fed-batch cultures after 14 days. The antibody titer stability analysis showed consistency over 60 generations. Collectively, these findings establish Cas-CLOVER as a versatile genome editing tool for developing high-yield CHO host platforms in CLD.

Keywords:  CHO cells; Cas‐CLOVER; Harbor‐IN transposase; bioprocessing; cell line development; gene editing; trastuzumab

DOI:  https://doi.org/10.1002/btpr.70113
Phytomedicine. 2026 Feb 17. pii: S0944-7113(26)00216-3. [Epub ahead of print]153 157979

Acteoside targeting glutamine synthetase ameliorates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis.

Xiao Chu, Hui Zheng, Jingyi Sun, Ke Liu, Yang Shao, Siyuan Han, Liangge Zhao, Ruoshi Dou, Xingen Jia, Jiayao Huang, Meng Liu, Ziliang Zhang, Tao Li, Hao Li, Zhiping Guo, Guoguo Jin.

   BACKGROUND: Doxorubicin-induced cardiotoxicity (DIC) is a severe dose-limiting complication of chemotherapy. Acteoside (ACT), a bioactive phenylethanoid glycoside naturally isolated from various medicinal plants such as Plantago lanceolata and Acanthus ilicifolius, exhibits diverse pharmacological activities. However, its specific role and molecular targets in DIC remain largely unreported.
OBJECTIVE: To evaluate the cardioprotective efficacy of ACT in DIC and identify its direct molecular targets and cardiac protection mechanisms.
METHODS: Proteomic profiling of DOX-treated hearts and AAV9-mediated cardiac-specific silencing were integrated to identify and validate glutamine synthetase (GS) as a pivotal pathological driver of DIC. Subsequently, structure-based virtual screening of phytochemicals was employed to identify ACT as a potent GS inhibitor. The ACT-GS interaction was confirmed via molecular docking, pull-down, and cellular thermal shift assays. Functional and mechanistic validations were conducted using H9C2/HL-1 cells and C57BL/6 J mouse models.
RESULTS: Proteomics revealed significant myocardial GS upregulation and glutamate metabolic remodeling in DIC. ACT was identified as a direct inhibitor that specifically binds to GS. Mechanistically, ACT-mediated GS inhibition prevented pathological glutamate depletion and restored the GLU-GSH-GPX4 antioxidant axis, thereby suppressing lipid peroxidation and ferroptosis both in vitro and in vivo. Consequently, ACT administration significantly attenuated DOX-induced cardiac dysfunction, fibrosis, and myocardial atrophy, effectively recapitulating the protective effects observed with genetic GS knockdown.
CONCLUSION: ACT acts as a potent natural GS inhibitor that alleviates DIC by suppressing ferroptosis. This study establishes ACT as a promising natural lead compound for the management of DIC.

Keywords:  Acteoside; Doxorubicin; Ferroptosis; Glutamine synthetase; Lipid peroxidation; cardiotoxicity

DOI:  https://doi.org/10.1016/j.phymed.2026.157979
Res Sq. 2026 Feb 18. pii: rs.3.rs-8768856. [Epub ahead of print]

A phenotype-based cell culture model of melanoma cells that persist as residual disease after therapies leading to recurrence.

Balraj Singh, Vanessa Sarli, Nikil Erry, Anthony Lucci.

A crucial adaptability trait of stem-like melanoma cells that persist under all selection pressures, including therapies, is their ability to survive in deep quiescence. This ability coupled with their intrinsic ability to proliferate leads to recurrence. Here we describe an approach to modeling this trait in cell culture. A lack of glutamine proved to be a selection pressure for the highly metastatic human melanoma cell line A375SM, killing more than 99% of cells and selecting rare cells based on their ability to survive in deep quiescence. After 4 weeks, cells gradually exited quiescence and proliferated indefinitely. Interestingly, by not providing fresh glutamine-free medium at this stage, we could select rare cells that persist in deep quiescence as single cells. Alternatively, we could model deeper quiescence lasting longer than 4 weeks by increasing the severity of the selection pressure using dialyzed serum in medium. The cells selected in this manner were much more resistant to paclitaxel than was their parental cell line. We obtained similar results with the highly metastatic mouse melanoma cell line B16-BL6. Thus, our phenotype-based approach is suitable for modeling abnormal deep quiescence in melanoma that is responsible for therapy resistance, disease progression, and recurrence/metastasis.

DOI: https://doi.org/10.21203/rs.3.rs-8768856/v1
Int Immunopharmacol. 2026 Feb 24. pii: S1567-5769(26)00205-5. [Epub ahead of print]175 116361

Machine learning derived proliferating T cell-related signature: a novel biomarker for prognosis and treatment efficacy in clear cell renal cell carcinoma.

Dingbang Liu, Ling Wang, Xiuyi Pan, Junjie Zhao, Yanfeng Tang, Jiayu Liang, Hao Zeng.

   BACKGROUND: Clear cell renal cell carcinoma (ccRCC) exhibits profound molecular heterogeneity, and reliable biomarkers for predicting clinical outcomes are urgently needed. Proliferating T cells (Tprolif) are central to immune system activation but their related signatures in predicting prognosis and therapeutic effect of ccRCC patients remains unexplored.
METHODS: We developed a Tprolif-related RCC score (TRRS) using an integrative machine learning framework. Transcriptomic data from the CheckMate025 trial formed the discovery cohort. The model was validated across multiple independent cohorts, including IMmotion151, JAVELIN Renal 101, TCGA-KIRC, and West China Hospital (WCH) cohort from our center. Multi-omics analyses, including spatial and single-cell transcriptomics, were employed to investigate the associated biology and identify key mediators.
RESULTS: The final TRRS model, built from 7 genes, demonstrated robust performance in stratifying patients for overall survival (OS) and progression-free survival (PFS) in training and all validation sets. TRRS was a powerful predictor of improved outcomes not only for immune checkpoint inhibitor (ICI) monotherapy but also for ICI-based combination therapy and targeted therapies. Biologically, a high TRRS was associated with aggressive tumor hallmarks, a distinct metabolic profile favoring aerobic glycolysis and glutamine metabolism, and an immunosuppressive tumor microenvironment despite high immune cell infiltration based on WCH cohort transcriptome expression profile. Through multi-omics screening, we identified CST3 as a key target, with spatial and single-cell analyses confirming its role in promoting tumor malignancy and enhancing cell-cell communication among microenvironment components.
CONCLUSION: The TRRS is a novel, validated biomarker that effectively predicts prognosis and therapeutic responses in advanced ccRCC. It reflects critical biological features of tumor aggressiveness and immune evasion, with CST3 emerging as a potential central mediator and therapeutic target.

Keywords:  Clear cell renal cell carcinom; Machine learning; Proliferating T cell

DOI:  https://doi.org/10.1016/j.intimp.2026.116361
Scand J Clin Lab Invest. 2026 Feb 26. 1-11

Lower serum threonine and glutamine levels could be a predictor for multiple sclerosis in pregnancy.

Nuray Yazihan, Burcu Bozkurt Ozdal, Ayse Gulcin Bastemur, Ozlem Dogan, Iclal Sena Gezer, Ersin Ulusoy, Atakan Tanacan, Ozgur Kara, Dilek Sahin.

  Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system. Recently, research has highlighted the significance of biochemical evaluation of metabolic pathways and circulating amino acids beyond their fundamental role as protein building blocks. They also function as key modulators of the immune system, neurotransmission, collagen synthesis, metabolic and regenerative pathways, which may influence disease progression. We hypothesized that a disturbed amino acid profile could be used as a biomarker for MS in pregnancy. Amino acid profiles of pregnant women diagnosed with MS and healthy pregnant women were evaluated. MS diagnosis is done according to the McDonald criteria. The Expanded Disability Status Scale (EDSS) was used to evaluate MS patients. The medications used by pregnant women with MS for their disease were recorded. During the pregnancy period, none of them used a drug regimen. Progressive MS forms and EDSS > 3,5 were excluded from the study. Amino acid levels of MS patients were found to be different from healthy pregnant women. Excitatory amino acid levels were found to increase in MS patients. Glutamine and threonine levels are found to be decreased in MS pregnant women. Also, amino acids that take part in collagen synthesis are found to be different. Glutamic acid, histidine, asparagine, aspartate, proline, serine, ornithine, threonine, and tryptophan levels and citrulline/ornithine ratios are found to be significantly different between groups. These findings suggest that amino acid profiles could be potential biomarkers for early detection and new therapeutic targets for MS.

Keywords:  Multiple sclerosis; amino acids; glutamic acid; glutamine; pregnancy; threonine

DOI:  https://doi.org/10.1080/00365513.2026.2636045
Front Biosci (Landmark Ed). 2026 Feb 10. 31(2): 48370

Neonatal Hyperoxia Induces Metabolic Reprogramming in Senescent Alveolar Macrophages, Leading to Persistent Lung Injury.

Fanjie Lin, Elena Pineda, Bethany McGonnigal, Joselynn Wallace, Wenju Lu, Phyllis A Dennery, Hongwei Yao.

   BACKGROUND: Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants. Neonatal hyperoxia induces a BPD-like phenotype and lung cell senescence in rodents. In our 3-day hyperoxia model, senescent cells were predominantly lung macrophages, with their abundance peaking at postnatal day 7 (pnd7). However, the molecular and functional characteristics of these senescent macrophages remain undefined.
METHODS: We reanalyzed a scRNA-seq dataset (GSE207866) generated from senescent lung cells isolated at pnd7 (SD7) following neonatal hyperoxia. Hierarchical clustering combined with manual annotation was used to compare transcriptional profiles with age-matched air-exposed controls (AirD7) and hyperoxia-exposed mice without senescent-cell enrichment (O2D7). Key molecular findings were validated by immunofluorescence. In vivo, neonatal mice received daily injections of the pyruvate dehydrogenase kinase inhibitor, dichloroacetate (DCA) from pnd4 to pnd6, and a senolytic cocktail consisting of quercetin and dasatinib from pnd4 to pnd14, following 3 days of hyperoxia exposure.
RESULTS: Macrophages accounted for 65.90% of senescent cells in the SD7 group. Seven macrophage clusters were identified, enriched in M1-like and alveolar macrophage phenotypes. Two major clusters (clusters 0 and 1), together representing nearly half of all senescent macrophages, exhibited strong expression of genes associated with innate immunity, inflammation, and DNA damage responses. These clusters also showed a shift toward glycolysis, the pentose phosphate pathway, and glutamine metabolism, with reduced reliance on β-oxidation. Administration of DCA activated pyruvate dehydrogenase and attenuated hyperoxia-induced macrophage senescence and lung injury. Pathway enrichment analyses revealed enhanced metal-handling pathways, immune and stress signaling (including p38 mitogen-activated kinase, ataxia-telangiectasia mutated, and mechanistic target of rapamycin), apoptosis, and RNA regulatory processes. Conversely, genes involved in reactive oxygen species detoxification, DNA repair, phagocytosis, cytoskeletal organization, and cell adhesion were downregulated. Notably, reducing senescent cells by a senolytic cocktail during the alveolar stage mitigated hyperoxia-induced persistent lung injury.
CONCLUSION: Neonatal hyperoxia drives the emergence of a heterogeneous population of senescent macrophages characterized by metabolic reprogramming and dysregulated signaling pathways, which contribute to the development and persistence of lung injury.

Keywords:  bronchopulmonary dysplasia; cellular senescence; macrophages; metabolism; single-cell gene expression analysis

DOI:  https://doi.org/10.31083/FBL48370
Front Biosci (Landmark Ed). 2026 Feb 12. 31(2): 47739

Metabolic Portrait of Breast Cancer in Mixed Saliva.

Lyudmila V Bel'skaya.

   BACKGROUND: The metabolic profile of cancer includes changes in energy metabolism and biosynthetic (plastic) metabolism, and redox balance of tumor cells. This study aimed to identify clinically significant salivary metabolic features associated with breast cancer phenotypes.
METHODS: This study included 660 patients with breast cancer (age 54.6 ± 12.7 years) and 127 healthy volunteers (49.3 ± 14.2 years). Saliva samples were collected from all participants, strictly before the initiation of treatment, and the biochemical composition of saliva was determined, including indicators of antioxidant system activity, lipid profile, cytokines, and free amino acids.
RESULTS: Salivary metabolic features correlated with the breast cancer phenotype. In particular, for luminal A breast cancer, which has the most favorable prognosis, the presence of an active inflammatory process in saliva (C-reactive protein +136.6%, p < 0.0001; IL-1β +317.7%, p = 0.0004) and a pronounced immune anti-inflammatory response (INF-γ +79.1%, p = 0.0004) were shown. In contrast, for triple-negative breast cancer, a low anti-inflammatory response (INF-γ -4.1%) and active cell proliferation (glutamine +45.0%, p = 0.0342) were shown, which correlated with the disease severity, low immunogenicity, and the least favorable prognosis for this subtype of breast cancer.
CONCLUSIONS: Overall, salivary composition reflects systemic metabolic changes in breast cancer, which makes it possible to construct a metabolic portrait of breast cancer across distinct phenotypes.

Keywords:  DNA damage; amino acids; antioxidant enzymes; breast cancer; cytokines; lipids; metabolic profile; saliva

DOI:  https://doi.org/10.31083/FBL47739
Cancer Commun (Lond). 2026 ;46 0005

WTAP-Mediated Glutaminase Splicing Bias Suppresses Ferroptosis in Hepatocellular Carcinoma.

Can Zhu, Ke Wu, Tong Wu, Jun Ma, Bo Ding, Nan Jiang, Keyi Du, Guomin Ju, Haiyang Xie, Chuanhui Peng, Jian Wu, Shusen Zheng.

Background: Hepatocellular carcinoma (HCC), a highly aggressive malignancy with poor prognosis, is characterized by hyperactivation of the epidermal growth factor receptor (EGFR) signaling pathway. Glutaminase (GLS) is commonly overexpressed in numerous malignant tumors and acts as an oncogene to support cell growth and tumor progression, making it a target for cancer treatment. This study aimed to elucidate the underlying mechanisms of EGFR activation in driving glutaminolysis reprogramming and conferring ferroptosis resistance in HCC. Methods: Untargeted metabolomics, stable isotope-assisted metabolomic analysis, and RNA sequencing analysis were utilized to elucidate the mechanisms underlying glutaminolysis reprogramming upon EGFR activation. Immunoprecipitation, RNA pulldown, and dual-luciferase reporter assays were employed to examine the regulatory role of Wilms' tumor 1-associated protein (WTAP) phosphorylation in GLS alternative splicing. Flow cytometry, cell viability assays, tumor-bearing mouse models, and HCC clinical specimens were used to validate the role of the AKT-WTAP-GLS axis in ferroptosis resistance and tumor progression. Results: Here, we demonstrated that AKT activated by EGFR signaling phosphorylated WTAP S176 and increased WTAP binding to methyltransferase-like protein 3. The enhanced interaction promoted the site-specific N6-methyladenosine (m6A) modification of GLS pre-mRNA, which in turn favored the alternative splicing of GLS toward glutaminase C (GAC) over kidney-type glutaminase. This switch led to increased glutamine utilization and glutathione/nicotinamide adenine dinucleotide phosphate (reduced form) biosynthesis, thereby alleviating ferroptosis and promoting tumor growth in mice. In addition, the levels of WTAP pS176 and GAC expression, which were mutually correlated, were positively associated with poor prognosis of patients with HCC. Conclusions: These findings uncover a critical mechanism by which tumor cells counteract ferroptosis by WTAP-mediated GLS alternative splicing under EGFR activation, highlighting the therapeutic potential of targeting the m6A-dependent GLS isoform switch in HCC and offering a rationale for the development of combination therapies.

DOI: https://doi.org/10.34133/cancomm.0005
PLoS One. 2026 ;21(2): e0329048

The EAAT1 aspartate/glutamate transporter is dispensable for acute myeloid leukemia cell growth and response to therapy.

Hernán A Tirado, Nithya Balasundaram, Jean Jacobs, Fleur Leguay, Lotfi Laaouimir, Nick van Gastel.

Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic stem and progenitor cells characterized by profound metabolic dysregulation. Pyrimidine biosynthesis has emerged as a critical metabolic dependency in AML, but clinical translation has been hampered by unacceptable toxicity of current pyrimidine synthesis inhibitors. Since aspartate is an essential nutrient for pyrimidine biosynthesis, we investigated the role of aspartate import via the excitatory amino acid transporter 1 (EAAT1) in AML. We found that EAAT1 is broadly expressed across AML cell lines and patient samples, with enrichment in M4 and M5 subtypes and increasing levels following chemotherapy treatment. Pharmacological inhibition of EAAT1 impaired AML cell viability in vitro, but metabolomic profiling and nutrient rescue experiments showed that these effects were independent of intracellular aspartate levels. Moreover, AML cells cultured in aspartate-free medium maintained proliferation and did not become more sensitive to chemotherapy. EAAT1 inhibition in mice increased bone marrow plasma aspartate levels, confirming inhibition of cellular aspartate uptake, but did not affect growth or chemosensitivity of MLL-AF9-expressing AML cells in vivo. These findings suggest that AML cells possess several complementary mechanisms to support their aspartate requirements and that EAAT1 inhibition does not impair AML growth or response to chemotherapy.

DOI: https://doi.org/10.1371/journal.pone.0329048
Cell Rep. 2026 Feb 23. pii: S2211-1247(26)00064-1. [Epub ahead of print]45(3): 116986

Glutathione is critical for NK cell-mediated immunity.

Luana Guerra, Melanie Grusdat, Takumi Kobayashi, Joseph Longworth, Henry Kurniawan, Davide G Franchina, Georgios Theodorakis, Carole Binsfeld, Charlène Verschueren, Lynn Bonetti, Anouk Ewen, Leticia Soriano-Baguet, Sarah Alhamouieh, Sophie Farinelle, Catherine Dostert, Ying Chen, Vasilis Vasiliou, Eric Vivier, Philipp A Lang, Dirk Brenner.

  Natural killer (NK) cells are essential for immune protection against tumors and viruses. Disease environments impose oxidative stress and impair immune cell functions. Glutathione (GSH) is a major cellular antioxidant and is critical for the immune response, but how it modulates NK cell function remains largely unknown. Using a mouse model with a specific deletion of the catalytic subunit of glutamate-cysteine ligase (Gclc) in NK cells, we demonstrate that GSH supports interleukin-15 (IL-15)-driven activation of NK cells. Gclc deficiency causes an intracellular accumulation of reactive oxygen species (ROS), which impairs the metabolism of NK cells. This is accompanied by defective proliferation and cytokine production concurrent with subverted mTOR and STAT5 activation. During acute lymphocytic choriomeningitis virus (LCMV) infection, Gclc-deficient NK cells are unable to suppress the antiviral T cell response. Remarkably, Gclc deficiency impairs NK cell-mediated protection against tumor lung metastases. Our findings highlight an essential role of GSH in maintaining NK cell functionality.

Keywords:  CP: immunology; CP: metabolism; IL-15; LCMV; NK cells; cancer; cytotoxic T cells; glutathione; immunometabolism; mTOR; metastasis; redox metabolism

DOI:  https://doi.org/10.1016/j.celrep.2026.116986
bioRxiv. 2026 Feb 16. pii: 2026.02.13.705805. [Epub ahead of print]

Injury Causes Altered Metabolism including O 2 Consumption in Bovine and Human Chondrocytes.

Aidan J Gregory, Priyanka P Brahmachary, Molly E Piazza, William S Rockwell, Erik Myers, Mark Greenwood, Ross P Carlson, Ronald K June.

Traumatic joint injuries both disrupt chondrocyte metabolism and increase the risk for post-traumatic osteoarthritis. Yet the relationships between trauma, altered metabolism, and cartilage degradation remains unclear. This study compares the metabolic responses of bovine (normal) and osteoarthritic (OA) chondrocytes to physiological and injurious mechanical stimuli under normoxic (20% O 2 ) and hypoxic (5% O 2 ) conditions. Using primary chondrocytes encapsulated in agarose, physiological and injurious mechanical stimulation, targeted metabolomic profiling of central carbon metabolites, and O 2 saturation measurements, we find that healthy bovine chondrocytes exhibit robust, time-dependent adaptation to mechanical stimuli, whereas OA chondrocytes display a blunted response, particularly under injury conditions. Injurious mechanical stimuli led to altered O 2 consumption and glutamine accumulation, suggesting disrupted respiration and reduced protein synthesis hypothesized to be a result of altered mitochondrial metabolism in OA cells. These findings underscore the role of mechanical cues in chondrocyte metabolism and inform future studies aimed at identifying metabolic targets relevant to post-traumatic osteoarthritis progression.

DOI: https://doi.org/10.64898/2026.02.13.705805
Viruses. 2026 Jan 29. pii: 186. [Epub ahead of print]18(2):

Multi-Omics Analyses Reveal Metabolic Alterations Regulated by Orf Virus in Primary Ovine Fetal Turbinate Cells.

Ran Zhang, Fei Gao, Jiyu Guan, Lijun Lv, Zhuomei Li, Mengshi Xu, Yiran Sun, Pin Lv, Yiguang Wu, Huijun Lu, Zi Li, Yungang Lan, Feng Gao, Wenqi He, Kui Zhao.

  Orf virus (ORFV) is a member of the Parapoxvirus genus of the Poxviridae family causing contagious diseases in sheep, goats, and wild ungulates, with zoonotic potential in humans. Although many viruses, including poxviruses, are known to utilize the host cellular machinery to reproduce viral particles, the metabolic changes induced by ORFV remain unclear. In the present study, non-targeted metabolomics and proteomics were employed to investigate the impact of ORFV infection on the host cellular metabolism network. A total of 301 metabolites and 802 proteins were significantly altered during the early stages of ORFV infection, and most of them were involved in cellular lipid metabolism, amino acid metabolism, nucleotide metabolism, and glucose metabolism. We further determined the effect of the host's metabolic system on ORFV replication using the TCID50 assay. Virus titers were significantly decreased in the absence of glucose or when treated with the de novo fatty acid synthesis inhibitor, indicating that glucose metabolism and de novo fatty acid synthesis pathway were required for ORFV replication. However, glutamine did not affect viral titers. Our findings provide insights into ORFV-host interactions, which are critical for developing new preventive or therapeutic strategies against ORFV by targeting altered metabolic pathways.

Keywords:  ORFV; host cellular metabolism; non-targeted metabolomics; proteomics; viral–host interaction

DOI:  https://doi.org/10.3390/v18020186
bioRxiv. 2026 Feb 18. pii: 2026.02.17.706183. [Epub ahead of print]

Untargeted metabolomic profiling reveals mTORC1-dependent regulation of amino acid utilization in lymphatic endothelial cells.

Jie Zhu, Felix Darko, Fei Han, Summer Simeroth, Lingjun Li, Haiwei Gu, Pengchun Yu.

The lymphatic vascular system plays essential roles in tissue fluid drainage, dietary fat absorption and transport, and immune cell trafficking. To support these physiological functions, the lymphatic vasculature forms an extensive and highly organized network throughout the body. We have recently discovered that the mechanistic target of rapamycin complex 1 (mTORC1), with RAPTOR as an indispensable component, directs glycolysis and glutaminolysis in lymphatic endothelial cells (LECs) to promote lymphatic vessel formation. However, the role of mTORC1 in regulating LEC metabolism remains incompletely understood. Here, by conducting untargeted metabolomic profiling of control and RAPTOR-deficient LECs, we uncover a global impact of mTORC1 inhibition on amino acid utilization. Specifically, RAPTOR deficiency impairs the conversion of glutamine to glutamic acid, resulting in decreased levels of glutamic acid and aspartic acid, as well as reduced abundance of N-acetyl-glutamic acid and N-acetyl-aspartic acid-two metabolites unexpectedly detected in LECs. Integrated metabolomic and transcriptomic analyses further reveal that impaired glutaminolysis in RAPTOR-depleted LECs is accompanied by an increase in intracellular asparagine, arginine, and metabolites associated with arginine catabolism, potentially driven by upregulation of their respective transporters. In addition, RAPTOR depletion results in abnormal accumulation of branched-chain amino acids (BCAAs) and other essential amino acids primarily involved in protein synthesis. Mechanistically, our data suggest that defective BCAA catabolism and impaired translational control contribute to these metabolic alterations. Collectively, these findings reveal an important role of mTORC1 signaling in coordinating amino acid utilization and suggest that this regulation is critical for lymphatic vessel formation.

DOI: https://doi.org/10.64898/2026.02.17.706183
Mol Biomed. 2026 Feb 26. pii: 15. [Epub ahead of print]7(1):

Lactate metabolism and protein lactylation in cancer.

Zhaoyun Liu, Aili Li, Ziyu Ma, Junzhu Wang, Xinyu Chen, Zhiwei Wang, Rong Fu.

  Lactylation is a recently identified post-translational modification that links cellular metabolism to gene regulation, playing pivotal roles in cancer development and the tumor microenvironment (TME). Derived from lactate produced by glycolysis and glutamine metabolism, lactylation occurs on both histone and non-histone proteins, modulating transcription, protein function, and cellular signaling. In tumors, lactylation contributes to proliferation, metastasis, therapy resistance, and immune evasion by influencing the function of Treg cells, macrophages, dendritic cells, and NK cells. Its dynamic regulation by "writers" (e.g., p300), "erasers" (e.g., Histone deacetylases (HDACs), Sirtuins3 (SIRT3)), and transporters (e.g., monocarboxylate transporters (MCT) 1/4) provides multiple intervention points for therapy. Preclinical studies demonstrate that targeting lactylation directly or indirectly-through LDH (lactate dehydrogenase) inhibition, MCT blockade, or modulation of lactyltransferases-enhances the efficacy of immune checkpoint inhibitors, Chimeric Antigen Receptor T (CAR-T) therapy, and chemotherapeutic agents.Despite these advances, critical questions remain regarding the specificity of lactylation compared with other post-translational modifications, the tumor types most dependent on lactylation, and reliable biomarkers to guide treatment. Additionally, clinical validation of lactylation-targeting strategies is limited. Future research integrating mechanistic studies, patient-derived samples, and multi-omics approaches is essential to elucidate context-dependent functions, refine therapeutic targets, and develop precision interventions.This review provides a comprehensive summary of lactylation biology in cancer, highlighting its metabolic-epigenetic interplay, immunomodulatory roles, and therapeutic potential. By synthesizing current evidence, we aim to guide future studies and clinical strategies targeting lactylation to improve cancer treatment outcomes.

Keywords:  Cancer therapy; Histone modification; Immune evasion; LDH; Lactylation; Tumor microenvironment

DOI:  https://doi.org/10.1186/s43556-026-00417-4
Free Radic Biol Med. 2026 Feb 19. pii: S0891-5849(26)00147-4. [Epub ahead of print]248 210-221

Alpha-ketoglutarate dehydrogenase: more than just a TCA cycle enzyme.

Ryan J Mailloux.

Alpha-ketoglutarate dehydrogenase (KGDH; EC 1.2.4.2) catalyzes the fourth step of the tricarboxylic acid (TCA) cycle and links carbohydrate, fatty acid and amino acid metabolism to the aerobic production of ATP. KGDH is classically viewed as indispensable to energy metabolism and strictly located to mitochondria. Therefore, it is generally thought that the loss of its activity has catastrophic consequences for mammalian cells. However, recent advances in molecular biology and redox biology tools coupled with the implementation of new genetically modified mouse lines and cultured cells knocked down for components of KGDH have revealed it is a multifunctional cellular enzyme that localizes to the mitochondria and nucleus where it uses superoxide (O2•-)/hydrogen peroxide (H2O2) and metabolites related to its catalysis (e.g., alpha-ketoglutarate (KG), succinyl-CoA, succinate) to control cell fate decisions. In addition, it has been revealed that over-stimulation of KGDH causes severe oxidative stress through the hyper-production of O2•-/H2O2 and disturbs cell signals and epigenome regulation, which has been linked to cancer cell transformation, metabolic diseases like metabolic dysfunction-associated steatotic liver disease (MASLD), and inflammation. Furthermore, inhibition of KGDH with competitive inhibitors, redox modifications, or shRNAs has shown that the targeted disruption of the enzyme can alleviate these diseases. The aim of this review is to update the literature on KGDH. It is not just a TCA cycle enzyme anymore.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.02.050
Indian J Hematol Blood Transfus. 2026 Mar;42(2): 542-550

Evaluation of SLC38A1 in Pediatric and Adult Acute Leukemias; A Potential New Prognostic Factor.

Maryam Khajavi, Hossein Ayatollahi, Mohammad Reza Keramati, Arefeh Mazhari, Maryam Sheikhi, Habibollah Esmaily, Mohammad Hadi Sadeghian, Hassan Mehrad-Majd, Samaneh Boroumand-Noughabi.

  Solute carrier family 38 member 1 (SLC38A1) is a principal glutamine transporter associated with solid tumor development and progression. However, it has rarely been investigated in hematologic malignancies. This study aimed to assess the expression status and correlation of SLC38A1 with clinicopathological features in acute leukemia patients. In this cross-sectional study, SLC38A1 expression was evaluated via RTQ-PCR in 140 denovo acute leukemia patients (70 adult AML cases and 70 pediatrics B-ALL cases) and 70 healthy controls (40 adults and 30 children for the AML and B-ALL groups, respectively). Statistical analysis was done by IBM SPSS software version 20. Other clinical and laboratory data including genetic testing, when available, were extracted from the Hospital Information System (HIS). We found that SLC38A1 was overexpressed in both types of acute leukemia patients compared with controls (Median (IQR): 4.26(11.32) for AML vs. 1.08(1.68) for control; P = 0.026, and 5.76(15.97) for B-ALL vs. 0.65(1.18) for control; P = 0.019). The distribution of FAB and WHO classifications varied significantly between AML patients with high SLC38A1 expression compared to those with low expression (P = 0.005 and P = 0.017, respectively). In addition, B-ALL patients in low or high SCL38A1 expression groups showed various distributions regarding WHO classification (P = 0.03). In Kaplan-Meier analysis, both AML and B-ALL patients with SLC38A1 high had shorter overall survival (OS) compared to SLC38A1 low patients (P < 0.001 and P = 0.007, respectively). Multivariate analysis confirmed that SLC38A1 upregulation was an independent indicator for prognosis in acute leukemia patients (HR = 3.856, 95% CI = 1.766-8.421, P = 0.001 for AML and HR = 2.718, 95% CI = 1.086-6.797, P = 0.03 for B-ALL). Our results indicated that overexpression of SLC38A1 was correlated with poor OS in both AML and B-ALL patients. Therefore, SLC38A1 may be used as a prognostic marker in acute leukemias.
Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-025-02030-x.

Keywords:  ALL; AML; Acute leukemia; SLC38A1; Survival

DOI:  https://doi.org/10.1007/s12288-025-02030-x