bims-glucam 2026-03-22 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–03–22
eighteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Structural reassignment of compound 968, an allosteric glutaminase inhibitor.
Glutamine promotes acute wound healing by mediating glutamine metabolism and M2 macrophage polarization via the MEK/ERK/SLC1A5 signaling pathway.
Metabolic Tracing Reveals IL-2 Driven Glutaminolysis and De Novo Pyrimidine Synthesis in Human Natural Killer Cells.
A CHKA-PML autophagy checkpoint enables tumors to evade glutamine starvation.
BMAL1 modulates glutamine supply to control hematopoietic stem and progenitor cell expansion.
Extracellular levels of glutamate, glutamine, cystine, glutathione, and xanthine correlate with transporter expression in tamoxifen - resistant MCF-7 cells and poor overall survival in breast cancer patients.
Protein S-acylation dynamics provide metabolic plasticity to acute myeloid leukemia cells.
Single-Cell RNA-Sequencing of Peripheral Blood Reveals Neutrophil Heterogeneity in Childhood ANCA-Associated Vasculitis.
Vaccinia-related kinase 2 inhibition elicits vulnerability of glutathione metabolism in pancreatic cancer.
A metabolic trade-off between malignant plasma cells and mesenchymal stromal cells sustains multiple myeloma growth.
Catabolism of extracellular glutathione supplies cysteine to support tumours.
Construction of ammonia death-related lncRNA prognostic signature model and immunomodulatory effect in glioblastoma multiforme.
3-Methylcrotonyl-CoA Carboxylase Expression Among Astrocytes and Neurons in the Human Brain and the Effect of Hyperglycemia on the Catabolic Flux of 13C6, 15N-Leucine in Cultured Astrocytes.
A systematic characterization of amino acid metabolism-related genes reveals molecular subtypes and a prognostic signature in bladder cancer.
Theasinensin C Mitigates HFrD-Induced Neuroinflammation by Enriching Akkermansia muciniphila and Orchestrating a Gln/Ser-Centered Multiorgan Metabolic Relay to Drive Creatine Biosynthesis.
Metabolic-based therapeutic strategies to treat Huntington's disease.
Progress in metabolic reprogramming of gastric malignant tumors to remodel tumor immune microenvironments.
L-2-hydroxyglutarate impairs neuronal differentiation through epigenetic activation of MYC expression.

Beilstein J Org Chem. 2026 ;22 455-460

Structural reassignment of compound 968, an allosteric glutaminase inhibitor.

Lindsey A Albertelli, Sainabou Jallow, Chun Li, Scott M Ulrich.

  Many cancer cells require extracellular glutamine to meet the energetic, biosynthetic, and redox demands of the proliferative state. Glutaminases catalyze the hydrolysis of glutamine to glutamate, which supports the biosynthesis of amino acids, lipids, and glutathione and can also be oxidatively deaminated to α-ketoglutarate and enter the citric acid cycle. The "glutamine addiction" of cancer cells has made glutaminase an attractive anticancer drug target. Compound 968 is a glutaminase inhibitor that is widely used to probe cancer cells' dependence on glutaminase activity. Here, we show by NMR spectroscopy and X-ray crystallography that the reported benzo[c]phenanthridine structure of compound 968 is incorrect; its true structure is the isomeric benzo[c]acridine. The structural reassignment of compound 968 will aid the medicinal chemistry development of this important compound.

Keywords:  cancer metabolism; compound 968; glutaminase

DOI:  https://doi.org/10.3762/bjoc.22.33
Sci Rep. 2026 Mar 19.

Glutamine promotes acute wound healing by mediating glutamine metabolism and M2 macrophage polarization via the MEK/ERK/SLC1A5 signaling pathway.

Yan Shi, Mingheng Pan, Xue Chen, Ye Bi, Xiaolong Wei, Feiyang Zheng, Hao Xia, Xiaoqing He.

  To demonstrate glutamine (Gln) promotes acute wound healing by mediating Gln metabolism and macrophage M2 polarization through the Mitogen-Activated Protein Kinase Kinase (MEK)/Extracellular Regulated Protein Kinases (ERK)/Solute Carrier Family 1 Member 5 (SLC1A5) signaling axis.Thirty C57BL/6J mice were used to establish a full-thickness skin defect model and randomly divided into six groups (n = 5 per group): Control group, Model group, Gln treatment group (Gln), Gln combined with MEK inhibitor U0126 group (Gln + MEK inhibitor), Gln combined with GLS1 inhibitor group (Gln+GLS1 inhibitor), and Gln combined with SLC1A5 inhibitor group (Gln+SLC1A5 inhibitor). Immunofluorescence (IF) was used to detect the angiogenesis marker CD31, the fibroblast activation marker α-smooth muscle actin (α-SMA), and macrophage polarization markers (CD86 for M1, CD206 for M2). Gln upregulates the expression of SLC1A5 by activating MEK/ERK pathway, thus promoting Gln metabolic reprogramming and accelerating acute wound healing. This subsequently drives M2 macrophage polarization, angiogenesis, and tissue remodeling. Our findings elucidate the critical role of the Gln metabolism-immune regulation axis in wound repair and provide a novel therapeutic target for metabolically targeted wound interventions.

Keywords:  Glutamine; Glutamine metabolism; M2 macrophage polarization; MEK/ERK/SLC1A5; Metabolic reprogramming; Wound healing

DOI:  https://doi.org/10.1038/s41598-026-41545-9
J Biol Chem. 2026 Mar 12. pii: S0021-9258(26)00237-1. [Epub ahead of print] 111367

Metabolic Tracing Reveals IL-2 Driven Glutaminolysis and De Novo Pyrimidine Synthesis in Human Natural Killer Cells.

Karen Slattery, Gearóid Conlon, Ethan Collins, Derek P Nolan, Clair M Gardiner, Geraldine M O'Connor.

Natural Killer (NK) cells are innate lymphocytes that are key to intrinsic cancer immunosurveillance and an important target for cancer immunotherapy. Understanding fundamental human NK cell metabolism provides opportunities for optimising NK cell therapies. Little is known about how glutamine, an important cell nutrient and carbon source, is utilised by human NK cells. To address this, we performed U13C-glutamine tracing experiments by Liquid Chromatography Mass Spectrometry (LCMS) and Gas Chromatography Mass Spectrometry (GCMS) analysis of human NK cells stimulated with IL-2 for 18 hours to provide a global overview of glutamine usage by these cells. Our results show that glutamine is taken up by resting NK cells and that this increases further upon IL-2 stimulation. Metabolite labelling analysis identified that IL-2 results in greater conversion of glutamine to glutamate, allowing for anaplerotic flux into the TCA cycle. The fate of the glutamine-derived carbons diverged at oxaloacetate (OAA) allowing both bioenergetic and biosynthetic outcomes - some carbons continued around the TCA cycle while others were exported, converted to aspartate and subsequently used for pyrimidine synthesis. Nucleotide synthesis by IL-2 activated NK cells was found to be essential for expression of the activation marker CD69. The data indicate that glutamine is a key nutrient taken up by human NK cells, and that IL-2 drives glutaminolysis. Subsequent glutamate is used to support the TCA cycle, generating energy and providing intermediates for de novo pyrimidine synthesis.

DOI: https://doi.org/10.1016/j.jbc.2026.111367
Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2523253123

A CHKA-PML autophagy checkpoint enables tumors to evade glutamine starvation.

Ruijie Wang, Leixi Cao, Xianwei He, Rick Francis Thorne, Qichen Wu, Caoyuan Ding, Jinjing Zhang, Mengfan Li, Zeyuan Shi, Xinyi Dong, Jing Li, Hongxiang Li, Suhua Gao, Jinming Li, Xu Dong Zhang, Lei Jin, Tianli Fan, Mian Wu.

  Glutamine metabolism is essential for tumor cell proliferation and biosynthesis. However, solid tumors often face chronic glutamine deprivation, and the underlying adaptive mechanisms remain incompletely understood. Here, we show that glutamine scarcity upregulates choline kinase alpha (CHKA), whose monomerization enhances its noncanonical protein kinase activity. CHKA phosphorylates promyelocytic leukemia (PML) at tyrosine 339, promoting its cytoplasmic localization. Notably, this reflects a compartment-specific switch in PML activity: while nuclear PML facilitates protein degradation through Small Ubiquitin-like Modifier (SUMO)-ubiquitin cascades, cytoplasmic PML acts oppositely to block degradation. Specifically, cytoplasmic PML then induces SUMOylation of WD Repeat Domain Phosphoinositide-Interacting Protein 2 (WIPI2) at lysines 281 and 283, thereby blocking HUWE1-mediated ubiquitination and proteasomal degradation. Stabilized WIPI2 increases autophagic flux, supporting tumor cell survival under metabolic stress. This study identifies a critical CHKA-PML-WIPI2 axis mediating adaptation to glutamine deprivation, providing insight into metabolic plasticity and a potential therapeutic target for glutamine-dependent cancers.

Keywords:  CHKA; PML; WIPI2; autophagy; glutamine deprivation

DOI:  https://doi.org/10.1073/pnas.2523253123
Development. 2026 Mar 19. pii: dev.204726. [Epub ahead of print]

BMAL1 modulates glutamine supply to control hematopoietic stem and progenitor cell expansion.

Tim Petzold, Lydia K Lutes, Keila Navarro I Batista, Antonia Konle, Bastien Baechler, Stéphane Jemelin, Holger Gerhardt, Rachel Golub, Christoph Scheiermann, Julien Y Bertrand.

  Following specification in the dorsal aorta, hematopoietic stem and progenitor cells (HSPCs) proliferate in the HSPC niche, known as the caudal hematopoietic tissue (CHT) in zebrafish. Here we demonstrate that bmal1a, a core component of the circadian clock machinery, is expressed in CHT endothelial cells (ECs) and affects HSPCs in a non-cell autonomous manner. Using endothelial cell-specific dominant-negative Bmal1a zebrafish lines, we demonstrate a striking increase in HSPC numbers in the CHT, resulting from enhanced HSPC proliferation. RNA-sequencing of dominant-negative bmal1a ECs sorted from the CHT shows a downregulation of glud1a, resulting in increased glutamine levels in the CHT. This newly discovered bmal1a-glud1a-glutamine pathway fuels HSPC expansion. We demonstrate that this glutamine synthesis pathway controlling HSPC expansion is likely conserved in the mouse fetal liver (FL) niche, in which hepatocytes are the likely source of glutamine. Together, our data uncover a novel mechanism of HSPC homeostasis, in which EC BMAL1, expressed by the niche, controls the amount of bioavailable glutamine for HSPCs by regulating the expression of genes involved in glutamine synthesis.

Keywords:  Endothelial cell; Expansion; Glutamine; HSPC; Mouse; Niche; Zebrafish

DOI:  https://doi.org/10.1242/dev.204726
Cell Biochem Biophys. 2026 Mar 16.

Extracellular levels of glutamate, glutamine, cystine, glutathione, and xanthine correlate with transporter expression in tamoxifen - resistant MCF-7 cells and poor overall survival in breast cancer patients.

Ala A Alhusban, Lama A Hamadneh, Mohammad Alwahsh, Mays E Altaweel, Ola A Tarawneh, Wassan Jarrar, Ahmad A Deeb, Aya Hasan.



Keywords:  Breast cancer; LC–MS/MS; MCF-7; Metabolite transporter; Tamoxifen resistance

DOI:  https://doi.org/10.1007/s12013-026-02045-9
bioRxiv. 2026 Mar 03. pii: 2026.03.02.708949. [Epub ahead of print]

Protein S-acylation dynamics provide metabolic plasticity to acute myeloid leukemia cells.

Nithya Balasundaram, Ayşegül Erdem, Azeem Sharda, Veerle W Daniels, Phillip L Chea, Fleur Leguay, Youzhong Liu, Mark A Keibler, Charles Vidoudez, Andrew A Lane, Didier Vertommen, Hans Casteur, Michaël R Laurent, Sunia A Trauger, Gregory Stephanopoulos, David T Scadden, Nick van Gastel.

Though cancer cells' altered metabolism has been recognized for a century, the clinical success of metabolic targeting remains limited due to metabolic plasticity. Here, we use acute myeloid leukemia (AML) as a model to investigate this adaptability through combinatorial metabolic compound screening. Synthetic lethality emerged when AML cells were simultaneously treated with a glutaminase inhibitor and TOFA, a hypolipidemic agent. Sensitivity to this combination was also seen in primary patient samples and in other cancer types, while healthy hematopoietic progenitors were not affected. Unexpectedly, we discovered that TOFA acts through a non-canonical inhibition of protein S-acyltransferases. Protein S-acylation in AML cells specifically requires 16-to-18 carbon long fatty acids and is essential to maintain mitochondrial respiration upon glutaminolysis inhibition. Healthy cells in contrast have high intrinsic metabolic flexibility independent of S-acylation. Our results expose a unique mechanism of metabolic plasticity in cancer that could be targeted to enhance metabolic anti-cancer therapies.

DOI: https://doi.org/10.64898/2026.03.02.708949
J Inflamm Res. 2026 ;19 545080

Single-Cell RNA-Sequencing of Peripheral Blood Reveals Neutrophil Heterogeneity in Childhood ANCA-Associated Vasculitis.

Shengsen Wei, Liwen Tan, Lin Tang, Hua-Ying Xiong, Qin Yang, Jia Jiao, Zilin Liu, Gaofu Zhang, Haiping Yang, Qiu Li, Aihua Zhang, Mo Wang.

   Background: The intolerance of the body to neutrophil antigens drives the pathogenesis of childhood anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV), making neutrophils a central focus of research on the disease's underlying mechanisms.
Methods: We performed single-cell RNA sequencing on 18 peripheral blood samples (including three healthy human samples, twelve samples from patients with different types of AAV, and three samples from patients after AAV treatment) to investigate neutrophil heterogeneity in AAV. These bioinformatics findings were subsequently validated through comprehensive experimental approaches, including in vitro cellular assays, in vivo animal studies, clinical sample analyses, and correlation with patient clinical data.
Results: In AAV, neutrophils were reclassified into seven distinct clusters, Neutrophils2 (N2, CD10+CD11B++) exhibited significant expansion (P<0.01), while Neutrophils5 (N5, CD10-CD11B++) showed a trend toward increase (P>0.05). This phenomenon has been confirmed by the experimental autoimmune vasculitis model (CD10+CD11B++, P<0.001; CD10-CD11B++, P<0.05). The bioinformatics results indicated that both CD10+CD11B++ neutrophils and CD10-CD11B++ neutrophils exhibited dominant pro-inflammatory activities, including neutrophil activation, reactive oxygen species production, neutrophil extracellular trap formation, and degranulation. Pseudotime trajectory and RNA velocity analyses indicated direct differentiation of CD10+CD11B++ neutrophils from CD10-CD11B++ neutrophils. Experiments using HL-60 cells demonstrated that the peripheral blood microenvironment of AAV promotes the generation of CD11B++ neutrophils (P<0.001). Functionally relevant metabolic profiling revealed a substantial reduction in glutamine metabolism in the CD10+CD11B++ neutrophils of AAV patients compared to controls (P<0.001), which was restored following treatment (P<0.001). Experimental results demonstrated that increasing glutamine concentration in the microenvironment of HL-60 cells can decrease the production of CD11B++ neutrophils (P<0.001). Clinical data demonstrate that peripheral blood GGT concentrations increase in patients following treatment (P<0.01).
Conclusion: These findings identify two novel pathogenic neutrophil subsets and suggest that modulation of glutamine metabolism is a promising avenue for further investigation as a potential therapeutic strategy in childhood AAV.

Keywords:  AAV; heterogeneity; metabolic reprogramming; neutrophil; single-cell RNA sequencing

DOI:  https://doi.org/10.2147/JIR.S545080
Cell Death Dis. 2026 Mar 19.

Vaccinia-related kinase 2 inhibition elicits vulnerability of glutathione metabolism in pancreatic cancer.

Sisi Chen, Xiaowei Fu, Tianyue Zhang, Rui Zhou, Long Liu, Liuhai Zeng, Bin Xu, Hengqing Zhu, Zhiyu Li.

Metabolic reprogramming has garnered significant attention in recent years due to its therapeutic potential in cancer treatment. However, identifying responsive tumor subpopulations remains a major obstacle in developing metabolism-targeted therapies, as metabolic vulnerabilities vary among cancers with different oncogene expression profiles. Therefore, elucidating the association between oncogene expression and metabolic characteristics could enable more precise metabolic interventions in clinical settings. Using pharmacological approaches, we demonstrate that VRK2-deficient pancreatic cancer (PC) cells exhibit heightened vulnerability to glutathione (GSH) metabolic pathway inhibition. This susceptibility stems from reduced basal GSH levels caused by impaired plasma membrane expression of SLC7A11. Mechanistically, we reveal that VRK2 inhibition disrupts endoplasmic reticulum (ER)-to-Golgi trafficking of SLC7A11, consequently diminishing GSH biosynthesis and predisposing PC cells to ferroptosis. Collectively, our findings establish a novel link between the oncogene VRK2 and GSH synthesis metabolism, providing a molecular basis for developing stratified metabolic therapies for PC patients.

DOI: https://doi.org/10.1038/s41419-026-08573-9
Blood Neoplasia. 2026 May;3(2): 100195

A metabolic trade-off between malignant plasma cells and mesenchymal stromal cells sustains multiple myeloma growth.

Giuseppe Taurino, Erika Griffini, Denise Toscani, Chiara Maccari, Saverio Tardito, Massimiliano G Bianchi, Lavinia Casati, Erica Dander, Giovanna D'Amico, Roberta Andreoli, Nicola Giuliani, Ovidio Bussolati, Martina Chiu.

Multiple myeloma (MM) is a glutamine (Gln)-auxotroph and Gln-addicted cancer, with Gln synthetase (GS)-deficient MM cells avidly taking up extracellular Gln to sustain their metabolism. Thus, MM cells create a peculiar metabolic niche in the patients' bone marrow (BM), where low levels of Gln contribute to the osteolytic bone lesions by inhibiting the osteoblastic differentiation of mesenchymal stromal cells (MSCs). The effects of the altered MM metabolic niche on other BM cell populations remain to be clarified. We demonstrate here that MM cells secrete high amounts of glutamate through the exchange transporter SLC7A11/xCT. In turn, BM MSCs, but neither MM cells nor osteoblasts (OBs), actively take up extracellular glutamate through the transporter EAAT3 (SLC1A1), whose expression decreases during osteogenesis. GS-positive MSCs secrete Gln, a process boosted by extracellular glutamate in undifferentiated MSCs, but not in differentiated OBs. Coculture of MSCs with MM cells promotes the expression of the bidirectional transporter SNAT5 (SLC38A5), suggesting its involvement in Gln efflux. Consistently, MSCs, derived from either patients with MM or healthy donors, sustain MM growth in a low-Gln environment, an effect suppressed by the inhibition or silencing of glutamate uptake or Gln synthesis. In conclusion, a metabolic cycle occurs in MM BM microenvironment, where Gln-auxotroph MM cells extrude glutamate that is converted into Gln by MSC, sustaining in turn MM anabolism through Gln secretion. The inhibition of this metabolic trade-off impairs MM cell growth, thus highlighting novel potential, niche-oriented therapeutic targets.

DOI: https://doi.org/10.1016/j.bneo.2026.100195
Nature. 2026 Mar 18.

Catabolism of extracellular glutathione supplies cysteine to support tumours.

Fabio Hecht, Marco Zocchi, Emily T Tuttle, Nathan P Ward, Fatemeh Alimohammadi, Amal Afzal Khan, Veronica C Gomes, Bradley Smith, Jennifer J Twardowski, Bradley N Mills, Kevin A Welle, Sina Ghaemmaghami, Zhuoran Zhou, Yuhan Gan, Yun Pyo Kang, Juliana Cazarin, Zamira G Soares, Mete Emir Ozgurses, Huiping Zhao, Colin Sheehan, Guillaume Cognet, Lila D Munger, Dhvani Trivedi, Gloria Asantewaa, Sara K Blick-Nitko, Jason J Zoeller, Ying Chen, Vasilis Vasiliou, Bradley M Turner, Stephano S Mello, Brian J Altman, Alexander Muir, Jonathan L Coloff, Joshua Munger, Gina M DeNicola, Isaac S Harris.

Restricting amino acids from tumours is an emerging therapeutic strategy with substantial promise1. Although typically considered an intracellular antioxidant with tumour-promoting capabilities2, glutathione (GSH), as a tripeptide of cysteine, glutamate and glycine, can be catabolized to release amino acids. The extent to which GSH-derived amino acids are essential to cancers is unclear. Here we show that depletion of intracellular GSH does not alter tumour growth and extracellular GSH is highly abundant in the tumour microenvironment, highlighting the potential importance of GSH outside tumours. Supplementation with GSH rescues cancer cell survival and growth in cystine-deficient conditions, and this rescue depends on the catabolic activity of γ-glutamyltransferases. Finally, pharmacological targeting of the activity of γ-glutamyltransferases prevents the breakdown of circulating GSH, reduces tumour cysteine levels and slows tumour growth. Our findings indicate a non-canonical role for GSH in supporting tumours by acting as a reservoir of amino acids. Depriving tumours of extracellular GSH or inhibiting its breakdown is potentially a therapeutically tractable approach for patients with cancer. Furthermore, these findings change our view of GSH and how amino acids, including cysteine, are supplied to cells.

DOI: https://doi.org/10.1038/s41586-026-10268-2
Brain Res. 2026 Mar 18. pii: S0006-8993(26)00125-3. [Epub ahead of print] 150266

Construction of ammonia death-related lncRNA prognostic signature model and immunomodulatory effect in glioblastoma multiforme.

Zhe Han, Cheng Zhong, Eyu Tan, Mingliang He, Jinman Liu.

   BACKGROUND: Glioblastoma (GBM) is characterized by "glutamine addiction," a metabolic state that generates toxic ammonia byproducts. We explored the prognostic value of long non-coding RNAs (lncRNAs) associated with ammonia-induced cell death-a novel mechanism distinct from apoptosis and ferroptosis-to identify potential biomarkers and elucidate the metabolic-immune landscape of GBM.
METHODS: Ammonia death-associated genes were identified via co-expression analysis in TCGA-GBM datasets. A prognostic signature was constructed using LASSO-Cox regression and validated in independent CGGA cohorts. Single-cell RNA sequencing (scRNA-seq) was utilized to characterize cellular heterogeneity and map ammonia death scores to specific cell populations. The expression of signature lncRNAs was validated in vitro using human GBM cell lines (U-251, U-87 MG) and normal human astrocytes via RT-qPCR.
RESULTS: A robust three-lncRNA signature (LINC00645, AC011451.4, AC093627.22) was established. The high-risk score served as an independent predictor of significantly poorer overall survival (P < 0.001). scRNA-seq revealed that regulatory T cells (Tregs) and macrophages exhibited the highest ammonia death scores. Consistently, high-risk tumors displayed a profoundly immunosuppressive microenvironment, characterized by increased infiltration of M2 macrophages and Tregs, elevated ESTIMATE scores, and upregulation of immune checkpoints (e.g., PD-L1, IDO1). RT-qPCR results confirmed the dysregulated expression of these lncRNAs in GBM cells consistent with bioinformatic predictions.
CONCLUSIONS: This novel signature effectively links metabolic ammonia stress to immune evasion in GBM. It serves as a reliable prognostic tool and suggests that targeting the ammonia death-related metabolic-immune axis could offer new avenues for personalizing immunotherapy.

Keywords:  Ammonia; Glioblastoma multiforme; Immunotherapy; LncRNAs; Prognosis

DOI:  https://doi.org/10.1016/j.brainres.2026.150266
Neurochem Res. 2026 Mar 19. pii: 113. [Epub ahead of print]51(2):

3-Methylcrotonyl-CoA Carboxylase Expression Among Astrocytes and Neurons in the Human Brain and the Effect of Hyperglycemia on the Catabolic Flux of 13C6, 15N-Leucine in Cultured Astrocytes.

Radovan Murín, Jakub Šofranko, Andrej Kováč, Markéta Murínová, Eduard Gondáš.

  Leucine is an essential amino acid which is imported into the brain parenchyma with high capacity. Animal studies have demonstrated that leucine plays a significant role in several cellular and physiological processes in brain parenchyma. In addition to its role in protein synthesis, leucine possesses signaling and regulatory functions. Furthermore, leucine catabolism may provide brain cells with amino nitrogen for the synthesis of glutamate and glutamine with an impact on sustaining glutamatergic and GABA-ergic neurotransmission. The entry of leucine's carbon skeleton into the intermediary metabolism of astrocytes yields the production of ketone bodies and acetyl-CoA. In order to investigate the metabolic capabilities of human astrocytes regarding leucine, we enriched their culture media with 13C₆,15N-leucine and conducted a metabolomic study using liquid chromatography-mass spectrometry (LC-MS) to identify and quantify isotopically labelled metabolites. Furthermore, we employed an antiserum against 3-methylcrotonyl-CoA carboxylase (MCC), the unique enzyme in the irreversible phase of leucine catabolism, to identify MCC-expressing cells both in culture and in situ. Our results indicate that cultured human astrocytes efficiently removed leucine from the medium, which was then enriched with several compounds containing nitrogen and/or carbon atoms derived from leucine. Among the released metabolites, glutamine and citrate were the most abundant. Leucine uptake was independent of glucose concentration; however, hyperglycemic conditions stimulated the capacity for the irreversible catabolism of the leucine-derived carbon skeleton. Immunoprobing with the MCC antiserum confirmed the mitochondrial expression of MCC in astrocytes in culture as well as in situ. In addition to astrocytes, immunofluorescent double-labelling revealed the colocalization of MCC with a neuronal marker in human brain sections. This study confirms that human astrocytes are capable of catabolizing leucine and incorporating leucine-derived atoms into the intermediary metabolism. The presence of MCC in cultured astrocytes underscores their ability to convert leucine into acetyl-CoA and ketone bodies. Additionally, MCC expression in astrocytes and neurons present in brain parenchyma suggests that these cells are enzymatically equipped to catabolize leucine into compounds entering their cellular metabolism.

Keywords:  3-methylcrotonyl-CoA carboxylase; Astrocyte; Brain; Citrate; Fluxomics; Glutamate; Glutamine; LC–MS; Leucine; Metabolism; Neuron

DOI:  https://doi.org/10.1007/s11064-026-04732-8
Front Oncol. 2026 ;16 1754912

A systematic characterization of amino acid metabolism-related genes reveals molecular subtypes and a prognostic signature in bladder cancer.

Junrui He, Xu Liu, Shirui Li, Zhongyou Xia, Xiaojun Tan, Lijuan Peng, Qiongxian Long, Ji Wu.

   Background: Amino acid metabolism is integral to tumor proliferation, redox control, and immune regulation. Yet, studies in bladder cancer have largely centered on single amino acids, leaving the broader metabolic gene network insufficiently characterized.
Methods: Transcriptomic and clinical data from TCGA-BLCA, GSE13507, and GSE32894 were integrated with 32 MSigDB amino acid metabolism gene sets. Differential analysis, enrichment profiling, and consensus clustering defined metabolic subtypes. WGCNA and survival filtering identified candidates for a prognostic model, which was optimized using the MIME platform. Immune features and drug sensitivities were evaluated through multiple deconvolutions and pharmacogenomic resources. Single-cell data (GSE222315) were used to trace the cellular origin of model genes. PSPH expression and function were validated in tissues and bladder cancer cell lines.
Results: A total of 144 dysregulated amino acid metabolism-related genes were identified and used to define two distinct metabolic subtypes. One subtype was marked by coordinated upregulation of glutamine, branched-chain amino acid, tryptophan, and serine metabolic programs, accompanied by higher grade and stage, significantly worse survival, and dense but functionally impaired immune infiltration. From 24 candidate genes, a 16-gene metabolic signature was constructed and consistently validated across TCGA, GSE13507, and GSE32894, showing strong and stable prognostic performance superior to several published models. High-risk group displayed activation of cell-cycle, DNA-replication, mTORC1, and inflammatory-stress pathways, together with predicted sensitivity to PI3K/mTOR inhibitors, DNA-damaging agents, and selected epigenetic or cytoskeletal drugs. In the IMvigor210 cohort, the high-risk group showed a greater likelihood of responding to PD-1/PD-L1 blockade. Single-cell profiling localized signature expression predominantly to malignant epithelial cells. PSPH, a core model gene, was overexpressed in tumor tissues and cell lines, and functional assays demonstrated its role in promoting proliferation, migration, invasion, and survival of bladder cancer cells.
Conclusions: This study highlights the central role of amino acid metabolic networks in shaping bladder cancer heterogeneity and provides a metabolically grounded framework for risk stratification and therapeutic development.

Keywords:  PSPH; amino acid metabolism; bladder cancer; machine learning; molecular subtype; prognostic signature

DOI:  https://doi.org/10.3389/fonc.2026.1754912
J Agric Food Chem. 2026 Mar 16.

Theasinensin C Mitigates HFrD-Induced Neuroinflammation by Enriching Akkermansia muciniphila and Orchestrating a Gln/Ser-Centered Multiorgan Metabolic Relay to Drive Creatine Biosynthesis.

Wenting Ji, Guijie Chen, Jianhua Zeng, Yanhui Feng, Guoyuan Xiong, Chuanlai Du, Xiaoxiong Zeng, Chunxu Chen.

  This study synthesized and structurally validated theasinensin C (TSC, > 98%) and evaluated its neuroprotective effects in a high-fructose diet (HFrD)-induced mouse model of neuroinflammation. TSC (150 mg/kg/day, 8 weeks) improved cognition, reduced pro-inflammatory cytokines, mitigated neuropathology, and restored intestinal barrier integrity. Concomitantly, TSC remodeled the gut microbiota, selectively enriching Akkermansia muciniphila. We isolated A. muciniphila XJ 240720 and demonstrated that its synergy with TSC elevated creatine in serum and the brain, identifying creatine as a key mediator. Multiomics analyses showed that TSC enhanced A. muciniphila hydrolysis of mucin proline-threonine-serine (PTS) domains, releasing proline (Pro) and serine (Ser), and promoted the conversion of Pro via glutamate (Glu) to glutamine (Gln), driving luminal Gln and Ser accumulation. Enterocytes subsequently converted Gln to citrulline (Cit) and aspartate (Asp). In the kidney, the Cit/Asp→arginine (Arg) route coupled with the Ser→glycine (Gly) pathway generated guanidinoacetate (GAA), which the liver methylated via S-adenosylmethionine (SAM) to creatine. Circulating creatine reached the brain and suppressed neuroinflammation. Gln and Ser Supplementation in germ-free mice reproduced behavioral and antineuroinflammatory effects. Thus, TSC enriches A. muciniphila and drives a Gln/Ser-centered multiorgan creatine pathway that alleviates diet-induced neuroinflammation and informs gut-brain axis interventions.

Keywords:  A. muciniphila; amino acid metabolism; creatine; gut-brain axis; neuroinflammatory; theasinensin C

DOI:  https://doi.org/10.1021/acs.jafc.6c00881
Neural Regen Res. 2026 Mar 14.

Metabolic-based therapeutic strategies to treat Huntington's disease.

Mariana Coelho Moraes, Muhammad Olanrewaju Buhari, Luciene Bruno Vieira, Fabiola Mara Ribeiro.

   ABSTRACT: Huntington's disease is an autosomal dominant neurodegenerative disorder marked by progressive motor, cognitive, and psychiatric decline. Huntington's disease arises from the expansion of particular DNA sequences (cytosine/ adenosine/guanine repeats that encode glutamine) within the huntingtin (HTT) gene. This expansion leads to the synthesis of a mutant huntingtin protein (mhtt) featuring an excessively long polyglutamine segment, which is harmful and prone to form aggregates or clusters within cells. A range of abnormalities has been observed in both the central nervous system and peripheral tissues as a consequence of mhtt. These include inhibition in autophagy, mitochondrial dysfunction leading to metabolic deficiencies, immune system dysregulation, metabolic alterations, skeletal muscle deterioration, heart failure, testicular shrinkage, and bone density loss. Additionally, mhtt has been implicated in altering lipid metabolism pathways, leading to an increase in lipid accumulation, especially within neuronal cells. This lipid accumulation contributes significantly to cellular toxicity and dysfunction, further exacerbating the neurodegeneration seen in Huntington's disease. Although most studies have focused on neurological, behavioral, motor, and cognitive changes associated with Huntington's disease, several studies have reported changes in proteins, nucleic acids, lipids, and carbohydrate metabolism, which may lead to an anomalous molecular energy profile in individuals with Huntington's disease. This review will focus on understanding how metabolic changes may contribute to central alterations in Huntington's disease by analyzing preclinical and clinical evidence. Additionally, it will explore potential pathways that could be targeted to develop more effective treatments for Huntington's disease.

Keywords:  Huntington’s disease; bioenergetic deficits; metabolic dysfunction; mitochondrial impairment; neurodegeneration

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01573
J Cancer Res Ther. 2026 Mar 16.

Progress in metabolic reprogramming of gastric malignant tumors to remodel tumor immune microenvironments.

Na Wang, Kai Wang, Feixue Song.

   ABSTRACT: Metabolic reprogramming alters the processes by which tumor cells generate energy and synthesize products, affecting their growth and survival. It also reshapes the tumor microenvironment by influencing immune cell function and interaction. Current literature suggests that the metabolic characteristics of gastric malignancies are closely associated with tumor immune evasion and inflammatory responses, thereby influencing immune cell infiltration, tumor progression, and patient prognosis. Despite some progress, research on metabolic reprogramming in gastric cancer (GC) is challenging, particularly in understanding the specific mechanisms involved and their clinical applications. This review aims to comprehensively explore the mechanisms of metabolic reprogramming in GC and analyze its impact on the tumor immune microenvironment. We also propose potential metabolic-immune therapeutic strategies, such as glutaminase inhibitors, lactate transport blockers, and immune checkpoint therapy combined with metabolic regulators, providing new ideas and directions for immunotherapy in GC.

Keywords:  Gastric cancer; immune microenvironment; immunotherapy; metabolic reprogramming

DOI:  https://doi.org/10.4103/jcrt.jcrt_23_25
J Clin Invest. 2026 Mar 17. pii: e197010. [Epub ahead of print]

L-2-hydroxyglutarate impairs neuronal differentiation through epigenetic activation of MYC expression.

Wen Gu, Xun Wang, Ashley Solmonson, Ling Cai, Yi Xiao, Alpaslan Tasdogan, Jordan Franklin, Yuannyu Zhang, Hua Zhang, Aundrea K Westfall, Ashley Rowe, Hetali Trivedi, Brandon Faubert, Zheng Wu, Jessica Sudderth, Lauren G Zacharias, Bushra Afroze, Ilya Bezprozvanny, Sunil Sudarshan, Feng Cai, Samuel K McBrayer, Thomas P Mathews, Ralph J DeBerardinis.

  High levels of L- and D-2-hydroxyglutarate (2HG), the reduced forms of α-ketoglutarate (αKG), are implicated in neurodevelopmental disorders and cancer by modulating αKG-dependent dioxygenases involved in histone, DNA and RNA demethylation. L-2HG dehydrogenase (L2HGDH) deficiency, a rare autosomal recessive inborn error of metabolism associated with systemic L-2HG elevation, causes progressive neurological disability and increased brain tumor risk of unclear mechanism. Using an isogenic, patient-derived induced pluripotent stem cell (iPSC) system, we examined the impact of L2HGDH deficiency on neural progenitor cell (NPC) function and neuronal differentiation. L2HGDH deficiency caused L-2HG accumulation, NPC hyperproliferation, increased clonogenicity, and defective neuronal differentiation in 2D cultures and cortical spheroids. Editing the L2HGDH locus to wild-type reversed these effects. Inhibiting glutaminase reduced L-2HG levels and induced neuronal differentiation. L-2HG-dependent inhibition of KDM5 histone demethylases led to widespread retention of H3K4me2/3, markers of active gene expression, with prominent enrichment at the MYC locus and elevated MYC expression across multiple neural cell types. Despite broadly altered histone methylation, genetically or pharmacologically normalizing MYC completely restored neuronal differentiation. These data indicated that a primary metabolic disturbance activated MYC to favor self-renewal and suppress neuronal lineage commitment.

Keywords:  Clinical Research; Development; Epigenetics; Human stem cells; Metabolism; Neurodevelopment

DOI:  https://doi.org/10.1172/JCI197010