bims-glucam 2026-02-08 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–02–08
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine metabolism remodels tumor-associated macrophage: mechanistic explorations and new strategies in translational medicine.
Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor.
ZNF395 Is a Hypoxia-Responsive Regulator of Mitochondrial Glutaminolysis in Clear Cell Renal Cell Carcinoma.
HB023: A glutamine antagonist prodrug boosting antitumor lmmunity via PD-L1 suppression and mitochondrial membrane remodeling.
Momordin Ic suppresses breast cancer growth by targeting ACTL8‑dependent glutamine metabolism and PI3K/AKT/mTOR-MYC.
Glutamine Dependence Is Not a Cancer-specific Vulnerability in Contrast to Methionine Dependence.
Metabolic reprogramming in cancer: signaling pathways and therapeutic targets.
Identification and validation of a glutamine metabolism-related gene signature as a diagnostic and therapeutic target in osteoarthritis through integrated multi-omics analysis.
Glutaminase promotes the malignant progression of esophageal squamous cell carcinoma via TGF-β canonical and noncanonical.
Metabolomic profiling and stable isotope tracing of human schwannomas: A novel perspective on tumor biology and radiation response.
Ginsenosides remodel tumor immune microenvironment through metabolic reprogramming: Targets and mechanisms.
IMP metabolic mechanisms and IMPDH targeting strategies in tumor metabolic reprogramming and therapy (Review).
ZFTA-RELA ependymomas make itaconate to epigenetically drive fusion expression.
Local Glutamate-Glutamine Cycling Underlies Presynaptic ATP Homeostasis.
Multi-omics insights into Shenling Baizhu Powder's amelioration of murine asthma through gut microbiota and Glutamine-GLS1 pathway.
Fungal infection drives metabolic reprogramming in epithelial cells via aerobic glycolysis and an alternative TCA cycle shunt.
Untangling amino acid metabolism in renal diseases: mechanisms, dysregulation, and critical gaps.

Front Immunol. 2025 ;16 1715170

Glutamine metabolism remodels tumor-associated macrophage: mechanistic explorations and new strategies in translational medicine.

Juya Cui, Xia Yan, Jianbo Song.

  Glutamine metabolism provides energy and raw materials for tumor survival and proliferation. In addition to affecting cancer cells, many studies have investigated the role of glutamine metabolism on the tumor microenvironment in depth. The macrophages, which show high frequently distribution in the majority of solid tumors, are important immune cells in the tumor microenvironment. Tumor-associated macrophage metabolic network remodeling is enormous and complicated. This review links TAM with glutamine metabolism, and combs the network relationship between the unique functional state of macrophages and the key programs of glutamine metabolism in terms of epigenetic modification, signaling pathway transduction, and metabolic checkpoint regulation. In addition, we will summarize the existing glutamine metabolism-targeting drugs and explore the new technologies and strategies for glutamine metabolism to regulate the functional state of TAM.

Keywords:  glutamine metabolism; glutamine metabolism inhibitors; immune response; tumor microenvironment; tumor-associated macrophage

DOI:  https://doi.org/10.3389/fimmu.2025.1715170
bioRxiv. 2026 Jan 16. pii: 2026.01.15.699810. [Epub ahead of print]

Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor.

Jack M Scully, Michael J Sun, Siddharth Das, Nataly J Arias, Edmund D Kapelczak, Tiffany D Robinson, Katie G Vineall, Teagan S Dean, Tara TeSlaa, Ajit S Divakaruni, Danielle L Schmitt.

Glutamine is the most abundant amino acid in serum, used as a key nutrient by cells for protein synthesis, energy production, carbon and nitrogen metabolism, and cellular redox balance. The use of glutamine in the cell is highly compartmentalized, but the dynamics of glutamine metabolism across organelles and individual cells are not fully understood. To illuminate subcellular glutamine dynamics, we developed an intracellular glutamine optical reporter, iGlo. We find iGlo is sensitive and specific for glutamine and can be used to measure glutamine uptake, production, and consumption with high spatiotemporal resolution in multiple cell types. Furthermore, multiplexed imaging of iGlo with a lactate biosensor in single cells reveals temporal crosstalk between glucose and glutamine metabolism to maintain energy homeostasis. Thus, iGlo enables the sensitive and precise study of compartmentalized glutamine dynamics and represents a new and enhanced tool for studying the spatiotemporal dynamics and regulation of metabolism.

DOI: https://doi.org/10.64898/2026.01.15.699810
Cancer Res. 2026 Feb 04. OF1-OF14

ZNF395 Is a Hypoxia-Responsive Regulator of Mitochondrial Glutaminolysis in Clear Cell Renal Cell Carcinoma.

Joanna Koh, Chengheng Liao, Michelle Shu Wen Ng, Jing Han Hong, Hong Lee Heng, Dan Y Gui, Zhenxun Wang, Benjamin Yan-Jiang Chua, Zhimei Li, Radoslaw M Sobota, Lye Siang Lee, Jabed Iqbal, Kevin Junliang Lim, Divya Bezwada, Ralph J DeBerardinis, Gertrud Steger, Jianhong Ching, Patrick Tan, Bin Tean Teh, Qing Zhang, Xiaosai Yao.

Hypoxia signaling induced by VHL deficiency fuels growth but also imposes metabolic stress on clear cell renal cell carcinomas (ccRCC). Many ccRCC cells depend on glutamine as the primary source of tricarboxylic acid (TCA) anaplerosis. Hypoxia-inducible factor α (HIFα) governs glycolysis but does not directly regulate glutamine metabolism; instead, the factor responsible for orchestrating glutamine metabolism and mitochondrial adaptations to hypoxia remains elusive. In this study, we showed that ZNF395 is a hypoxia-responsive factor that regulates glutamine metabolism in the mitochondria. When activated by a HIF2α-modulated superenhancer, ZNF395 facilitated the transcription of enzymes essential for glutaminolysis, including glutaminase (GLS) and isocitrate dehydrogenase 2. Functionally, ZNF395 depletion resulted in reduced TCA cycle intermediates and their derivatives, including amino acids, glutathione, and pyrimidine nucleotides, leading to impaired mitochondrial respiration. Restoration of mitochondrial complex I function and GLS expression partially rescued the effects of ZNF395 depletion on ccRCC tumor growth. Together, this study underscores the coordinated role of HIFα and ZNF395 in shaping metabolic adaptations in response to hypoxia in VHL-deficient ccRCCs.
SIGNIFICANCE: ZNF395 and HIF are complementary mediators of hypoxia-induced metabolic reprogramming and therapeutic targets in VHL-deficient kidney cancer, with the former regulating glutamine metabolism and the latter regulating glucose metabolism.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4745
J Adv Res. 2026 Feb 01. pii: S2090-1232(26)00101-3. [Epub ahead of print]

HB023: A glutamine antagonist prodrug boosting antitumor lmmunity via PD-L1 suppression and mitochondrial membrane remodeling.

Junyan Zhuang, Ye Chen, Yi Zhang, Yongrui Hai, Renming Fan, Jiarui Dou, Xintong Lu, Wenhui Wang, Bingjie Zhang, Zhuang Hou, Lei Liang, Yang Liu, Gaofei Wei.

   INTRODUCTION: Glutamine is a key nutrient that supports tumor cell metabolism, biosynthesis, and proliferation. It also shapes the tumor microenvironment and modulates cell death pathways. Glutamine antagonists have emerged as effective therapeutic agents by both disrupting tumor energy metabolism and enhancing antitumor immune responses. However, recent evidence reveals a paradoxical effect: glutamine deprivation can induce PD-L1 expression on tumor cells, facilitating immune escape and reducing the efficacy of immunotherapies.
OBJECTIVES: This study aims to overcome the immune evasion triggered by glutamine deprivation by developing a dual-functional therapeutic strategy that enhances metabolic stress while simultaneously inhibiting PD-L1 expression. The ultimate goal is to strengthen antitumor immunity and improve therapeutic outcomes.
METHODS: We designed and synthesized a novel prodrug, HB023, by covalently linking a glutamine metabolism inhibitor with JQ1, a well-characterized PD-L1 inhibitor. We evaluated the effects of HB023 on tumor cell pyroptosis, energy metabolism, PD-L1 expression, T cell-mediated cytotoxicity, and macrophage polarization using a combination of in vitro cell-based assays and in vivo tumor models.
RESULTS: HB023 significantly enhanced glutamine starvation in tumor cells, leading to increased pyroptosis and restricted energy supply. It effectively downregulated PD-L1 expression, which restored T cell cytotoxic activity. Additionally, HB023 induced mitochondrial membrane remodeling in macrophages, promoting M1 polarization and thereby enhancing innate immune responses. These mechanisms cooperatively activated both adaptive and innate antitumor immunity, thereby conferring HB023 with superior antitumor efficacy compared with JQ1, JHU083, or their combination.
CONCLUSION: HB023 successfully addresses the challenge of glutamine deprivation-induced immune escape by integrating metabolic inhibition with immune checkpoint blockade. This dual-modulatory approach reprograms the tumor immune microenvironment and improves immunotherapeutic efficacy, representing a promising strategy for advancing cancer treatment.

Keywords:  Cancer Immunotherapy; Glutamine; Macrophage; Mitochondrial membrane Remodeling; Prodrug

DOI:  https://doi.org/10.1016/j.jare.2026.01.077
Biochem Pharmacol. 2026 Jan 30. pii: S0006-2952(26)00092-4. [Epub ahead of print]247 117761

Momordin Ic suppresses breast cancer growth by targeting ACTL8‑dependent glutamine metabolism and PI3K/AKT/mTOR-MYC.

Ao Guo, Bijun Yang, Aolin Xiao Huang, Jie Ni, Yanhui Zhang, Qinlin Jiang, Yunwen Yan, Qichao Luo, Jing Yang, Bin Yuan.

  Glutamine metabolism is a key driver of tumor progression, yet the molecular basis and prognostic relevance of glutamine metabolism-related genes in breast cancer (BC) remain incompletely defined. In this study, integrated analysis of public datasets identified Actin-like protein 8 (ACTL8) as a key prognostic gene significantly upregulated in BC tissue and associated with poor patient survival. In vitro, shRNA knockdown of ACTL8 reduced MYC expression and its downstream targets SLC1A5 and GLS1, suppressing cell proliferation, migration and invasion. This disruption led to impaired redox homeostasis as evidenced by reduced GSH/GSSG and NADPH/NADP+ ratios. Mechanistically, MYC overexpression restored metabolic enzymes and phenotypes but failed to rescue p-AKT levels, confirming ACTL8 acts upstream of the PI3K/AKT/mTOR axis. Virtual screening identified Momordin Ic as a small molecule that directly interacts with ACTL8. Surface plasmon resonance (SPR) and Thermal shift assay (TSA) confirmed this high-affinity binding, which destabilized ACTL8 and promoted its ubiquitin-proteasome degradation. Moreover, ACTL8 knockdown significantly attenuated the sensitivity of BC cells to Momordin Ic treatment, confirming ACTL8 as the specific therapeutic target. In vivo, suppression of ACTL8 markedly reduced tumor growth. Together, these findings establish ACTL8 as a key oncogenic driver of BC progression. Targeting ACTL8 offers a novel strategy to disrupt glutamine-dependent metabolic reprogramming, and Momordin Ic represents a promising lead agent to combat ACTL8-driven BC.

Keywords:  ACTL8; Breast cancer; CB-839; Glutamine metabolism; Momordin ic; Therapeutic target

DOI:  https://doi.org/10.1016/j.bcp.2026.117761
Anticancer Res. 2026 Feb;46(2): 749-755

Glutamine Dependence Is Not a Cancer-specific Vulnerability in Contrast to Methionine Dependence.

Yuta Miyashi, Kohei Mizuta, Yohei Asano, Byung Mo Kang, Jin Soo Kim, Qinghong Han, Shukuan Li, Michael Bouvet, Yasunori Tome, Kotaro Nishida, Robert M Hoffman.

   BACKGROUND/AIM: Glutamine (GLN) addiction has been proposed as a cancer vulnerability and a therapeutic target. However, the glutamine requirement of normal cells is poorly understood. In the present study, we used a unique co-culture model to study the glutamine requirement of cancer cells compared to normal cells co-cultured together.
MATERIALS AND METHODS: The human fibrosarcoma cell line HT1080 and normal human fibroblasts HS27 were co-cultured in 12-well dishes seeded with equal numbers of cells of each type. Additionally, HS27 cells were cultured alone in 6-well plates. The cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) which did not contain GLN, methionine (MET), or cystine (CYS). 150 μM L-cystine 2HCl was added to all media. Co- and mono- cultures were grown under the following conditions: Complete medium (GLN 4 mM and MET 100 μM); MET restriction [Methionine restriction (MR), GLN 4 mM and MET 0 μM]; GLN restriction [Glutamine restriction (GR), GLN 0 mM and MET 100 μM] and MR+GR (GLN 0 mM and MET 0 μM). Cells were observed under phase-contrast and fluorescence microscopy for seven days. ImageJ was used to compare the three groups: MR, GR and MR+GR.
RESULTS: In complete DMEM, HT1080 fibrosarcoma cells dominated HS27 normal fibroblasts in co-culture. Under MR, HT1080 cells became mostly non viable, but HS27 cells remained viable. Under GR and MR+GR, both HT1080 and HS27 cells became mostly non-viable. Monoculture experiments showed that normal cells survived under MR but not GR.
CONCLUSION: GR is not a cancer-specific vulnerability, while MR is. Therefore, GR is not a promising cancer-therapy strategy.

Keywords:  Glutamine restriction; Hoffman effect; Warburg effect; cancer; cancer cells; co-culture; methionine addiction; methionine restriction; normal cells; vulnerability

DOI:  https://doi.org/10.21873/anticanres.17984
Mol Cancer. 2026 Feb 03.

Metabolic reprogramming in cancer: signaling pathways and therapeutic targets.

Shi Dong, Taiyuan Li.



Keywords:  Cancer; Glucose; Glutamine; Lipid; Metabolic reprogramming; Polyamine; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-026-02582-0
PeerJ. 2026 ;14 e20701

Identification and validation of a glutamine metabolism-related gene signature as a diagnostic and therapeutic target in osteoarthritis through integrated multi-omics analysis.

Yang Lu, Jinkun Liu, Shasha Wang, Jianping Gan, Wenfu Cao, Bin Wu.

   Background: The understanding of the pathogenesis of osteoarthritis (OA) is often fragmented, with studies focusing on individual tissues. A holistic view integrating multi-tissue molecular changes with systemic metabolic shifts is urgently needed. Glutamine metabolism, a central bioenergetic and biosynthetic hub, represents a critical but largely unexplored nexus in this disease network. This study leverages a multi-omics, multi-tissue approach to deconstruct the role of glutamine metabolism in OA and identify a robust, blood-based signature for potential diagnostic use.
Methods: We conducted a comprehensive bioinformatic investigation by integrating multiple GEO transcriptomic datasets from cartilage, synovium, subchondral bone, and peripheral blood. A machine learning pipeline, incorporating weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression, was employed to identify a signature of glutamine metabolism-related genes (GMRGs). The signature's clinical relevance was then validated in an independent cohort of 62 subjects (31 OA patients vs. 31 healthy controls) using RT-qPCR on peripheral blood samples and plasma metabolomics. Furthermore, we computationally explored its potential regulatory mechanisms and predicted candidate therapeutic compounds.
Results: Our multi-layered analysis identified a core three-gene signature (F13A1, IRS2, RELA). Functional analysis linked this signature to pathways essential for OA pathogenesis, including mechanical stress, metabolic regulation, and inflammatory responses. Clinical validation in an independent cohort confirmed significant downregulation of all three genes in OA peripheral blood (P < 0.001) and revealed distinct regulatory patterns, including disease-specific activation of RELA and a metabolic regulatory reversal of IRS2, as well as negative correlations with disease severity and alterations in circulating glutamine-related metabolites. The resulting diagnostic model showed strong discriminatory performance across both training and validation datasets. Plasma creatine emerged as an independent predictor of disease severity. Finally, exploratory analyses suggested potential epigenetic regulation and identified several candidate drugs capable of modulating the signature.
Conclusions: This study identifies a blood-based, multi-omics-derived gene signature that links localized joint pathology with systemic metabolic dysfunction in osteoarthritis. The signature offers a robust non-invasive diagnostic marker and reveals new opportunities for patient stratification and therapeutic development.

Keywords:  Diagnostic biomarkers; Glutamine metabolism; Metabolic reprogramming; Multi-omics analysis; Osteoarthritis

DOI:  https://doi.org/10.7717/peerj.20701
Eur J Med Res. 2026 Jan 30.

Glutaminase promotes the malignant progression of esophageal squamous cell carcinoma via TGF-β canonical and noncanonical.

Xiu Zhang, Tao Wang, Yu Chen, Mingde Huang.

  Accumulating evidence indicates that glutaminase (GLS) serves as a crucial player in cell proliferation and survival of cancers. Nonetheless, the roles and mechanisms of GLS in esophageal squamous cell carcinoma (ESCC) have not been elucidated. Herein, we found that GLS was over-expressed in glutamine-dependent ESCC cells and ESCC tissues. Patients with high GLS expression had a worse prognosis than those with low GLS expression. In ESCC cells, GLS knockdown inhibited the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of ESCC cells and promoted apoptosis. RNA-Seq analysis combined with immunoblotting showed that GLS knockdown reduced the TGF-β, p-Smad2/3, p-p38MAPK, p-ERK1/2, and p-MEK1/2 proteins, increased ROS and glutamine levels in both KYSE30 and KYSE150 cells. Overall, our study showed that GLS promoted the malignant progression via the TGF-β signaling pathway, suggesting that GLS can be a potential therapeutic target and diagnostic biomarker for ESCC.

Keywords:  Esophageal squamous cell carcinoma; Glutaminase; Invasion; Proliferation; TGF-β

DOI:  https://doi.org/10.1186/s40001-026-03992-y
Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdaf223

Metabolomic profiling and stable isotope tracing of human schwannomas: A novel perspective on tumor biology and radiation response.

Mark C Dougherty, Hashim S Syed, Linjing Xu, S John Liu, David R Raleigh, Adam J Rauckhorst, Eric B Taylor, Marlan R Hansen.

   Background: Although schwannomas are common and benign, their growth patterns are often hard to predict. Currently, surgery and radiotherapy are the only standard treatments. Since metabolites are the end products of genes and proteins, metabolomics may reveal downstream tumor features in ways that other -omics cannot. Here, we use metabolomic profiling and stable isotope tracing to characterize primary human schwannomas and describe their changes following radiation in patient-derived xenografts.
Methods: Schwannomas collected during surgical resection underwent metabolomic profiling with gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry (N = 44) as well as DNA methylation profiling (N = 29). Large tumors were also implanted subcutaneously in athymic mice as patient-derived xenografts. Mice were randomized to radiation treatment or control 4-6 weeks post-implantation. Xenografts were harvested 72 h after radiation for metabolomic profiling (N = 53). Another group of xenografts (N = 33) was injected with U-13C-glutamine prior to tumor harvest for stable isotope tracing.
Results: The schwannoma metabolome differs from that of Schwann cells, and metabolomics-based clustering of schwannomas resembles DNA methylation-based classification. In xenografts, radiation decreases cellular proliferation and produces small but detectable changes to the tricarboxylic acid (TCA) cycle and nucleotide metabolism. 13C-glutamine tracing shows that schwannomas can produce urea cycle intermediates, TCA cycle intermediates, cytosine monophosphate (CMP), and cytosine triphosphate from glutamine even after radiation. CMP was the only metabolite with altered 13C uptake following radiation.
Conclusions: Schwannomas have distinct metabolic signatures compared to the Schwann cells from which they originate. Schwannoma xenograft metabolism is surprisingly robust to radiotherapy, and xenografts readily incorporate glutamine into the TCA cycle, urea cycle, and pyrimidine synthesis.

Keywords:  NF2; metabolomics; radiation; schwannoma

DOI:  https://doi.org/10.1093/noajnl/vdaf223
Phytomedicine. 2026 Jan 30. pii: S0944-7113(26)00140-6. [Epub ahead of print]153 157901

Ginsenosides remodel tumor immune microenvironment through metabolic reprogramming: Targets and mechanisms.

Zhong-Wei Yao, Yong-Qing Wang, He Zhu.

   BACKGROUND: Metabolic reprogramming is a hallmark of cancer development. By regulating energy and nutrient metabolism, it shapes an immunosuppressive tumor microenvironment (TME) that supports rapid tumor proliferation and promotes cancer progression. Ginsenosides, the major active components of Panax ginseng, have recently been found not only to directly inhibit tumor cell proliferation and induce apoptosis, but also to remodel the TME through metabolic regulation in both tumor and immune cells, thereby enhancing antitumor immune responses. However, the underlying mechanisms have not been fully elucidated.
PURPOSE: This study systematically summarizes the metabolic targets and regulatory mechanisms of ginsenosides in key pathways of metabolic reprogramming involving glucose, lipid, amino acid, and nucleotide metabolism, aiming to provide a theoretical basis and new perspectives for tumor metabolism-based immunotherapy.
METHODS: Using "ginsenoside", "glucose metabolism", "Warburg effect", "lipid metabolism", "fatty acid", "cholesterol", "amino acid metabolism", "nucleotide metabolism", " tumor" and combinations of these keywords in PubMed, Web of Science, and CNKI.
RESULTS: Ginsenosides primarily restore immune cell function by reversing the Warburg effect, suppressing fatty acid synthesis and oxidation, downregulating cholesterol and arachidonic acid metabolism, and inhibiting the depletion of glutamine and tryptophan as well as the catabolism of arginine. In addition, ginsenosides downregulate purine and pyrimidine biosynthesis, thereby limiting tumor cell proliferation.
CONCLUSIONS: Ginsenosides alleviate the immunosuppressive state of the TME and restore immune effector cell functions through multidimensional metabolic regulation. In the future, it is necessary to conduct further clinical investigations and develop metabolism-targeted ginsenoside delivery systems to ultimately achieve precise cancer therapy.

Keywords:  Amino acid metabolism; Ginsenosides; Glucose metabolism; Lipid metabolism; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.phymed.2026.157901
Int J Mol Med. 2026 Apr;pii: 81. [Epub ahead of print]57(4):

IMP metabolic mechanisms and IMPDH targeting strategies in tumor metabolic reprogramming and therapy (Review).

Hao Zhu, Hao Wang, Xia Li, Weisong Zhang, Yihao Wang, Qingze Tan, Dongxu Ying, Zhan Shi, Jianxiang Song.

  Metabolic reprogramming is a hallmark feature of malignant tumors. These metabolic pathways are regulated in a cell‑autonomous manner by oncogenic signaling and transcriptional networks, and tracking their metabolic reprogramming is frequently used in the diagnosis, detection and treatment of cancer. There are currently promising therapeutic prospects for a variety of types targeting fixed core metabolic pathways in tumor metabolic reprogramming. Among these, inosine monophosphate (IMP) is an essential intermediate in purine nucleotide synthesis that demonstrates significant target potential. Nevertheless, further research is needed to elucidate the regulatory networks that control IMP metabolism in tumor cells. This review combines the latest insights into IMP metabolism into an interesting conceptual framework. This includes the supply of IMP precursor substrates (reprogramming of glucose metabolism, serine/one‑carbon metabolism, glutamine and mitochondrial metabolism), the dynamic regulation of important enzymes [phosphoribosyl pyrophosphate synthetase, phosphoribosyl pyrophosphate amidotransferase, IMP dehydrogenase (IMPDH)], purinosomes and signaling pathways (RAS‑ERK, PI3K/AKT‑mTORC1 and Hippo‑YAP) that ultimately regulate IMP synthesis in tumor cells. Additionally, it focused on downstream associations between IMPDH and the immune microenvironment, offering a fresh perspective for current research on tumor therapy targeting IMP metabolism.

Keywords:  IMP metabolism; IMPDH; cancer; metabolic reprogramming; purinosome; signaling pathways

DOI:  https://doi.org/10.3892/ijmm.2026.5752
Nature. 2026 Feb 04.

ZFTA-RELA ependymomas make itaconate to epigenetically drive fusion expression.

Siva Kumar Natarajan, Joanna Lum, James Haggerty Skeans, Minal Nenwani, Sanjana Eyunni, Mateus Mota, Jill M Bayliss, Akash Deogharkar, Erin Taya Hamanishi, Matthew Pun, Stefan R Sweha, Simon Hoffman, Eleanor Young, Qiuyang Zhang, Rijul Mehta, Olamide Animasahun, Pranav Narayanan, Sushanth Sunil, Abhijit Parolia, Peter Sajjakulnukit, Pooja Panwalkar, Robert Doherty, Madison Clausen, Derek Dang, Debra Hawes, Fusheng Yang, Mariarita Santi, Alexander R Judkins, Yelena Wilson, Thomas Vigil, Andrea Franson, Richard M Mortensen, Tatsuya Ozawa, Andrea Griesinger, Eric C Holland, Nicholas K Foreman, Kulandaimanuvel Antony Michealraj, Sameer Agnihotri, Michael Taylor, Richard J Gilbertson, Carl Koschmann, Arul M Chinnaiyan, Costas A Lyssiotis, Deepak Nagrath, Sriram Venneti.

ZFTA-RELA+ ependymomas are malignant brain tumours defined by fusions formed between the putative chromatin remodeller ZFTA and the NF-κB mediator RELA1. Here we show that ZFTA-RELA+ cells produce itaconate, a key macrophage-associated immunomodulatory metabolite2. Itaconate is generated by cis-aconitate decarboxylase 1 (ACOD1; also known as IRG1). However, the production of itaconate by tumour cells and its tumour-intrinsic role are not well established. ACOD1 is upregulated in a ZFTA-RELA-dependent manner. Functionally, itaconate enables a feed-forward system that is crucial for the maintenance of pathogenic ZFTA-RELA levels. Itaconate epigenetically activates ZFTA-RELA transcription by enriching for activating H3K4me3 via inhibition of the H3K4 demethylase KDM5. ZFTA-RELA+ tumours enhance glutamine metabolism to supply carbons for itaconate synthesis. Antagonism of ACOD1 or glutamine metabolism reduces pathogenic ZFTA-RELA levels and is potently therapeutic in multiple in vivo models. Mechanistically, ZFTA-RELA epigenetically suppresses PTEN expression to upregulate PI3K-mTOR signalling, a known driver of glutaminolysis. Finally, suppression of ACOD1 or a combination of glutamine antagonism with PI3K-mTOR inhibition abrogates spinal metastasis. Our data demonstrate that ZFTA-RELA+ ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA-RELA driver, which implicates itaconate as a candidate oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA+ ependymomas. Our work has implications for future drug development to reduce pathogenic ZFTA-RELA expression for this brain tumour, and will advance our understanding of oncometabolites as a new class of therapeutic dependencies in cancers.

DOI: https://doi.org/10.1038/s41586-025-10005-1
Neural Comput. 2026 Feb 02. 1-36

Local Glutamate-Glutamine Cycling Underlies Presynaptic ATP Homeostasis.

Reinoud Maex.

Presynaptic axon terminals maintain in their cytosol an almost constant level of adenosine triphosphate (ATP) to safeguard neurotransmission during varying workloads. In the study reported in this letter, it is argued that the vesicular release of neurotransmitter and the recycling of transmitter via astrocytes may itself be a mechanism of ATP homeostasis. In a minimal metabolic model of a presynaptic axon bouton, the accumulation of glutamate into vesicles and the activity-dependent supply of its precursor glutamine by astrocytes generated a steady-state level of ATP that was independent of the workload. When the workload increased, an enhanced supply of glutamine raised the rate of ATP production through the conversion of glutamate to the Krebs cycle intermediate α-ketoglutarate. The accumulation and release of glutamate, on the other hand, acted as a leak that diminished ATP production when the workload decreased. The fraction of ATP that the axon spent on the release and recycling of glutamate was small (4.7%), irrespective of the workload. Increasing this fraction enhanced the speed of ATP homeostasis and reduced the futile production of ATP. The model can be extended to axons releasing other, or coreleasing multiple, transmitters. Hence, the activity-dependent formation and release of neurotransmitter may be a universal mechanism of ATP homeostasis.

DOI: https://doi.org/10.1162/NECO.a.1490
Sci Rep. 2026 Feb 04.

Multi-omics insights into Shenling Baizhu Powder's amelioration of murine asthma through gut microbiota and Glutamine-GLS1 pathway.

Yuning Zeng, Hui Qi, Weijian Guo, Xueyi Tan, Bo Huang, Ruihui Hu, Xueren Ouyang.

  Shenling Baizhu Powder (SLBZP) is a prominent formulation widely used in the treatment of pulmonary diseases. However, studies examining the mechanisms of SLBZP for treating asthma are limited. This study aimed to clarify the efficacy and possible mechanisms of SLBZP in the context of asthma from the perspective of gut microbiota-metabolism-immune crosstalk. Key parameters including airway hyperresponsiveness, lung pathological features and the expression of inflammatory mediators from Th2 and Th17 cells were employed to validate the anti-inflammatory properties of SLBZP. The anti-asthma mechanism of SLBZP was investigated using metagenomic sequencing, metabolomics, flow cytometry, RT-qPCR, immunohistochemistry (IHC) and immunofluorescence (IF). SLBZP demonstrated significant capacity to mitigate histopathological alterations associated with ovalbumin-induced asthma and suppress the secretion of inflammatory mediators (IL-4, IL-5, IL-13 and IL-17A) in BALF. Metagenomic results demonstrated that the protective effects of SLBZP were primarily associated with Ligilactobacillus, Eubacterium and Clostridium. Additionally, metabolomics results identified that three vital metabolic pathways were substantially regulated by SLBZP in asthmatic mice, especially D-glutamine and -glutamate metabolism. Furthermore, IHC and IF results showed that SLBZP significantly inhibited the expression of GLS1 and GOT1, which inhibited the conversion of L-glutamine to α-ketoglutarate and regulated the imbalance of Th1/Th2 and Treg/Th17. RT-qPCR results showed that SLBZP promoted the expressions of T-bet, IFN-γ, IL-10 and Foxp3 mRNA, and inhibited the expression of GATA3, IL-4, IL-5, IL-13, IL-17A and RORγt mRNA. The findings from flow cytometry provided additional evidence. Thus, this modulated the imbalance of Th1/Th2 and Treg/Th17 and exerted the immunomodulatory properties of SLBZP. SLBZP exerted protective effects against OVA-induced asthma and modified the structure and functional characteristics of the gut microbiota, and serum metabolite profiles in asthmatic mice. The anti-asthma mechanism of SLBZP may be associated with the modulation of the gut microbiota and Glutamine-GLS1 pathway.

Keywords:  Asthma; Glutamine metabolism; Metabolomics; Metagenomic sequencing; SLBZP

DOI:  https://doi.org/10.1038/s41598-026-38440-8
Sci Adv. 2026 Feb 06. 12(6): eaea0405

Fungal infection drives metabolic reprogramming in epithelial cells via aerobic glycolysis and an alternative TCA cycle shunt.

Aize Pellon, Shervin Dokht Sadeghi Nasab, Gholamreza Bidkhori, James S Griffiths, Stefania Vaga, Neelu Begum, Mariana Blagojevic, Nitesh Kumar Sigh, Natalia K Kotowicz, Ifeanyi Uzochukwu, Adrien Le Guennec, Rhonda Henley-Smith, Harry Gregson-Williams, Frederick Clasen, Miranda Pryce, Nadia Karimpour, Richard Cook, Juan Anguita, Jonathan P Richardson, Selvam Thavaraj, Julian R Naglik, Saeed Shoaie, David L Moyes.

Candida albicans-induced immunometabolic changes drive complex responses in immune cells. However, whether and how C. albicans causes remodeling of oral epithelial cell (OEC) metabolism is unclear. Here, we use in vitro experiments and patient biopsies to demonstrate that OECs undergo metabolic reprogramming when infected by C. albicans independently of candidalysin secretion, increasing glycolysis and decreasing tricarboxylic acid (TCA) cycle activity. Glycolysis and glucose transport inhibition show that these pathways support OEC cytokine release, highlighting the partial control of antifungal epithelial immunity by cellular metabolism. However, glucose supplementation disrupts OEC responses both in vitro and in vivo, suggesting that the fungus benefits from these metabolic shifts and that increased aerobic glycolysis in OECs is detrimental. Genome-scale metabolic modeling predicted a shutdown of the TCA cycle and a previously unidentified role for glutamic-oxaloacetic transaminase 1 (GOT1) in response to C. albicans, which was subsequently shown to be important for OEC survival during infection. This study reveals a fundamental role for hexose metabolism and identifies a GOT1-mediated TCA cycle shunt in regulating OEC survival and immune responses during mucosal fungal infections.

DOI: https://doi.org/10.1126/sciadv.aea0405
Clin Kidney J. 2026 Feb;19(2): sfaf380

Untangling amino acid metabolism in renal diseases: mechanisms, dysregulation, and critical gaps.

Petr Heneberg, Daniela Heneberg Šimčíková.

  Amino acid metabolism is closely linked with kidney physiology and pathology. In acute kidney injury, chronic kidney disease, diabetic kidney disease, and autosomal dominant polycystic kidney disease, disturbances in the branched-chain amino acids, tryptophan, glutamine, taurine, and sulfur amino acids pathways are consistently observed. Specific metabolites such as D-serine, kynurenine intermediates, and branched-chain keto acids are associated with disease progression. Taurine and indoxyl sulfate have also been proposed as therapeutic targets. At the nephron level, transporters and enzymes controlling amino acid flux influence nitrogen balance, oxidative stress, fibrosis, inflammation, and tubular injury. In chronic kidney disease, impaired amino acid handling contributes to protein-energy wasting, altered muscle metabolism, and systemic complications. In autosomal dominant polycystic kidney disease, cyst fluid metabolomics has revealed alterations in tryptophan and polyamine metabolism. The use of nutritional interventions, microbiome modulation, and selective supplementation as therapeutic strategies is being explored, although clinical trial evidence remains limited. Several key issues remain unresolved, including the need for isotope tracer studies to define renal amino acid kinetics in humans, the rigorous validation of metabolite biomarkers across diverse populations, the integration of diet and microbiome-derived metabolites into mechanistic frameworks, and the systematic evaluation of sex-specific differences. Longitudinal studies are scarce, thus restricting predictive power and therapeutic translation. Further mechanistic clarification may support the development of biomarkers and targeted therapies.

Keywords:  dietary modulation; disease progression markers; nutrient signaling; renal fibrosis; tubular regeneration

DOI:  https://doi.org/10.1093/ckj/sfaf380