bims-glucam 2026-07-12 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–07–12
seven papers selected by
Sreeparna Banerjee, Middle East Technical University

CircTAF15 (hsa_circ_0043138) promotes NSCLC progression through stabilizing YBX1 to initiate GOT1 transcription.
Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice.
The Role of the Glutamate-Glutamine Cycle in Synaptic Transmission During Ischemia and Recovery.
Metabolic reprogramming of macrophages during mycobacterial infection: a review of immunometabolic crosstalk and pathogen manipulation.
Dysregulated Metabolism in People Living With HIV in the Modern ART-Era: A Systematic Review of Targeted Metabolomics Studies.
Multi-omics profiling reveals LncRNA ENSG00000253374 as a regulator of GLS-mediated cuproptosis and platinum resistance in ovarian cancer.
Targeting of solute carrier family 1 member 1 that links metabolic reprogramming and ferroptosis sensitivity in pancreatic ductal adenocarcinoma.

Int J Biol Macromol. 2026 Jul 09. pii: S0141-8130(26)03357-X. [Epub ahead of print] 153417

CircTAF15 (hsa_circ_0043138) promotes NSCLC progression through stabilizing YBX1 to initiate GOT1 transcription.

Zixuan Chen, Ziyuan Chen, Zhen Ge, Jiayuan Liu, Shuai Fang, Wei Chen, Zhiqi Hong, Yufei Sheng, Xiaodong Zhao, Wentao Hu, Chengwei Zhou.

   BACKGROUND: Non-small cell lung cancer (NSCLC) remains one of the most lethal malignancies globally, largely due to its asymptomatic early course and poor prognosis at advanced stages. The rapid proliferation of NSCLC cells drives an increased demand for bioenergy and biosynthetic precursors, which is met through metabolic reprogramming. Targeting this reprogramming to cut off the energy for tumors therefore represents a promising therapeutic strategy for NSCLC.
METHODS: We analyzed two NSCLC circRNA microarray datasets (GSE146689 and GSE158695) to identify a novel circRNA, which was confirmed through Sanger sequencing as being derived from exons 3-6 of the TAF15 pre-mRNA, designated circTAF15. We performed knockdown experiments to investigate the functional role of circTAF15 in NSCLC cells. From a mechanistic perspective, we assessed the interaction between circTAF15 and YBX1, investigating the inhibitory role of circTAF15 in ubiquitin-mediated degradation. Furthermore, we analyzed the influence of the circTAF15-YBX1 complex on the transcriptional activation of the key enzyme in glutamine metabolism, GOT1.
RESULTS: We identified a novel circRNA, circTAF15, confirmed by Sanger sequencing to originate from exons 3-6 of the TAF15 pre-mRNA. Knockdown of circTAF15 significantly suppressed NSCLC cell proliferation and migration by inhibiting glutamine metabolism. Mechanistically, circTAF15 binds to YBX1, protecting it from ubiquitination-mediated degradation. This circTAF15-YBX1 complex enhances the transcriptional activation of GOT1, a key enzyme in glutamine metabolism, thereby facilitating NSCLC cell proliferation and migration.
CONCLUSIONS: Our findings reveal a critical circRNA-driven regulatory axis in NSCLC metabolism and highlight circTAF15 as a promising therapeutic target.

Keywords:  CircTAF15; GOT1; Glutamine catabolism; Non-small cell lung cancer; Ubiquitination-mediated degradation; YBX1

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153417
Nat Commun. 2026 Jul 04.

Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice.

Renming Fan, Xintong Lu, Bingjie Zhang, Zhuang Hou, Ting Zhao, Yongrui Hai, Ye Chen, Wenhui Wang, Yue Chen, Qiu Sun, Lei Liang, Le Yang, Gaofei Wei.

Colorectal cancer (CRC) often exhibits a suppressive tumor microenvironment that is associated with elevated glutamine metabolism and induction of immunosuppressive macrophages. Glutamine antagonists such as 6-diazo-5-oxo-L-norleucine (DON) and its prodrug JHU-083 can limit tumor growth, but their toxicity and immune cell selectivity remain suboptimal. Here, we conjugate DON with the macrophage-targeting moiety artesunate to develop WGF-T17 (T17), which blocks glutamine metabolism in macrophages. In vitro, T17 rewires macrophage metabolism toward glycolysis, inducing lactate buildup and histone lactylation, enhancing mitochondrial fission and phagocytic activity, and thereby reprogramming macrophages to an inflammatory state. In vivo, T17 controls tumor growth better than JHU-083 via macrophage-dependent pathways, and also increases the efficacy of immunotherapy, chemotherapy and anti-angiogenic therapy in female mice carrying subcutaneous CRC tumors. Our findings thus hint T17 as a promising treatment strategy for CRC by targeting macrophage glutamine metabolism to reverse immune suppression.

DOI: https://doi.org/10.1038/s41467-026-75208-0
Eur J Neurosci. 2026 Jul;64(1): e70604

The Role of the Glutamate-Glutamine Cycle in Synaptic Transmission During Ischemia and Recovery.

Hannah van Susteren, Christine R Rose, Michel J A M van Putten, Hil G E Meijer.

  Cerebral ischemia impairs neuronal and glial function, ranging from transient synaptic failure to irreversible damage. The effects of ischemia on excitatory synaptic transmission remain incompletely understood. Here, we present a detailed biophysical model, including the first full implementation of the glutamate-glutamine cycle (GG-cycle), which is essential for proper functioning of glutamatergic synapses. We model a presynaptic neuron and an astrocyte in a finite extracellular space (ECS), surrounded by an oxygen bath as a proxy for energy supply. The model includes ionic currents with corresponding channels and transporters such as the sodium-potassium ATPase. To model synaptic transmission, we combine calcium-dependent glutamate release, its uptake by the sodium-dependent excitatory amino acid transporters (EAATs), and the GG-cycle, including glutamine synthesis. We simulate ischemia by blocking energy supply completely. This drives the neuron into depolarization block, with pathological ion concentrations and extracellular glutamate accumulation despite disrupted synaptic release. Synaptic transmission failure is not primarily caused by excessive glutamate release or by failure of glutamine synthetase, but mainly results from EAAT dysfunction, driven by the collapse of the sodium gradient. Restoring synaptic transmission is not possible by solely targeting glutamate dynamics but is possible by restoring ion gradients by inhibition of the voltage-gated Na+-channel. Our study highlights the critical role of ion homeostasis, in particular the sodium gradient, in failure and recovery of synaptic function and the EAAT during metabolic stress.

Keywords:  cerebral ischemia; computational model; glutamate; glutamine; neurotransmitter; synaptic transmission

DOI:  https://doi.org/10.1111/ejn.70604
Front Cell Infect Microbiol. 2026 ;16 1806805

Metabolic reprogramming of macrophages during mycobacterial infection: a review of immunometabolic crosstalk and pathogen manipulation.

Xiaohe Lu, Yanping Zhao, Pingfan Qin, Yongquan Shi, Xiong Xiao.

  Macrophages undergo dynamic metabolic reprogramming that critically shapes their functional polarization and antimicrobial responses during mycobacterial infection. This review integrates current knowledge on how infection reprograms major metabolic pathways in macrophages. Mycobacterial infection triggers a complex and often dual-purposed rewiring of glycolysis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism. Pathogens actively manipulate these pathways to simultaneously suppress host antimicrobial effector functions and acquire nutrients for their own survival. Enhanced glycolysis, typically linked to M1 macrophages, can be exploited by the pathogen. Reprogramming of the TCA cycle, particularly through metabolites like itaconate, drives macrophages polarization toward an M2 phenotype that favors bacterial persistence. Amino acid metabolism becomes a site of metabolic competition where the bacterium secures substrates such as arginine and tryptophan to induce M2 phenotype, while the host attempts to sustain M1 macrophage functions through glutamine metabolism and the arginine nitric oxide pathway. Fatty acid metabolism further contributes to macrophage polarization in a context dependent manner. Understanding this immunometabolic interplay provides novel insights into tuberculosis pathogenesis and highlights metabolic pathways as potential targets for host-directed therapies. Future research should clarify the heterogeneity of metabolic responses across different mycobacterial species, infection stages, and macrophage subsets to guide therapeutic strategies.

Keywords:  TCA cycle; amino acid metabolism; fatty acid metabolism; glycolysis; immunometabolic interplay; macrophages; mycobacterial infection

DOI:  https://doi.org/10.3389/fcimb.2026.1806805
Rev Med Virol. 2026 Jul;36(4): e70179

Dysregulated Metabolism in People Living With HIV in the Modern ART-Era: A Systematic Review of Targeted Metabolomics Studies.

Levanco K Asia, Du Toit Loots, Shayne Mason, Esme Jansen Van Vuren, Monray E Williams.

  HIV remains a significant public health issue, with 1.3 million new infections and 630,000 deaths annually, and 40.8 million people living with HIV (PLHIV) globally in 2024. Although antiretroviral therapy (ART) suppresses viral replication, it does not eradicate the virus, and metabolic dysregulation persists despite treatment. Metabolomics allows for a detailed investigation of these alterations; however, targeted metabolomics studies in ART-treated PLHIV are limited, and there is no consensus on consistently dysregulated metabolites in PLHIV compared to healthy controls (HCs). This systematic review aimed to identify frequently investigated metabolites and key metabolic alterations in ART-treated PLHIV. A search strategy was designed for this study. PubMed, Scopus, and Web of Science were searched to identify relevant articles. We collected all search results in a reference manager and assessed titles and abstracts, as well as the full-text of the articles, for inclusion eligibility according to PRISMA guidelines. A total of 3217 studies were identified, of which 15 studies met the inclusion criteria. The review included 15 studies, comprising 886 PLHIV and 389 HCs. The most investigated metabolites were glutamine, tryptophan (Trp), kynurenine (Kyn), Kyn/Trp ratio, glycine, and ornithine. Consistent trends showed lower glutamine and glycine, and higher Kyn/Trp and ornithine, in PLHIV compared to HCs. Notably, metabolic dysregulation persisted in PLHIV despite viral suppression. Furthermore, studies conducted in the Global North more frequently reported metabolic dysregulation in PLHIV relative to HCs, compared with studies from the Global South, potentially reflecting regional variation or methodological differences. These findings offer insight into the targeted metabolic profiles of ART-treated PLHIV using metabolomics and suggest that metabolites such as glutamine, glycine, Kyn/Trp ratio and ornithine may play important roles in understanding HIV-1 pathogenesis in the modern ART-era.

Keywords:  HIV‐1; antiretroviral therapy; targeted metabolomics

DOI:  https://doi.org/10.1002/rmv.70179
Discov Oncol. 2026 Jul 08.

Multi-omics profiling reveals LncRNA ENSG00000253374 as a regulator of GLS-mediated cuproptosis and platinum resistance in ovarian cancer.

Rujun Chen, Qiran Sun, Jina Chen, Yating Huang, Ying Yang, Ningning Hu, Susu Jiang, Xiaoqin Wang, Liwen Zhang, Ke Sun, Fuyun Dong.

   BACKGROUND: Ovarian cancer (OC) has a dismal prognosis due to late diagnosis and platinum resistance, with the molecular mechanisms linking cuproptosis, lncRNAs, and the tumor microenvironment (TME) remaining poorly defined. LncRNA ENSG00000253374 was previously identified as a prognostic biomarker for OC, while its correlation with cuproptosis and platinum resistance remains unclear.
METHODS: Integrated bulk RNA-seq (TCGA-OV) and single-cell RNA-seq (GSE300897) analyses were performed, combined with in vitro CCK-8 assays, intracellular Cu⁺ detection, survival analysis, WGCNA, pseudotime trajectory, CellChat, virtual knockout, and functional enrichment analyses. OC cells with ENSG00000253374 knockdown were subjected to cuproptosis induction, and GLS-centered co-expression patterns and TME features were characterized.
RESULTS: ENSG00000253374 knockdown correlates with altered cellular response to cuproptosis induction, and shows close expression correlation with GLS. The ENSG00000253374-GLS correlated signature is linked to abnormal glutamine metabolism, cell cycle and stemness features, and is associated with immunosuppressive myeloid differentiation and enhanced pro-resistance intercellular communication that correlate with platinum refractoriness. WGCNA constructed a GLS-centered co-expression network enriched in immune and stromal remodeling pathways; in silico GLS perturbation predicted altered stemness, angiogenesis and apoptotic signaling signatures. Elevated GLS expression in tumor and stromal cells coincides with stronger TME crosstalk and dominant M2 macrophage populations.
CONCLUSION: LncRNA transcripts of the ENSG00000253374 locus are associated with platinum-resistant ovarian cancer phenotypes via a GLS-related correlative signature, alongside disrupted cuproptosis and metabolic-immune remodeling. Our in vitro assays reflect overall transcriptional activity of this genomic locus rather than single splice variant function. ENSG00000253374 and GLS may serve as candidate prognostic biomarkers. Combinatorial interventions targeting this correlative axis together with cuproptosis inducers or immune modulators could provide potential strategies to relieve platinum resistance in OC.

Keywords:  Cuproptosis; LncRNA; Multi-omics; Ovarian cancer; Platinum resistance

DOI:  https://doi.org/10.1007/s12672-026-05545-5
Oncogene. 2026 Jul 10.

Targeting of solute carrier family 1 member 1 that links metabolic reprogramming and ferroptosis sensitivity in pancreatic ductal adenocarcinoma.

Jie Tang, Dongyun Hang, Xiaotong He, Qingyu Wang, Lingmei Feng, Guoyu Chen, Ming Xu.

Solute carrier family 1 member 1 (SLC1A1, also known as excitatory amino acid transporter 3) is a member of the EAAT family of sodium-dependent glutamate carriers. Ferroptosis is a nonapoptotic cell death that is caused by phospholipid peroxidation promoted by radical reactions involving iron. Here, we identify SLC1A1 as a driver of ferroptosis resistance in PDAC cells and delineate the cause of its upregulation. SLC1A1 was overexpressed in PDAC tumors and correlated with poorer prognosis. Knockdown of SLC1A1 reduced cystine uptake by inhibiting glutamate transport, leading to decreased cysteine, GSH, and glutathione peroxidase 4 (GPX4) content, and the production of ROS and lipid peroxidation. Knockdown of SLC1A1 enhanced the ferroptosis sensitivity of PDAC cells and promoted ferroptosis inducer RSL3-induced ferroptosis and tumor suppression. Long noncoding RNA RASSF1-AS1 bound to CCCTC-binding factor (CTCF) protein, thereby inhibiting CTCF-mediated SLC1A1 transcription. Overexpression of RASSF1-AS1 enhanced the ferroptosis sensitivity of PDAC by blocking glutamate transport in vitro and in vivo, which was reversed by restoring CTCF/SLC1A1 signaling. Taken together, RASSF1-AS1 enhances the ferroptosis sensitivity of PDAC by inhibiting the CTCF/SLC1A1 axis-mediated intracellular transport of glutamate.

DOI: https://doi.org/10.1038/s41388-026-03888-5