bims-glucam 2025-10-19 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–10–19
twenty-one papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutaminase I and Glutamine Transaminase-ω-Amidase Pathways in Colorectal Cancer: Metabolic Reprogramming and Emerging Therapeutic Strategies.
Glutaminase Reprogramming in Hepatocellular Carcinoma: Implications for Diagnosis, Prognosis, and Potential as a Novel Therapeutic Target.
Glutamine: a new strategy for targeted metabolic therapy in the tumor microenvironment.
Envirotune-CAR-T: a hypoxia-responsive and glutamine-enhanced CAR-T cell therapy for overcoming tumor microenvironment-mediated suppression.
Glutaminase activity maintains NK cell cytotoxicity through metabolic regulation of effector function.
Dual-sensitization nanoformulation combining glutamine metabolism inhibition and Fas/FasL activation for enhanced colorectal cancer immunotherapy.
Glutamine: A novel player in maintaining skeletal strength and body fitness in obese mice.
Glutamine alleviates immunosuppression in polymicrobial sepsis by augmenting bacterial phagocytosis through sustaining the GFAT-DRP1 dependent mitochondrial calcium dynamics.
Aged mice exhibit widespread metabolic changes but preserved major fluxes.
Mitochondrial dynamics and metabolic attributes regulate function of natural killer cell and infiltration in tumor microenvironment modulating disease progression.
Protein glycosylation and synaptic transmission: brain glycogen keeps them separated.
Spatial metabolic gradients in the liver and small intestine.
NSUN2 Promotes the Growth, Metastasis and Glutamine Metabolism of Non-Small Cell Lung Cancer.
Targeting mitochondrial transporters and metabolic reprogramming for disease treatment.
CircRBM33 facilitates colorectal cancer progression by regulating the miR-512-5p/SLC1A5 axis.
Metabolomics fingerprinting of thyroid malignancies: a GC/MS-based approach for subtype classification and biomarker discovery.
Integrated metabolomic and transcriptomic analysis identifies adipogenic differentiation of mesenchymal stem cells as a driver of chemoresistance in acute myeloid leukemia.
Metabolite characterization and in vitro antiplasmodial potential assessment of Sonchus arvensis L. callus under glutamine treatment.
Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy.
Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia.
Design, Synthesis, and Biological Evaluation of Rapamycin Derivatives as the First Mammalian Target of Rapamycin and GLS1 Dual Inhibitors.

Anal Biochem. 2025 Oct 10. pii: S0003-2697(25)00228-3. [Epub ahead of print] 115989

Glutaminase I and Glutamine Transaminase-ω-Amidase Pathways in Colorectal Cancer: Metabolic Reprogramming and Emerging Therapeutic Strategies.

Sarah F Voor, Arthur J L Cooper, John T Pinto.

  Colorectal cancer (CRC) cells exhibit a pronounced dependence on L-glutamine to support anabolic growth, redox balance, and mitochondrial metabolism, a phenomenon known as "glutamine addiction." The canonical glutaminase I pathway is mediated by a liver type glutaminase isozyme (LGA; GLS1), a kidney type glutaminase isozyme (KGA; GLS2), and a shortened form (glutaminase C, GAC). GLS1 and GLS2 convert glutamine to glutamate and subsequently to α-ketoglutarate (α-KG) by glutamate dehydrogenase, fueling the TCA cycle. GLS1 inhibitors, such as CB-839 (Telaglenastat), are under clinical evaluation and shows promise in treatment of CRC, particularly in combination therapies. In addition to the canonical pathway, the glutamine transaminase-ω-amidase (GTωA) pathway, a noncanonical route involving transamination of glutamine to α-ketoglutaramate (KGM) by KYAT1/2 and subsequent hydrolysis by ω-amidase (NIT2), offers metabolic flexibility under hypoxic or nutrient-limited conditions. Preclinical studies suggest that GTωA may compensate for GLS1 inhibition, contributing to therapeutic resistance. This review explores the dual roles of glutamine metabolism in CRC, emphasizing the GTωA pathway as a potentially targetable metabolic route that may contribute to therapeutic resistance. While GLS1 inhibitors are under clinical evaluation, emerging evidence suggests that dual targeting of both pathways may enhance treatment efficacy by overcoming metabolic compensation. Understanding the regulatory mechanisms driving the "glutamine shift" between these pathways is critical for developing effective metabolic interventions in CRC.

Keywords:  L-glutamine addiction; glutaminase I; glutamine shift; glutamine transaminase-ω-amidase; metabolic reprogramming; α-ketoglutaramate

DOI:  https://doi.org/10.1016/j.ab.2025.115989
Int J Mol Sci. 2025 Oct 03. pii: 9653. [Epub ahead of print]26(19):

Glutaminase Reprogramming in Hepatocellular Carcinoma: Implications for Diagnosis, Prognosis, and Potential as a Novel Therapeutic Target.

Vincent Tambay, Valérie-Ann Raymond, Simon Turcotte, Marc Bilodeau.

  Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, with a poor prognosis due to late diagnosis, limited curative therapies, and underlying liver disease. Glutamine metabolism, a crucial pathway in cancer, remains poorly understood in HCC, which develops in an already metabolically dynamic organ. This study aimed to characterize glutamine metabolism in HCC. Glutamine metabolism in HCC was explored through in vitro analysis of neoplastic characteristics, experimental hepatocarcinogenesis in C57BL/6 mice, and examination of liver samples from patients with HCC, cirrhosis, and non-diseased liver. The evaluation included metabolite abundance and mRNA/protein expressions. In mice, tumors exhibited hyperactive glutaminolysis compared to adjacent tissue. Notably, glutaminase expression shifted from the liver isoform (GLS2) in normal and cirrhotic livers to the kidney isoform (GLS1) in HCC. In samples from patients, HCC tumors showed overexpression of glutamine synthetase and GLS1 along with a loss of GLS2 expression, providing excellent discrimination of HCC lesions from cirrhotic and normal liver samples. Inhibiting GLS1 with CB-839 significantly impacted glutamine metabolism in HCC cells while showing limited activity on normal hepatocytes. HCC tumors show reprogramming of GLS2 to GLS1, with a concomitant increase in glutamine synthetase. These characteristics can discriminate HCC from cirrhotic and normal liver tissues. Overexpressed GLS1 and loss of GLS2 within tumors convey an unfavorable prognosis in patients with HCC. Pharmacological inhibition of GLS1 in HCC cells successfully harnesses glutamine metabolism, representing an attractive target for novel therapeutic approaches.

Keywords:  CB-839; glutamine; hepatocellular carcinoma; liver; metabolic reprogramming; metabolism

DOI:  https://doi.org/10.3390/ijms26199653
Cell Death Discov. 2025 Oct 13. 11(1): 459

Glutamine: a new strategy for targeted metabolic therapy in the tumor microenvironment.

Haixu Lv, Xiao Han, Yuanshuang Yang, Jianfeng Shen, Yixuan Yin, Yu Liu.

In the tumor microenvironment, glutamine has a profound impact not only on the growth, metabolism, metastasis, and invasion of tumor cells but also on the survival and function of immune cells and the behavior of nonimmune cells. Given the limited amount of glutamine in the tumor microenvironment, there is a competitive relationship between tumor and nontumor cells. Owing to the metabolic reprogramming of tumor cells, many nutrients, including glutamine, are necessary for tumor cells to maintain their rapid growth and high metabolic demand. Therefore, tumor cells are in a superior position to compete for glutamine. These findings provide solid theoretical support for targeting glutamine metabolism for anticancer therapy. This review summarizes the importance and necessity of glutamine for tumor cells and nontumor cells in the tumor microenvironment. According to the mechanism of action of glutamine in tumor cells and the regulatory mechanism of related signaling pathways, the currently developed anticancer drugs that target glutamine metabolism are categorized on a scientific basis, and the importance of basic medicine applied in clinical medicine is emphasized. This review not only provides anticancer information for clinicians but also brings hope to cancer patients.

DOI: https://doi.org/10.1038/s41420-025-02767-4
J Immunother Cancer. 2025 Oct 13. pii: e012321. [Epub ahead of print]13(10):

Envirotune-CAR-T: a hypoxia-responsive and glutamine-enhanced CAR-T cell therapy for overcoming tumor microenvironment-mediated suppression.

Wenying Li, Jiannan Chen, Jiayi Li, Shuai Wang, Zhengliang Chen, Lianfeng Zhao, Yaoyao Zhao, Lili Gu, Jiaqi Liu, Yan Zhang, Xinhao Yang, Tianyu Chen, Zhigang Guo.

   BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable success in hematologic malignancies; however, its efficacy in solid tumors remains limited. A major barrier is the immunosuppressive tumor microenvironment (TME), which is characterized by hypoxia and nutrient deprivation, leading to impaired CAR-T cell proliferation, persistence, and cytotoxic function. To address these barriers, we designed a dual-regulatory CAR-T strategy that integrates hypoxia-responsive control with metabolic enhancement to improve therapeutic efficacy in solid tumors.
METHODS: To overcome these barriers, we developed a next-generation CAR-T platform with dual adaptations targeting the metabolic and transcriptional constraints of the TME. Specifically, we engineered hypoxia-responsive regulatory elements derived from VEGF to drive sustained CAR expression under hypoxic conditions. Concurrently, we overexpressed the glutamine transporter SLC38A2 to enhance glutamine uptake and metabolic fitness in nutrient-deprived environments.
RESULTS: Compared with conventional CAR-T cells, our engineered CAR-T cells exhibited superior antitumor activity under hypoxia and nutrient stress, with enhanced proliferation, elevated memory phenotype, and reduced exhaustion markers. Mechanistically, quantitative PCR demonstrated upregulation of glutamine metabolic and glycolytic pathways, while Seahorse assays confirmed enhanced oxidative phosphorylation and glycolysis. SLC38A2 knockout reversed these enhancements, highlighting its role in sustaining CAR-T metabolic fitness.
CONCLUSION: Our findings establish SLC38A2 as a critical metabolic regulator that enhances CAR-T antitumor efficacy, providing a promising strategy to improve the durability and efficacy of CAR-T cell therapies in TME.

Keywords:  Chimeric antigen receptor - CAR; Immunotherapy; Memory; Solid tumor; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2025-012321
J Inflamm (Lond). 2025 Oct 14. 22(1): 45

Glutaminase activity maintains NK cell cytotoxicity through metabolic regulation of effector function.

M Jedlička, T Feglarová, V Švubová, E Mašínová, V Graman, K Kuglerová, J Szabová, F Jahan, M Korhonen, K Kuželová, M Hortová-Kohoutková, J Frič.

   BACKGROUND: Natural killer (NK) cells are responsible for monitoring and eliminating malignant or virus-infected cells. To become activated, NK cells must upregulate oxidative phosphorylation and glycolysis to meet the high energetic demands associated with cytotoxic and effector functions. While glutamine can also fuel the tricarboxylic acid cycle through its conversion to alpha-ketoglutarate, the precise role of this pathway in NK-cell cytotoxic activity is unclear.
RESULTS: To investigate NK-cell dependency on glutamine, we selectively inhibited kidney-type glutaminase to prevent glutamine metabolism. We analysed the metabolism and cytotoxicity of expanded primary NK cells, treated or not with glutaminase inhibitor. Glutaminase inhibition significantly reduced oxidative phosphorylation and led to a significant decrease in NK cell cytotoxic function. Furthermore, glutaminase inhibition reduced protein synthesis in activated NK cells. Meanwhile, supplementation with alpha-ketoglutarate rescued both the metabolic and cytotoxic capacities of primary expanded NK cells.
CONCLUSIONS: Our findings highlight the importance of glutaminase activity in supporting NK cell respiratory metabolism and cytotoxic function, and the need for caution when combining glutaminase inhibitors with NK cell-based therapies.

Keywords:  Alpha-ketoglutarate; Cell cytotoxicity; Glutaminase; Immunometabolism; Natural killer cell

DOI:  https://doi.org/10.1186/s12950-025-00470-w
J Control Release. 2025 Oct 13. pii: S0168-3659(25)00938-1. [Epub ahead of print] 114324

Dual-sensitization nanoformulation combining glutamine metabolism inhibition and Fas/FasL activation for enhanced colorectal cancer immunotherapy.

Dan Yan, Wenzhe Yi, Ting Wu, Shuangshuang Hu, Yan Ding, Xindi Qian, Zhiwen Zhao, Dangge Wang, Huae Xu, Ying Cai, Yaping Li.

  Altered glutamine metabolism in colorectal cancer (CRC) promotes immune evasion by inducing an immunosuppressive tumor microenvironment. Herein, we developed a nanocomplex by linking the anti-programmed death ligand 1 (PD-L1) antibody (αPDL1) with alanine-serine-cysteine transporter 2 antagonist V-9302 covalently via a glutathione-responsive linker (PVN). The PVN disintegrated and released V-9302, which suppresses glutamine uptake and upregulates the expression of PD-L1 and the Fas cell surface death receptor (Fas/CD95/Apo-1) in tumor cells via the Ca2+/NF-κB signaling axis. This converted the PD-L1 elevation into therapeutic vulnerability, sensitizing tumor cells to immune checkpoint blockade. The upregulated tumor-associated Fas expression was utilized by Fas ligand (FasL)-overexpressing dendritic cell (FasL-DC) to activate death receptor pathways and induce Fas/FasL-mediated tumor apoptosis. The combination strategy termed PVN/FasL-DC, promoted dendritic cell maturation, epitope spreading, and increased the infiltration of CD8+ T cells, thereby enhancing antitumor efficacy. This study emphasizes the synergistic modulation of glutamine metabolism and death receptor pathways as a dual-sensitization strategy with promise for CRC immunotherapy.

Keywords:  Colorectal cancer; Engineered immune cells; Fas ligand; Glutamine inhibition; Immunotherapy

DOI:  https://doi.org/10.1016/j.jconrel.2025.114324
Clin Nutr. 2025 Oct 09. pii: S0261-5614(25)00266-3. [Epub ahead of print]54 162-176

Glutamine: A novel player in maintaining skeletal strength and body fitness in obese mice.

Martina Dzubanova, Michaela Ferencakova, Dung K Nguyen, Kristina Bardova, Elena Golovina, Heleen Fehervary, Andrea Benova, Yusuf Odabaşı, Ravindra Naraine, Radek Sindelka, Frantisek Spoutil, Jan Prochazka, Tomas Cajka, G Harry van Lenthe, Rita Sarkis, Olaia Naveiras, Martin Rossmeisl, Jan Kopecky, Michaela Tencerova.

   BACKGROUND AND AIMS: Glutamine plays a key role in cellular metabolism and tissue homeostasis. In obesity, circulating glutamine levels decline, accompanied by impaired bone homeostasis and increased fracture risk. While dietary glutamine supplementation shows metabolic benefits, its effects on bone and fat metabolism remain unclear. This study investigates whether glutamine supplementation mitigates obesity-induced alterations in bone and fat metabolism.
METHODS: C57BL/6J male mice were subjected to a 2-month dietary intervention with either high-fat diet (HFD) or HFD supplemented with glutamine (HFD + G) and low-fat diet (LFD) as a control group. Body weight, fat mass, glucose tolerance, white adipose tissue (WAT) morphology, and bone parameters were analyzed. Functional assays of adipose-derived mesenchymal stem cells (AT-MSCs) and bone marrow stromal cells (BMSCs) assessed metabolic phenotype and differentiation potential. Glutamine turnover was evaluated, and findings were extended to human BMSCs to assess sex-specific patterns of glutaminolysis.
RESULTS: Glutamine supplementation attenuated body weight gain, fat mass, and WAT weight, along with improved glucose tolerance compared to HFD-fed mice. In WAT, glutamine reduced adipocyte hypertrophy and inflammation, while in AT-MSCs it suppressed obesity-driven hyper-metabolic phenotype by shifting cells toward quiescence. In bone, glutamine improved bone quality, along with reduced bone marrow adiposity and decreased bone resorption. BMSCs from glutamine-treated mice showed decreased adipogenic and increased osteogenic potential, supported by enhanced glutamine turnover, which maintained the stemness of the cells and reduced the inflammation induced by obesity. In human BMSCs, glutamine metabolism displayed sex-specific differences, underscoring its physiological relevance.
CONCLUSION: Glutamine supplementation improves systemic metabolic health and bone integrity at both the organ and cellular levels, highlighting its potential as a therapeutic strategy for preventing obesity-related metabolic and bone diseases.

Keywords:  Adipose-derived stem cells; Bone marrow adiposity; Bone marrow stromal cells; Glutamine metabolism; Glutamine-enriched diet; Obesity-induced bone impairment

DOI:  https://doi.org/10.1016/j.clnu.2025.09.018
Clin Sci (Lond). 2025 Oct 08. pii: CS20256651. [Epub ahead of print]

Glutamine alleviates immunosuppression in polymicrobial sepsis by augmenting bacterial phagocytosis through sustaining the GFAT-DRP1 dependent mitochondrial calcium dynamics.

Yuanfeng Zhu, Xiaoli Chen, Lin Xia, Shijun Fan, Qian Chen, Yan Wei, Yongling Lu, Xin Liu, Xi Peng.

  Sepsis triggers impaired macrophage bacterial phagocytosis, rendering the host more vulnerable to secondary infections, a manifestation termed sepsis-associated immunosuppression. Glutamine is a vital nutrient in critical illness that not only supports energy production and biomass synthesis but also potentially exerts immunomodulatory effects. The aim of this study was to investigate whether supplementation of glutamine modulates macrophage phagocytosis and mitigates sepsis-induced immunosuppression. Using a murine model of polymicrobial sepsis, we evaluated the effects of glutamine supplementation on bacterial load, cytokine production, and survival. In multiple in vitro assays, we employed molecular and pharmacological approaches to dissect glutamine-dependent signaling pathways in recovering the immunosuppressive macrophages. We found that glutamine deficiency impaired macrophage phagocytosis and exacerbated sepsis-induced immunosuppression. In contrast, exogenous glutamine supplementation restored macrophage function and improved survival in septic mice-effects that were abolished upon macrophage depletion. Mechanistically, glutamine promoted glutamine-fructose-6-phosphate transaminase (GFAT)-dependent protein O-GlcNAcylation, leading to dynamin-related protein 1 (DRP1) oligomerization. Concurrently, glutamine activated a GFAT-mediated, CDK1-dependent pathway that induced DRP1 phosphorylation at Ser616 irrelevant of O-GlcNAcylation. These effects enhanced DRP1-mediated mitochondrial fission, increased mitochondrial calcium efflux, and sustained cytosolic calcium levels essential for phagocytosis. In conclusion, our study demonstrates that glutamine strengthens macrophage phagocytosis and alleviates immunosuppression in sepsis through a dual GFAT-DRP1 mechanism coordinating mitochondrial dynamics and calcium signaling, highlighting the GFAT-DRP1-calcium axis as a potential therapeutic target for treating sepsis-induced immunosuppression.

Keywords:  DRP1; GFAT; glutamine; immunosuppression; mitochondrial; phagocytosis; sepsis

DOI:  https://doi.org/10.1042/CS20256651
Cell Metab. 2025 Oct 16. pii: S1550-4131(25)00394-8. [Epub ahead of print]

Aged mice exhibit widespread metabolic changes but preserved major fluxes.

Connor S R Jankowski, Laith Z Samarah, Michael R MacArthur, Sarah J Mitchell, Daniel R Weilandt, Craig J Hunter, Xianfeng Zeng, Melanie R McReynolds, Joshua D Rabinowitz.

  Metabolic dysregulation is a hallmark of aging. Here, we investigate in mice age-induced metabolic alterations using metabolomics and stable isotope tracing. Circulating metabolite fluxes and serum and tissue concentrations were measured in young and old (20-30 months) C57BL/6J mice, with young obese (ob/ob) mice as a comparator. For major circulating metabolites, concentrations changed more with age than fluxes, and fluxes changed more with obesity than with aging. Specifically, glucose, lactate, 3-hydroxybutryate, and many amino acids (but notably not taurine) change significantly in concentration with age. Only glutamine circulatory flux does so. The fluxes of major circulating metabolites remain stable despite underlying metabolic changes. For example, lysine catabolism shifts from the saccharopine toward the pipecolic acid pathway, and both pipecolic acid concentration and flux increase with aging. Other less-abundant metabolites also show coherent, age-induced concentration and flux changes. Thus, while aging leads to widespread metabolic changes, major metabolic fluxes are largely preserved.

Keywords:  aging; fluxomics; glutamine; metabolic flux; metabolism; metabolomics; obesity; stable isotope tracing; systemic metabolism

DOI:  https://doi.org/10.1016/j.cmet.2025.09.009
Biochim Biophys Acta Rev Cancer. 2025 Oct 10. pii: S0304-419X(25)00213-6. [Epub ahead of print]1880(6): 189471

Mitochondrial dynamics and metabolic attributes regulate function of natural killer cell and infiltration in tumor microenvironment modulating disease progression.

Sayak Ghosh, Rittick Dutta, Devyani Goswami, Debapriya Ghatak, Rudranil De.

  Mitochondria in natural killer (NK) cells orchestrate a dynamic interplay between energy production and immune regulation, placing them at the forefront of oncogenesis and tumor microenvironment (TME) infiltration. This review unravels the intricate disruptions in mitochondrial dynamics-fission, fusion, and biogenesis-that hypoxia imposes within the TME, culminating in impaired NK cell functionality. Hypoxia-driven mitochondrial fragmentation, mediated by HIF-1α and mTOR-Drp1 signaling, cripples NK cell cytotoxicity, proliferation, and maturation, while elevated ROS levels and metabolic reprogramming bolster tumor immune evasion. The metabolic landscape of the TME adds another layer of complexity, with amino acid depletion significantly hindering NK cell performance. Arginine and leucine deficiencies suppress proliferation and mTOR activation, whereas disrupted glutamine metabolism impairs cMyc-driven metabolic adaptation. Additionally, immunosuppressive catabolites like nitric oxide and L-kynurenine exacerbate NK cell dysfunction by curbing cytokine production and receptor expression. Targeting these metabolic vulnerabilities offers a promising strategy; specifically, interventions aimed at amino acid pathways could simultaneously restrict nutrient availability within the tumor microenvironment and preserve NK cell functionalities. Emerging strategies spotlight the potential of NK cells to induce autophagic death in hypoxic cancer cells, a mechanism that could restore their cytotoxic potential. Furthermore, immune checkpoint pathways, such as PD-1 and CTLA-4, amplify mitochondrial dysfunction, underscoring their therapeutic significance. By addressing hypoxia, metabolic dysregulation, and mitochondrial reprogramming, this review illuminates actionable strategies to reinvigorate NK cell-mediated antitumor responses and pave the way for transformative cancer therapies.

Keywords:  Cancer; Glutamine; Hypoxia; Immunometabolism; Mitochondria; Natural killer (NK) cells

DOI:  https://doi.org/10.1016/j.bbcan.2025.189471
Brain. 2025 Oct 17. pii: awaf396. [Epub ahead of print]

Protein glycosylation and synaptic transmission: brain glycogen keeps them separated.

Gabriele Trentini, Giulia Cazzanelli, Graziano Lolli.

  Brain glycogen has for long been regarded uniquely as a source of energetic support in situations of emergency or heightened activity. Recently, brain glycogen was found to contain a significant amount of glucosamine, which is used to sustain protein glycosylation. In this update, we highlight that glucosamine synthesis through the hexosamine pathway would subtract glutamine, which is instead indispensable for glutamate and GABA recycling. Brain glycogen seems then to serve an additional role. By providing glucosamine and, through it, inhibiting the hexosamine pathway, glycogen avoids glutamine depletion. In neurological glycogen storage diseases, the short-circuit between the hexosamine pathway and neurotransmitters recycling can cause epileptic seizures, which are the most common acute manifestation in these pathologies. We finally discuss the metabolic and symptomatic superposition of glycogen storage diseases with congenital disorders of glycosylation, concluding that treatments ameliorating the clinical symptoms in some of the discussed pathologies could also be beneficial in the others.

Keywords:  congenital disorders of glycosylation; epilepsy; glucosamine; glutamine; glycogen; glycogen storage diseases

DOI:  https://doi.org/10.1093/brain/awaf396
Nature. 2025 Oct 15.

Spatial metabolic gradients in the liver and small intestine.

Laith Z Samarah, Clover Zheng, Xi Xing, Won Dong Lee, Amichay Afriat, Uthsav Chitra, Michael R MacArthur, Wenyun Lu, Connor S R Jankowski, Cong Ma, Craig J Hunter, Michael Neinast, Daniel R Weilandt, Benjamin J Raphael, Joshua D Rabinowitz.

The properties of mammalian cells depend on their location within organs. Gene expression in the liver varies between periportal and pericentral hepatocytes1-3, and in the intestine from crypts to villus tips4,5. A key element of tissue spatial organization is probably metabolic, but direct assessments of spatial metabolism remain limited. Here we map spatial metabolic gradients in the mouse liver and intestine. We develop an integrated experimental-computational workflow using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS), isotope tracing and deep-learning artificial intelligence. Most measured metabolites (>90%) showed significant spatial concentration gradients in the liver lobules and intestinal villi. In the liver, tricarboxylic acid (TCA)-cycle metabolites and their isotope labelling from both glutamine and lactate localized periportally. Energy-stress metabolites, including adenosine monophosphate (AMP), also localized periportally, consistent with a high periportal energy demand. In the intestine, the TCA intermediates malate (tip) and citrate (crypt) showed opposite spatial patterns, aligning with higher glutamine catabolism in tips and lactate oxidation in crypts based on isotope tracing. Finally, we mapped the fate of the obesogenic dietary sugar fructose. In the intestine, oral fructose was catabolized faster in the villus bottom than in the tips. In the liver, fructose-derived carbon accumulated pericentrally as fructose-1-phosphate and triggered pericentral adenosine triphosphate (ATP) depletion. Thus, we both provide foundational knowledge regarding intestine and liver metabolic organization and identify fructose-induced focal derangements in liver metabolism.

DOI: https://doi.org/10.1038/s41586-025-09616-5
Am J Respir Cell Mol Biol. 2025 Oct 14.

NSUN2 Promotes the Growth, Metastasis and Glutamine Metabolism of Non-Small Cell Lung Cancer.

Yifan Zheng, Chunhui Ma, Shengguang Ding, Fuquan Zhang, Huibing Liu, Yiming Xu.

As a 5-methylcytosine (m5C) methyltransferase, increased NOP2/Sun RNA methyltransferase 2 (NSUN2) has been revealed to promote the progression of non-small cell lung cancer (NSCLC) through m5C modification. Herein, this study aimed to investigate the potential molecular mechanisms underlying the high NSUN2 expression in NSCLC, and the potential downstream m5C mRNAs of NSUN2 in promoting NSCLC progression. Functional analyses were conducted using in vitro MTT, EdU, transwell, wound healing, sphere and tube formation assays, and in vivo murine model. m5C modification was determined by MeRIP assay. RIP assay determined the binding between NSUN2 and SLC7A5 mRNA. The upstream molecular mechanism of the upregulation of NSUN2 expression was explored using ChIP, Co-immunoprecipitation (Co-IP), and luciferase reporter assays. NSUN2 was highly expressed in NSCLC and predicted poor outcomes in NSCLC patients. Functionally, NSUN2 silencing suppressed cancer cell proliferation, migration, stemness properties, angiogenic ability and glutamine metabolism. Mechanistically, NSUN2 induced m5C methylation modification of SLC7A5, and stabilized SLC7A5 mRNA via a YBX1-dependent mechanism. Accordingly, SLC7A5 overexpression reversed the anticancer effects of NSUN2 on above oncogenic phenotypes. Further upstream molecular mechanism analysis showed that P300 could bind to and cooperate with transcription factor SP1 to increase NSUN2 expression by Histone H3 Lysine 27 acetylation (H3K27ac). Further in vivo analyses suggested that NSUN2 silencing suppressed ESCC growth and metastasis in vivo by regulating SLC7A5 expression. In conclusion, increased NSUN2 derived by P300/SP1 complex-mediated histone acetylation promoted the growth, metastasis and glutamine metabolism of NSCLC by stabilizing SLC7A5 mRNA via m5C modification.

DOI: https://doi.org/10.1165/rcmb.2025-0274OC
J Transl Med. 2025 Oct 16. 23(1): 1111

Targeting mitochondrial transporters and metabolic reprogramming for disease treatment.

Mboneye Anselme, Huafeng He, Chengyang Lai, Wenwei Luo, Shilong Zhong.

  In the realm of cellular biochemistry, mitochondria have been increasingly recognized for their critical role in both cellular metabolism and the etiology of various diseases. Mitochondrial transporters (MTs) are essential for maintaining cellular energy dynamics and metabolic fluxes by facilitating the bidirectional transfer of metabolites across mitochondrial membranes. Dysregulation of these transporters, such as the mitochondrial pyruvate carrier (MPC), citrate carrier (SLC25A1), and voltage-dependent anion channel (VDAC), disrupts energy metabolism, redox balance, and cellular signaling, contributing to the pathogenesis of neurodegenerative diseases (NDDs), cardiovascular diseases (CVDs), type 2 diabetes (T2D), and cancer. In NDDs, impaired transporters exacerbate oxidative stress and neuronal death, while in CVDs, they lead to energy deficits and heart failure. In T2D, dysfunctional transporters like MPC and carnitine palmitoyltransferase (CPT) systems drive insulin resistance and metabolic dysregulation. In cancer, upregulated transporters such as citrate carrier (SLC25A1), and dicarboxylate carrier (SLC25A10) as well as metabolic shifts like the Warburg effect support tumor growth and survival. Targeting MTs and metabolic reprogramming (MR) offers significant therapeutic potential. Preclinical studies have demonstrated the efficacy of mitochondrial-targeted therapies (MTT), such as adenosine monophosphate-activated protein kinase (AMPK) activators and antioxidants, in restoring metabolic homeostasis and reducing disease pathology. In cancer, inhibitors of glutamine transporters and VDAC1 are being explored to disrupt tumor metabolism. Several therapies are advancing to clinical trials, including mitochondrial-targeted drugs for NDDs and metabolic modulators for T2D and cancer, highlighting their translational potential. Despite notable individual achievements and isolated reviews in this field, there remains a lack of comprehensive syntheses that integrate these advancements. This review seeks to combine the prevailing scientific evidence and outline prospective research trajectories. The gathered data robustly support the significant potential of targeting MTs as a groundbreaking approach in the treatment of complex diseases, with the potential to significantly improve health outcomes and mitigate disease progression.

Keywords:  Cellular metabolism; Disease treatment; Metabolic reprogramming; Mitochondria; Mitochondrial transporters

DOI:  https://doi.org/10.1186/s12967-025-06976-4
Pathol Res Pract. 2025 Sep 25. pii: S0344-0338(25)00441-8. [Epub ahead of print]276 156248

CircRBM33 facilitates colorectal cancer progression by regulating the miR-512-5p/SLC1A5 axis.

Juan Zhang, Li Zhang, Kiyohito Tanaka, Feiyu Shi, Junjun She, Shuixiang He.

   BACKGROUND: Colorectal cancer (CRC) is a common malignant tumor of the digestive tract with high morbidity and mortality. Previous studies have shown that circular RNA (circRNA) circRBM33 (also known as hsa_circRNA_104532) was implicated in the pathogenesis of various human cancers. This study aims to investigate the potential function and working mechanism of circRBM33 in CRC.
METHODS: circRBM33, microRNA-512-5p (miR-512-5p), and solute carrier 1 family member 5 (SLC1A5) levels were detected using real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferative ability, apoptosis, and migration were analyzed using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, and wound healing assay. C-myc, CyclinD1, and SLC1A5 protein levels were measured using Western blot. The glycolysis levels were evaluated using specific kits. The biological role of circRBM33 on CRC tumor growth was assessed using the xenograft tumor model in vivo. After circular RNA Interactome and Targetscan prediction, the binding between miR-512-5p and circRBM33 or SLC1A5 was verified using a dual-luciferase reporter assay.
RESULTS: CircRBM33 and SLC1A5 were increased, and miR-512-5p was decreased in CRC tissues and cells. From a functional perspective, circRBM33 knockdown could hinder cell proliferation, migration, glutamine metabolism, and boost apoptosis in CRC cells. Also, circRBM33 silencing could suppress the cell growth of CRC in vivo. The mechanical analysis suggested that circRBM33 could increase SLC1A5 expression via sponging miR-512-5p.
CONCLUSION: CircRBM33 boosted CRC development partly by regulating the miR-512-5p/SLC1A5 axis, providing a promising therapeutic target for CRC therapy.

Keywords:  CircRBM33; Colorectal cancer; MiR-512–5p; SLC1A5

DOI:  https://doi.org/10.1016/j.prp.2025.156248
BMC Cancer. 2025 Oct 15. 25(1): 1586

Metabolomics fingerprinting of thyroid malignancies: a GC/MS-based approach for subtype classification and biomarker discovery.

Raziyeh Abooshahab, Maryam Zarkesh, Mehdi Hedayati.

   BACKGROUND: Thyroid cancer encompasses distinct histological subtypes, each potentially associated with unique metabolic characteristics. However, the comprehensive metabolic reprogramming underlying these malignancies remains insufficiently characterized. Hence, this study aimed to identify untargeted metabolomics alterations in plasma samples from patients diagnosed with papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), medullary thyroid carcinoma (MTC), and healthy controls, to elucidate potential metabolic signatures associated with each cancer type.
METHODS: Plasma samples from patients with PTC (n = 14), FTC (n = 8), and MTC (n = 15), along with samples from healthy subjects (n = 15), were collected for untargeted metabolomics analysis using gas chromatography-mass spectrometry (GC/MS). Multivariate and univariate analyses were performed for diagnostic assessment using MetaboAnalyst, SIMCA software, and R packages.
RESULTS: A total of 61 metabolites were annotated across all plasma samples. Multivariate analyses, including partial least squares discriminant analysis (PLS-DA) and orthogonal PLS-DA (OPLS-DA), revealed distinct group separations and demonstrated robust model performance. One-way ANOVA followed by Tukey's HSD and variable importance in projection (VIP ≥ 1) highlighted 35 significantly altered metabolites. Among these, linolenic acid (q = 4.76E-13) and arachidonic acid (q = 1.39E-12) showed substantial reductions across all thyroid cancer subtypes. Conversely, glutamine (q = 1.14E-10), methionine (q = 2.54E-09), and 2-hydroxybutanoic acid (q = 1.49E-07) were elevated in FTC and PTC. A Random Forest analysis further highlighted linolenic, linoleic, arachidonic acids, methionine, glutamine, and pyruvic acid, as crucial discriminative elements, achieving a macro-averaged AUC of 0.956 in multi-class classification.
CONCLUSION: This plasma metabolomics study reveals distinctive metabolic signatures associated with different thyroid cancer subtypes, suggesting potential biomarkers for differential diagnosis. These findings underscore the importance of metabolomics in enhancing subtype differentiation and provide insight into metabolic pathways associated with disease progression.

Keywords:  Cancer metabolism; GC/MS; Metabolic profile; Metabolomics; Thyroid cancers

DOI:  https://doi.org/10.1186/s12885-025-15073-0
J Exp Clin Cancer Res. 2025 Oct 17. 44(1): 291

Integrated metabolomic and transcriptomic analysis identifies adipogenic differentiation of mesenchymal stem cells as a driver of chemoresistance in acute myeloid leukemia.

Zhipeng Pan, Rong Hu, Dandan Li, Siwen Deng, Haishan Yi, Zhengwei Duan, Lixia Kang, Ling Chen, Mengyao Wang, Yue Duan, Xiaofan Jia, Pengfei Guo, Yang Chen.

   BACKGROUND: Acute myeloid leukemia (AML) remains a challenging hematological malignancy, with chemoresistance contributing significantly to treatment failure and relapse. The bone marrow microenvironment, particularly mesenchymal stem cells (MSCs), plays a critical role in AML cell survival and drug resistance. Although previous studies have extensively explored the MSCs differentiation, the regulatory role of the adipogenically differentiated MSCs on AML cells during co-culture remains unclear.
METHODS: An indirect co-culture model was established to evaluate the impact of MSCs on the drug sensitivity of AML cells. Based on the comparable chemosensitivity trends observed among THP-1, U937, and HL-60 cells, THP-1 were selected for subsequent experiments due to their stable growth characteristics and well-established utilization. Metabolic alterations between co-cultured and monocultured THP-1 were profiled using nuclear magnetic resonance spectroscopy. Concurrently, RNA sequencing was conducted to identify differentially expressed genes and enriched signaling pathways between co-cultured and monocultured THP-1. To validate the pathway alterations identified by transcriptomic analysis, the Akt inhibitor MK-2206 was applied, and its effects were evaluated by western blotting and cell viability assays.
RESULTS: The results demonstrated that AML cells co-cultured with adipogenic MSCs were less sensitive to daunorubicin and cytarabine in both in vitro and in vivo. Subsequent metabolomics analysis revealed significant alternative metabolic processes in AML cells following co-culture, specifically in the glycolysis, glutamine metabolism and lipid metabolism. Further transcriptomic profiling identified key differentially expressed genes and signaling pathways, with PI3K/Akt signaling pathway activation emerging as a contributor to the reduced chemotherapy sensitivity. Furthermore, elevated levels of IL-6 in the co-culture system suggested a role for cytokine-mediated signaling in promoting a protective microenvironment.
CONCLUSIONS: This work demonstrates that the adipogenically differentiated MSCs enhance the survival and chemoresistance of AML cells by modulating metabolic and signaling pathways. It provides integrated insights into the microenvironment-driven mechanisms of AML drug resistance and presents potential therapeutic targets to enhance treatment efficacy.

Keywords:  Acute myeloid leukemia; Adipogenic differentiation; Chemosensitivity; Co-culture; Mesenchymal stem cells

DOI:  https://doi.org/10.1186/s13046-025-03550-0
Sci Rep. 2025 Oct 15. 15(1): 35956

Metabolite characterization and in vitro antiplasmodial potential assessment of Sonchus arvensis L. callus under glutamine treatment.

Dwi Kusuma Wahyuni, Cici Tya Rahmawati, Alvi Jauharotus Syukriya, Niluh Dismayanti, Mamluatul Bariroh Arifin, Viol Dhea Kharisma, Sreeramanan Subramaniam, Ali Muhammad Zakariya, Mohd Zuwairi Saiman, Nur Kusaira Khairul Ikram, Stefaan P O Werbrouck, Hery Purnobasuki, Sehanat Prasongsuk.

  This study investigates the effects of glutamine supplementation on the morphology, anatomy, biomass, production of secondary metabolites, in-vitro antioxidant, and antiplasmodial activity of Sonchus arvensis L. callus. Callus was induced from leaf explants on Murashige and Skoog (MS) medium supplemented with 1 mg/L 2,4-Dichlorophenoxyacetic acid (2,4-D) and 0.5 mg/L 6-Benzylaminopurine (BAP), and subsequently treated with glutamine (0-350 mg/L). Glutamine supplementation affected callus morphology and anatomy, yielding mainly compact callus types. Gas Chromatography-Mass Spectrometry (GC-MS) analysis revealed a variety of metabolites in the callus extracts. Notably, a total of 51 metabolites were detected only in the glutamine-treated callus. In silico prediction suggested antioxidant and antimalarial potential for probable major compounds, including methyl α-D-glucopyranoside, methyl β-D-glucopyranoside, n-hexadecanoic acid, (9Z,12Z)-9,12-octadecadienoic acid, and stigmasterol. In vitro assays highlight that glutamine supplementation enhanced the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity by up to two-fold and increased the Plasmodium falciparum inhibition by up to three-fold compared to the control callus, with 250 mg/L glutamine being most effective. These findings provide novel insights into the glutamine's role in S. arvensis L. callus culture and demonstrate its potential to increase the valuable bioactive compounds production, particularly those with antimalarial activity.

Keywords:   Sonchus arvensis L; Antimalaria; Antioxidant; Callus; Glutamine

DOI:  https://doi.org/10.1038/s41598-025-12617-z
Sci Rep. 2025 Oct 13. 15(1): 35655

Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy.

Dong Eon Oh, Se Song Jang, Woo Joong Kim, Soo Yeon Kim, Byung Chan Lim, Ki Joong Kim, Seungbok Lee, Jong-Hee Chae.

  The GLUL gene encodes glutamine synthetase (GS), which plays a crucial role in glutamine-glutamate homeostasis. Both loss-of-function and gain-of-function variants of GLUL are known to cause genetic disorders in humans. Biallelic loss-of-function variants cause congenital glutamine deficiency, leading to developmental and epileptic encephalopathy (DEE) in an autosomal recessive manner. In contrast, certain variants of GLUL that lead to the loss of the N-terminal degron exert a gain-of-function effect, causing an autosomal dominant DEE. Only six autosomal recessive cases and ten autosomal dominant cases have been reported to date, and knowledge about GLUL-related DEE remains limited. In this study, we identified three unrelated patients with DEE carrying heterozygous de novo GLUL variants. One patient carried a variant that had been reported previously in two patients (c.-13-2A > G), and the other two patients carried novel candidate variants (c.-13-1G > C and c.604T > C). An alternative splicing event causing loss of the N-terminal degron of GS was confirmed by RNA sequencing in a patient carrying c.-13-1G > C variant. A comparison of our patients with previously reported cases revealed common symptoms, including epilepsy and global developmental delay. However, our patients exhibited additional phenotypes, such as hypertonia, cerebral atrophy, and T2 hyperintensity in deep grey matter, which have not been described in patients with autosomal dominant GLUL-related DEE. The seizure patterns and responses to antiseizure medications varied among patients, reflecting their diverse phenotypic spectrum. Similarly, biochemical analyses of plasma and cerebrospinal fluid showed heterogeneous profiles. We present analyses of the GLUL-related DEE with detailed clinical descriptions and identified novel causal variants. Comparative analysis of genotypes and phenotypes revealed the diverse nature of the disease, expanding our knowledge about the genetic and clinical spectrum of GLUL-related DEE.

Keywords:   GLUL ; Developmental delay; Epilepsy; Glutamine synthetase; N-terminal degron; Start-loss

DOI:  https://doi.org/10.1038/s41598-025-19666-4
Sci Adv. 2025 Oct 17. 11(42): eadx8662

Small-molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia.

Sofia La Vecchia, Saurav Doshi, Petros Antonoglou, Tanima Kundu, Wafa Al Santli, Kleopatra Avrampou, Matthew T Witkowski, Anna Pellattiero, Federico Magrin, Kristina Ames, Amit Verma, Kira Gritsman, Xiaoyang Su, Andrea Mattarei, Iannis Aifantis, Luca Scorrano, Christina Glytsou.

Acute myeloid leukemia (AML) is the most prevalent and deadliest adult leukemia. Its frontline treatment uses the BH3 mimetic venetoclax to trigger mitochondria-dependent apoptosis. However, drug resistance nearly always develops, calling for therapies to circumvent it. Advanced microscopy and genome-wide CRISPRi screen analyses pinpointed mitochondrial adaptations primarily mediated by the master regulator of cristae shape optic atrophy 1 (OPA1) as critical for BH3 mimetics resistance. Resistant AML cells up-regulate OPA1 to modify their mitochondrial structure and evade apoptosis. MYLS22 and Opitor-0, two specific and nontoxic OPA1 inhibitors, promote apoptotic cristae remodeling and cytochrome c release, synergizing with venetoclax in AML cells and xenografts derived from AML patients ex vivo and in vivo. Mechanistically, OPA1 loss renders AML cells dependent on glutamine and sensitizes them to ferroptosis by activating ATF4-regulated integrated stress responses. Overall, our data clarify how OPA1 up-regulation allows AML cells' metabolic flexibility and survival and nominates specific OPA1 inhibitors as efficacious tools to overcome venetoclax resistance in leukemia.

DOI: https://doi.org/10.1126/sciadv.adx8662
J Med Chem. 2025 Oct 17.

Design, Synthesis, and Biological Evaluation of Rapamycin Derivatives as the First Mammalian Target of Rapamycin and GLS1 Dual Inhibitors.

Liushun Wu, Mengting Lyu, Dong-Quan Gu, Yin Li, Ying Li, Hongsu Zhao, Tongsheng Wang, Feng-Qing Xu, Deling Wu, Wuxi Zhou.

The mammalian target of rapamycin (mTOR) and glutaminase 1 (GLS1) are key enzymes regulating metabolic reprogramming in breast cancer. The first generation of mTOR and GLS1 dual inhibitors was designed and synthesized on the basis of anticancer synergism. Compound 9d showed selective and potent antiproliferative activity against all breast cancer cell lines and displayed potent inhibitory activity against both mTOR (mTORC1 and mTORC2) and GLS1. Mechanism studies revealed that 9d effectively modulated the level of biomarkers and metabolites associated with mTOR and GLS1 inhibition and triggered sustained and massive reactive oxygen species generation, leading to cell death by autophagy, apoptosis, and ferroptosis. Moreover, 9d inhibited the metastasis, invasion, and angiogenesis of breast cancer cells. In vivo experiments demonstrated that 9d significantly inhibited tumor growth and metastasis, without observable toxicity. These findings proved mTOR/GLS1 dual inhibitors' great therapeutic potential for breast cancer.

DOI: https://doi.org/10.1021/acs.jmedchem.5c01841