bims-glucam 2025-12-07 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–12–07
23 papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine reprogramming affects the tumor microenvironment and immune response in hepatocellular carcinoma.
The glutamine metabolic switch influences the response of neonatal intestinal macrophages to breast milk.
Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing myogenesis.
Integrative bioinformatics and machine learning approach unveils potential biomarkers linking coronary atherosclerosis and glutamine metabolism-associated gene.
Indoxyl sulfate promoted glutamine metabolism and cell proliferation in urothelial carcinoma involving Runx2.
SLBP Promotes Lung Adenocarcinoma Progression by Inhibiting Ferroptosis and Reprogramming Glutamine Metabolism via FADS2 Interaction.
MicroRNA-Mediated Metabolic Control in HCC: From Molecular Networks to Therapy.
Adaptability of lung and liver metastatic breast cancer cells to glucose.
Glutamine modified lipid nanoparticles loaded with GPX4 siRNA for cervical cancer targeting.
Targeting distinct amino acid metabolic vulnerabilities in IDH-mutant and IDH-wildtype gliomas.
Stroma-driven horizontal transfer of TCA-related proteins mediates metabolic plasticity and imatinib resistance in chronic myeloid leukemia.
Nano-purpurin-Cu delivery via TPGS-induced macropinocytosis enables cuproptosis/metabolic synergy to ablate cancer stemness and Boost immunotherapy in colorectal cancer.
Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.
Targeting emerging amino acid dependencies and transporters in cancer therapy.
Effect of glutamine and arginine treatment on the inflammatory response in a rat model of pulmonary contusion.
Niosomal co-delivery of metformin and telaglenastat: A targeted nanotherapeutic strategy for breast cancer treatment and metastasis suppression in 2D and 3D models.
Metabolic reprogramming of CAR T cells: a new frontier in cancer immunotherapy.
Generation of Long-Lived CHO Cells Suitable for Production of Afucosylated Antibodies and Fc-Fusion Proteins.
USP16 S-nitrosylation aggravates coronary microembolization-induced myocardial injury via repressing KDM1A-mediated glutathione homeostasis.
Altered biopterin-related cofactor metabolism in the aqueous humor of glaucoma patients.
Structure-enabled discovery of carboxylate esters prodrugs as potential potent inhibitors targeting Glutaminase C.
In Vivo Glx Measurements From GABA-Edited HERMES at 3 T Are Not Consistent With Those From Short-TE PRESS Across Scanners, Brain Regions, Diagnostic and Age Groups.
Saliva from oral squamous cell carcinoma patients promotes tumor progression via Inflammation, stromal remodeling, and metabolic reprogramming in a mouse model.

Mol Biol Rep. 2025 Dec 01. 53(1): 144

Glutamine reprogramming affects the tumor microenvironment and immune response in hepatocellular carcinoma.

Yong Sun, Yi Cui, Daiqin Luo, Chuan Tian.

  Glutamine, recognized as a conditionally essential amino acid, plays a crucial role in cellular metabolism and significantly impacts the tumor microenvironment. Recent studies show that glutamine metabolism directly influences the growth and survival of hepatocellular carcinoma (HCC) cells. Recent research demonstrates that glutamine metabolism directly regulates the growth and survival of HCC cells. Additionally, it plays an instrumental role in the initiation and progression of HCC by modulating immune responses, maintaining redox balance, and facilitating metabolic reprogramming. Although current studies emphasize the diverse functions of glutamine within the HCC microenvironment, the specific mechanisms driving these processes remain not yet fully understood. This article aims to explore the metabolic pathways associated with glutamine in the context of the HCC microenvironment. It also evaluates the influence of glutamine on HCC progression and proposes future research avenues to facilitate the development of innovative therapeutic strategies for HCC management. The objective is to present novel therapeutic strategies and innovative approaches to effectively treat HCC.

Keywords:  Glutamine; Hepatocellular carcinoma; Immune response; Metabolic reprogramming; Microenvironment

DOI:  https://doi.org/10.1007/s11033-025-11309-1
Cell Mol Gastroenterol Hepatol. 2025 Nov 28. pii: S2352-345X(25)00224-3. [Epub ahead of print] 101683

The glutamine metabolic switch influences the response of neonatal intestinal macrophages to breast milk.

Xu Han, Yutong Hou, Taoying Chen, Zhenyu Jia, Fuqiang Yuan, Mingxin Wang, Yinling Su, Ru Yan, Xiaolei Wang, Weilai Jin, Yahui Zhou, Yun Li, Le Zhang.

   BACKGROUND & AIMS: Breast milk contains abundant glutamine and glutamate, yet their roles in neonatal gut health remain controversial. We aimed to investigate how these amino acids influence neonatal enteritis and the underlying mechanisms.
METHODS: We used a neonatal rat necrotizing enterocolitis (NEC) model to test the effects of glutamine and glutamate given either before disease onset or during NEC progression. Previously published human neonatal NEC scRNA-seq data were reanalyzed to assess immune cell composition and pathway activity. Bone marrow-derived macrophages (BMDMs) were used to examine inflammatory responses in vitro. Flow cytometry and transcriptomics were applied to analyze metabolic reprogramming of ileal macrophages.
RESULTS: Glutamine and glutamate prevented NEC when administered prophylactically but worsened disease when given during NEC progression. scRNA-seq revealed enrichment of macrophages with activated inflammatory pathways in NEC ileum. In vitro, pretreatment with glutamine or glutamate reduced lipopolysaccharide-induced cytokine expression in BMDMs, whereas administration after stimulation had no benefit. In vivo, glutamine pretreatment decreased CD45+F4/80+CD11b/c+TNFα+ macrophages, while treatment during NEC increased this subset. Integrated analyses showed NEC upregulated glutaminase (GLS) and downregulated glutamate dehydrogenase (GLUD1) in ileal macrophages. Pretreatment with glutamine or glutamate restored GLUD1 expression, favoring α-ketoglutarate (α-KG) rather than succinate metabolism. Supplementation with α-KG reversed glutamine-induced macrophage activation during NEC, whereas succinate abolished the protective effect of glutamine pretreatment.
CONCLUSIONS: Glutamine and glutamate exert dual, context-dependent effects in neonatal enteritis by modulating macrophage glutamine metabolism. These findings provide mechanistic insight and suggest a basis for personalized glutamine supplementation strategies in neonatal gut disorders.

Keywords:  breast milk; glutamine metabolism; macrophage; necrotizing enterocolitis

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101683
Am J Physiol Cell Physiol. 2025 Dec 05.

Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing myogenesis.

Angad Yadav, Susan Schmitt, Wenxia Ma, James A Mobley, Anna Elizabeth Thalacker-Mercer.

  Extracellular glutamine (Gln) is essential for muscle progenitor cell (MPC) function and skeletal muscle regeneration / development, especially under physiological stress like aging or catabolic conditions. Gln availability regulates MPC proliferation by modulating intracellular metabolic and epigenetic states. Gln deficiency reduces cell viability, induces G0/G1 cell cycle arrest, and downregulates MyoD expression, collectively inhibiting myogenesis in human primary myoblasts (HSMM) and mouse C2C12 cells. Mechanistically, Gln deficiency enhances nuclear localization of TCA cycle enzyme, KGDHC, components (i.e., DLST and OGDH), elevates histone succinylation, and reduces chromatin accessibility at the myogenic regulatory regions (MyoD1 locus). These changes establish a direct link between Gln availability and an epigenetic-metabolic axis crucial for myogenic gene regulation. Thus, extracellular Gln acts as a key regulator of MPC proliferation through metabolic mediated control of chromatin state.

Keywords:  Chromatin accessibility; Glutamine metabolism; Succinylation; TCA cycle compartmentalization; myogenesis

DOI:  https://doi.org/10.1152/ajpcell.00568.2025
J Cardiothorac Surg. 2025 Dec 01.

Integrative bioinformatics and machine learning approach unveils potential biomarkers linking coronary atherosclerosis and glutamine metabolism-associated gene.

Shiwei Wang, Man Zheng, Jing Yang.

   BACKGROUND: Atherosclerosis (AS), a chronic inflammatory disorder of the vasculature, remains the principal driver of cardiovascular disease, accounting for substantial morbidity, mortality, and healthcare burden worldwide. Beyond its vascular implications, recent research highlights the metabolic reprogramming of glutamine (Gln) as a central axis in disease biology. Glutamine metabolism, long recognized for its role in tumorigenesis, is now emerging as a critical determinant of clinical outcomes across diverse cancers, underscoring its broader relevance to pathological processes.
METHODS: A bioinformatics analysis was performed in this work to discover and validate putative Gln-Metabolism genes (GlnMgs) linked with AS. GlnMgs were discovered using a combination of differential expression analysis with a collection of 43 potential GlnMgs. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were used to determine the possible biological roles and pathways of the discovered GlnMgs. Following that, Lasso regression and SVM-RFE techniques were used to identify hub genes and assess the diagnostic efficiency of the nine GlnMgs in differentiating AS. The relationship between hub GlnMgs and clinical features was also studied. Finally, the GSE43292 and GSE9820 datasets were used to validate the expression levels of the nine GlnMgs.
RESULTS: Nine GlnMgs associated with AS were identified, namely NOXRED1, SIRT4, DDAH2, GOT1, MIR21, NOS3, CAD, ASRGL1, and GMPS. Functional enrichment analysis revealed their predominant involvement in key metabolic pathways, including the cellular amino acid metabolic process, glutamine family amino acid metabolic process, and α-amino acid metabolic process, underscoring their role in metabolic reprogramming during AS progression. Importantly, the diagnostic model constructed from these nine GlnMgs exhibited robust discriminatory power, achieving an AUC value of 0.980, thereby highlighting its potential as a highly reliable biomarker signature for AS. In parallel, immune infiltration analysis provided further mechanistic insight, revealing that M0 macrophages and memory B cells were significantly associated with the identified gene signature. These findings not only strengthen the diagnostic utility of the GlnMgs-based model but also suggest a pivotal link between glutamine metabolism and immune cell dynamics in shaping the atherosclerotic microenvironment.
CONCLUSIONS: This study successfully discovered nine GlnMgs that are associated with AS. These findings provide valuable insights into potential novel biomarkers for AS and offer prospects for monitoring disease progression.

Keywords:  Atherosclerosis (AS); Bioinformatics; Gln-Metabolism genes (GlnMgs); Lasso regression; SVM-RFE

DOI:  https://doi.org/10.1186/s13019-025-03685-3
Biomed Pharmacother. 2025 Dec 02. pii: S0753-3322(25)01059-5. [Epub ahead of print]193 118865

Indoxyl sulfate promoted glutamine metabolism and cell proliferation in urothelial carcinoma involving Runx2.

Jian-Ri Li, Tung-Min Yu, Yen-Chuan Ou, Chih-Cheng Wu, Shih-Yi Lin, Ya-Yu Wang, Jiaan-Der Wang, Su-Lan Liao, Wen-Ying Chen, Yu-Hsiang Kuan, Chun-Jung Chen.

  Patients with Chronic Kidney Disease (CKD) have an increased risk and poor prognosis of becoming diagnosed with urothelial carcinoma. Currently, the linking mechanisms underlying the connection between CKD and urothelial carcinoma are not well understood. CKD with declined renal function is associated with the accumulation of circulating indoxyl sulfate, a metabolite synthesized from tryptophan by gut microbes. We investigated the roles of CKD-related uremic toxins in regards to their linking with urothelial carcinoma by delivering indoxyl sulfate to urothelial carcinoma cells and tumor-bearing mice. Upon exposure to indoxyl sulfate, urothelial carcinoma T24 and NTUB1 cells increased proliferation, accompanied by enhanced glutamine uptake and metabolism. Mechanistically, Runt-Related Transcription Factor 2 (Runx2) had been identified as a contributor of both urothelial carcinoma cell proliferation and Solute Carrier Family 1 Member 5 (SLC1A5)-mediated glutamine uptake, while metabolism was demonstrated as being a target to the actions of Runx2 promoted by indoxyl sulfate. An elevated expression of Runx2 caused by indoxyl sulfate correlated with both a reduction of microRNA-204 and an induction of DNA Methyltransferase 1 (DNMT1). MicroRNA-204 agomiR decreased Runx2 expression, while DNMT1 inhibitors reversed indoxyl sulfate-induced reduction of miR-204 and induction of Runx2. Additionally, inhibition of the Aryl Hydrocarbon Receptor (AhR) alleviated indoxyl sulfate-induced signaling changes and cell proliferation. The cancer-promoting effects of indoxyl sulfate were further demonstrated in tumor-bearing mice. In short, our results suggest that indoxyl sulfate may act as a bridge in linking the gap between CKD and urothelial carcinoma by involving the enhancement of glutamine uptake and metabolism.

Keywords:  Chronic kidney disease; Glutamine; Runx2; Uremic toxin; Urothelial carcinoma

DOI:  https://doi.org/10.1016/j.biopha.2025.118865
Exp Cell Res. 2025 Dec 02. pii: S0014-4827(25)00449-5. [Epub ahead of print] 114849

SLBP Promotes Lung Adenocarcinoma Progression by Inhibiting Ferroptosis and Reprogramming Glutamine Metabolism via FADS2 Interaction.

Wei Yan, Pengfei Xu, Dan Xiao, Dong Hong, Huiqun Liu, Yigang Liu, Yaqi Wang, Tanxiu Chen, Anwen Liu.

  SLBP is significantly overexpressed in lung adenocarcinoma (LUAD) and correlates strongly with poor patient prognosis. Functional studies demonstrated that SLBP potently enhances proliferation, invasion, and metastasis of LUAD cells both in vitro and in vivo. Mechanistically, SLBP suppresses ferroptosis-a form of regulated cell death-by modulating key biochemical markers, including GSH, MDA, and Fe2+ levels, and it restores cell viability upon treatment with ferroptosis inducers. RNA-seq and biochemical analyses revealed that SLBP transcriptionally upregulates and stabilizes SLC7A11, a critical ferroptosis suppressor, thereby inhibiting lipid peroxidation and ferroptotic cell death. Additionally, immunopurification and mass spectrometry (IP-MS) identified FADS2 as a novel SLBP-interacting partner. SLBP binds to FADS2, promotes its expression, and drives metabolic reprogramming toward glutamine dependency, significantly altering choline and metal ion metabolism. This metabolic shift enhances cellular proliferation under nutrient stress. Crucially, SLBP-mediated proliferation was shown to be functionally dependent on FADS2, as FADS2 inhibition abrogates SLBP-driven growth without affecting SLBP levels. Collectively, these results uncover SLBP as a multifunctional oncoprotein that promotes LUAD progression through dual mechanisms: inhibiting ferroptosis via SLC7A11 and rewiring glutamine metabolism through FADS2, offering new potential targets for therapeutic intervention.

Keywords:  FADS2; Ferroptosis; Glutamine metabolism; LUAD; SLBP; SLC7A11

DOI:  https://doi.org/10.1016/j.yexcr.2025.114849
Exp Cell Res. 2025 Dec 03. pii: S0014-4827(25)00453-7. [Epub ahead of print] 114853

MicroRNA-Mediated Metabolic Control in HCC: From Molecular Networks to Therapy.

Dhuha D M Alrawi, Shahd Rajab Farhan, Ali G Alkhathami, Chou-Yi Hsu, Zahraa Khudhair Abbas Al-Khafaji, Amr Ali Mohamed Abdelgawwad El-Sehrawy, Yasser Fakri Mustafa, Wael Nabil, Zuhair I Al-Mashhadani.

  Hepatocellular carcinoma (HCC) is the most common histological subtype of primary liver cancer, accounting for nearly 80-90% of all liver cancer cases. While 'liver cancer' refers broadly to all malignant tumors arising in the liver (including HCC, cholangiocarcinoma, and others), HCC specifically originates from hepatocytes. HCC is characterized by extensive metabolic reprogramming, including not only higher levels of aerobic glycolysis, de novo lipogenesis, and altered glutamine metabolism but also altered one-carbon metabolism. Enhanced metabolic adaptation markers, therefore, serve as key indicators of malignant transformation but also contribute to cancer progression by promoting cell proliferation, metastasis, immune modulation, and therapy evasion. Emerging evidence suggests microRNAs (miRNAs) can coordinate these metabolic adaptations by targeting key enzymes, transporters, transcription factors, signaling molecules, or pathways involved in metabolism. For instance, miR-122, miR-27a, miR-148a, and miR-4310 inhibit lipid accumulation and mitochondrial dysfunction, while miR-21, miR-103a, and miR-30b-5p promote glycolysis, lipogenesis, and anabolic metabolism. Long non-coding RNAs (lncRNAs) and exosomal miRNAs interact with these upstream regulators to form a heterogeneous network of non-coding RNAs. These networks participate in remodeling the tumor microenvironment, modulating the immune response, and facilitating metabolic adaptation in HCC. miRNAs are ideal for the potential stratification of HCC risk, prognosis, and therapeutic response, as they occupy key upstream positions in regulatory hierarchies and have been described as both biomarkers and potential metabolic switches. This study aims to elucidate the role of microRNAs in regulating metabolic pathways in HCC by delineating numerous miRNA-target interactions involved in glycolysis, lipid, amino acid, and nucleotide metabolism. This knowledge will enable us to identify novel diagnostic biomarkers and therapeutic targets for prognosis and to explore effective novel precision treatment strategies.

Keywords:  Glycolysis; Hepatocellular carcinoma (HCC); Lipogenesis; Metabolic reprogramming; MicroRNA (miRNA)

DOI:  https://doi.org/10.1016/j.yexcr.2025.114853
Cancer Cell Int. 2025 Oct 24. 25(1): 374

Adaptability of lung and liver metastatic breast cancer cells to glucose.

Marjorie Anne Layosa, Madeline P Sheeley, Alekya Raghavan, Chaylen Andolino, Michael K Wendt, Stephen D Hursting, Dorothy Teegarden.

   BACKGROUND: Breast cancer is the most common cancer among women, and metastasis is the leading cause of mortality. It is still unknown how breast cancer cells metabolically adapt to successfully metastasize to different organs to survive adverse conditions, including varying nutrient availability. The purpose of this study is to elucidate the metabolic characteristics and glucose adaptation mechanisms of breast cancer cells that preferentially metastasize to the lungs or the liver.
METHODS: Using a Wnt-driven breast cancer model with preferential metastasis to lung (metM-WntLung) or liver (metM-WntLiver), we measured 14C-glucose uptake, 13C6-glucose metabolic flux, metabolic enzyme levels, and cell viability under normal (5 mM), high (25 mM), and low (1 or 0 mM) glucose conditions.
RESULTS: Under normal glucose conditions, metM-WntLung cells were more glycolytic, exhibiting greater flux of 13C6-glucose-derived carbons into glycolytic intermediates, such as pyruvate and lactate. In contrast, metM-WntLiver cells favored oxidative phosphorylation, with higher levels of 13C6-glucose-derived carbons in tricarboxylic acid (TCA) cycle metabolites such as oxaloacetate indicative of higher pyruvate carboxylase (PC) activity. Exposure to high glucose reduced metM-WntLiver cell viability, with no effect on metM-WntLung cells, suggesting better adaptability of metM-WntLung cells to glucose excess. This was accompanied by increased PC activity and oxidative phosphorylation in metM-WntLung cells, whereas metM-WntLiver cells shifted to a more glycolytic phenotype. Under glucose deprivation, metM-WntLung cells were more viable than metM-WntLiver cells, suggesting that metM-WntLung cells have better adaptability to glucose deprivation. Inhibiting phosphoenolpyruvate carboxykinase, a key enzyme in gluconeogenesis, reduced metM-WntLung cell viability compared to metM-WntLiver cells. Similarly, inhibiting catabolism of glutamine, a gluconeogenic substrate, decreased metM-WntLung cell viability compared to metM-WntLiver cells, indicating that metM-WntLung cells rely on more on gluconeogenesis and glutamine metabolism under glucose deprivation.
CONCLUSION: Our findings reveal that metM-WntLung cells exhibit greater metabolic flexibility to glucose than metM-WntLiver cells by shifting from glycolysis to oxidative phosphorylation under high glucose conditions while utilizing gluconeogenesis and glutamine under glucose deprivation conditions.

Keywords:  Breast cancer; Glucose; Metabolic adaptation; Metastasis

DOI:  https://doi.org/10.1186/s12935-025-04006-3
Int J Biol Macromol. 2025 Dec 01. pii: S0141-8130(25)09976-3. [Epub ahead of print]336 149419

Glutamine modified lipid nanoparticles loaded with GPX4 siRNA for cervical cancer targeting.

Yuxin Chen, Lanjie Zhong, Jianqiang Chen, Xinya Li, Jiaying Lv, Huali Chen, Rui Ran.

  Despite significant efforts to develop nanocarriers for siRNA delivery, clinical application in cancer therapy has been hindered by inadequate tumor-targeting specificity, with cervical cancer particularly affected by poor tumor-specific targeting. Our previous work identified aberrant glutamine metabolism and ASCT2 overexpression in cervical cancer, providing a rationale for designing glutamine-ASCT2 interaction-based delivery systems. Based on this, we developed a self-fabricated microfluidic device for the preparation of lipid nanoparticles (LNP) and constructed a glutamine-modified lipid nanoparticle (GLN-LNP) for targeted siRNA delivery to cervical cancer. GLN-LNP exhibited significantly enhanced cellular uptake in both 2D cell monolayers and 3D tumor spheroid models. The competitive inhibition of uptake by free glutamine and the significant inhibition by an ASCT2-specific inhibitor V-9302 further confirm the critical role of the glutamine-ASCT2 interaction in facilitating LNP transport. GLN-LNP significantly decreased GPX4 expression in vitro at both transcriptional and translational level. In vivo results illustrated GLN-LNP had enhanced tumor accumulation capability compared to PEG-LNP, which has no glutamine modification. Additionally, GLN-LPN induced obvious in vivo GPX4 knockdown. These findings demonstrate GLN-LNP as a promising preclinical delivery system for cervical cancer, highlighting their potential to advance the clinical development of siRNA-based therapeutic.

Keywords:  Glutamine modification; Modified lipid nanoparticles; siRNA deliver

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149419
Acta Neuropathol Commun. 2025 Nov 29.

Targeting distinct amino acid metabolic vulnerabilities in IDH-mutant and IDH-wildtype gliomas.

Shigeo Ohba, Akiyoshi Hirayama, Takao Teranishi, Keisuke Hitachi, Hisateru Yamaguchi, Kazuhiro Murayama, Manabu Natsumeda, Kensuke Tateishi, Kunihiro Tsuchida, Hiroaki Wakimoto, Hideyuki Saya, Russell Pieper, Yuichi Hirose.

  Lower grade gliomas frequently harbor mutations in isocitrate dehydrogenase (IDH), which define biologically distinct tumor subtypes. Although IDH-mutant and IDH-wildtype gliomas share similar histological morphology, they display markedly different metabolic profiles that may be exploited for targeted therapy. In this study, we investigated therapeutic approaches tailored to these metabolic differences. Using capillary electrophoresis-mass spectrometry, we compared the metabolomes of engineered IDH-wildtype and IDH-mutant glioma cell models. IDH-mutant cells exhibited elevated asparagine levels and reduced glutamine and glutamate levels compared with IDH-wildtype cells. These differences were corroborated in vivo by proton magnetic resonance spectroscopy of 130 patients with diffuse gliomas, showing lower glutamine and glutamate in IDH-mutant tumors. Pharmacological depletion of asparagine with L-asparaginase, which converts asparagine to aspartate, preferentially inhibited the growth of IDH-wildtype glioma cells, and this effect was potentiated by inhibition of asparagine synthetase. In contrast, inhibition of glutamate dehydrogenase 1 (GLUD1), the enzyme catalyzing the conversion of glutamate to α-ketoglutarate, selectively suppressed proliferation of IDH-mutant glioma cells by inducing reactive oxygen species accumulation and apoptosis. In vivo, L-asparaginase suppressed tumor growth in xenografted IDH-wildtype gliomas, whereas GLUD1 inhibition significantly reduced tumor growth in IDH-mutant glioma xenografts. These findings reveal distinct amino acid metabolic vulnerabilities defined by IDH mutation status and identify L-asparaginase and GLUD1 inhibition (via R162) as promising, mutation-specific therapeutic strategies. L-asparaginase demonstrated potent antitumor activity against IDH-wildtype gliomas, while GLUD1 inhibition selectively suppressed IDH-mutant gliomas both in vitro and in vivo. These results highlight the clinical potential of targeting amino acid metabolism in gliomas and provide a strong rationale for translating these mutation-specific approaches into future clinical trials.

Keywords:  Asparagine; Cancer metabolism; Glioma; Glutaminolysis; Isocitrate dehydrogenase

DOI:  https://doi.org/10.1186/s40478-025-02193-8
Cell Commun Signal. 2025 Dec 02.

Stroma-driven horizontal transfer of TCA-related proteins mediates metabolic plasticity and imatinib resistance in chronic myeloid leukemia.

Piotr Chroscicki, Nikodem Kasak, Dorota Dymkowska, Laura Turos-Korgul, Dominik Cysewski, Vira Chumak, Dawid Stepnik, Monika Kusio-Kobialka, Agata Kominek, Magdalena Lebiedzinska-Arciszewska, Alicja Krop, Joanna Szczepanowska, Mariusz Wieckowski, Tomasz Stoklosa, Krzysztof Zablocki, Katarzyna Piwocka.

   BACKGROUND: Alterations in cancer cell metabolism have recently gained considerable attention as a possible cause of adaptation and resistance to therapy. However, the underlying molecular mechanisms, particularly in leukemia resistance occurring in the bone marrow microenvironment, remain unclear. Here, we explore the role of direct stroma-leukemia interactions and transfer of membrane vesicles along with proteins as a mechanism of stroma-driven protection.
METHODS: K562 CML leukemia cells and primary CD34 + CML blasts were cultured alone or co-cultured with HS-5 stromal cells to mimic the bone marrow microenvironment conditions. Imatinib treatment was used experimentally as it is a standard first-line treatment in CML. Assessment of vesicles transfer, metabolic parameters, mitochondrial function phenotyping, Trans-SILAC proteomics and metabolomics, together with apoptosis assessment, verified the influence of stroma on metabolic plasticity, protein transfer and adaptation to imatinib in leukemic cells. Trans-system evaluated necessity of direct cell-cell contact. Data from single-cell atlas of diagnostic CML bone marrow were used to correlate gene expression profiles with clinical outcome. Telaglenastat was used to validate the clinical potential of our findings.
RESULTS: Stromal cells enhanced metabolic plasticity and oxidative capacity in leukemia, thereby protecting against metabolic decline and oxidative stress caused by imatinib. Direct stroma-leukemia contact was necessary for vesicles transfer, metabolic rearrangement and protection from imatinib-induced apoptosis. This was accompanied with shift towards OXPHOS activity, associated with increased utilization of non-glucose substrates. We found the presence of stromal TCA-related proteins in leukemic cells, associated with higher TCA cycle dynamics and activity, increased glutamine and reduced oxidative stress. The gene expression profiles correlated with clinical resistance to TKIs. Targeting the glutamine-TCA axis by telaglenastat in combination with imatinib reversed the stroma-driven protection, leading to increased apoptosis.
CONCLUSION: This study describes a novel mechanism of direct bone marrow-mediated protection of leukemic cells from imatinib/TKI, related to transfer of metabolic proteins leading to higher activity of TCA cycle, metabolic plasticity and adaptation. Targeting the stroma-driven TCA cycle-related metabolism combined with imatinib presents a promising strategy to achieve therapeutic efficacy to overcome bone marrow microenvironment-mediated protection in CML.

Keywords:  Bone marrow stroma; Glutamine; Imatinib; Leukemia microenvironment; Metabolic plasticity; Mitochondria; Proteome; Resistance; TCA; TNTs

DOI:  https://doi.org/10.1186/s12964-025-02564-7
Biomaterials. 2025 Nov 24. pii: S0142-9612(25)00794-X. [Epub ahead of print]328 123874

Nano-purpurin-Cu delivery via TPGS-induced macropinocytosis enables cuproptosis/metabolic synergy to ablate cancer stemness and Boost immunotherapy in colorectal cancer.

Yunfeng Song, Wenting Cheng, Hailong Tian, Yichun Huang, Canhua Huang, Yongfeng Jia, Li Xu.

  Limited intratumoral drug accumulation and stemness-mediated immune evasion constitute fundamental barriers to effective immunotherapy in colorectal cancer (CRC). Tumor cell plasticity, fueled by metabolic reprogramming and cancer stemness, drives immunosuppressive microenvironment formation and therapeutic resistance. To overcome this, we engineered a purpurin-copper coordinated nanoplatform (TPGS/P-C@Ce6 NPs) that synergistically integrates cuproptosis induction, photodynamic therapy (PDT), and metabolic intervention. Critically, we demonstrate that surface-engineered d-α-tocopheryl polyethylene glycol succinate (TPGS) potently activates tumor cell macropinocytosis, significantly enhancing intracellular nanocarrier accumulation. Concurrently, purpurin reprograms glutamine metabolism via glutaminase inhibition, which enhances dendritic cell (DC) maturation and initiates T-cell priming. Furthermore, copper ion-driven cuproptosis synergizes with chlorin e6 (Ce6)-generated reactive oxygen species (ROS) to ablate cancer stemness, effecting robust conversion of immunologically cold tumors to T cell-inflamed hot phenotypes. Therefore, this tripartite strategy established durable immunological memory, with 100 % survival in rechallenged mice at 90 days post-treatment. This work establishes a novel metabolic-immunological co-regulation paradigm, providing a readily adaptable nanotherapeutic solution for CRC with high translational potential.

Keywords:  Cancer stemness; Colorectal cancer; Cuproptosis; Immunotherapy; Macropinocytosis

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123874
Nat Metab. 2025 Dec 05.

Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.

Amy E Stewart, Derek K Zachman, Pol Castellano-Escuder, Lois M Kelly, Ben Zolyomi, Michael D I Aiduk, Christopher D Delaney, Ian C Lock, Claudie Bosc, John Bradley, Shane T Killarney, J Darren Stuart, Paul A Grimsrud, Olga R Ilkayeva, Christopher B Newgard, Navdeep S Chandel, Alexandre Puissant, Kris C Wood, Matthew D Hirschey.

Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene-gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML.

DOI: https://doi.org/10.1038/s42255-025-01410-x
Front Pharmacol. 2025 ;16 1717414

Targeting emerging amino acid dependencies and transporters in cancer therapy.

Alfred Akinlalu, Emmanuel Ogberefor, Tommy Gao, Dali Sun.

  Amino acid metabolism is an important vulnerability in cancer. Established strategies such as arginine depletion, glutaminase inhibition, tryptophan-kynurenine modulation, and methionine restriction have shown that these pathways can be targeted in patients. At the same time, clinical trials reveal two consistent challenges: tumors can adapt by redirecting their metabolism, and reliable biomarkers are needed to identify patients who are most likely to benefit. Recent studies point to additional amino acids with translational potential. In pancreatic cancer, histidine and isoleucine supplementation has been shown in preclinical models to be selectively cytotoxic to tumor cells while sparing normal counterparts. In glioblastoma, threonine codon-biased protein synthesis programs that support growth; in other contexts, lysine breakdown suppresses interferon signaling through changes in chromatin structure; and alanine released from stromal cells sustains mitochondrial metabolism and therapy resistance. These dependencies are closely tied to amino acid transporters, which act as both nutrient entry points and measurable biomarkers. In this review, we summarize current evidence on histidine, isoleucine, threonine, lysine, and alanine as emerging metabolic targets, and discuss opportunities and challenges for clinical translation, with emphasis on transporter biology, biomarker development, and therapeutic combinations.

Keywords:  SLC transporters; amino acid metabolism; amino acid transporters; cancer therapy; dietary modulation; glutaminase inhibition; metabolic targeting; nutritional intervention

DOI:  https://doi.org/10.3389/fphar.2025.1717414
Kardiochir Torakochirurgia Pol. 2025 Sep;22(3): 158-162

Effect of glutamine and arginine treatment on the inflammatory response in a rat model of pulmonary contusion.

Shukur Musayev, Volkan Karacam, Pınar A Yılmaz, Kemal C Tertemiz, Meltem Sevinç, Bekir U Ergur, Aydın Sanlı, Nezih Ozdemir.

   Introduction: Pulmonary contusion leads to alveolar damage and inflammation, which can progress to acute lung injury and acute respiratory distress syndrome. Glutamine and L-arginine play critical roles in immune regulation and inflammation control, showing potential protective effects in lung injury models.
Aim: This study aimed to investigate the effects of glutamine and/or arginine, which play significant roles in the immuno-inflammatory response, on mitigating inflammation in an experimentally induced pulmonary contusion model.
Material and methods: Thirty male Wistar Albino rats from the same colony were randomly divided into five groups (n = 6 per group). Group I (sham) received no trauma or treatment. Bilateral pulmonary contusion was induced in Groups II-V. Group II received 0.9% saline; Group III received 200 mg/kg/day intraperitoneal glutamine; Group IV received 200 mg/kg/day intraperitoneal arginine; and Group V received both glutamine (200 mg/kg/day) and arginine (150 mg/kg/day). All treatments were administered for 3 consecutive days. Rats were sacrificed three days after the procedure, and histopathologic evaluation was performed afterwards. Three different parameters were scored: inflammation intensity, intraalveolar hemorrhage, and alveolar congestion. Statistical analysis was performed using the Mann-Whitney U test.
Results: Compared to the untreated trauma group, all treatment groups showed significant histopathological improvement (p < 0.05). The arginine-only group demonstrated greater effectiveness across all parameters compared to the combined treatment group (p < 0.05). No significant difference was observed between the glutamine-only and arginine-only groups (p > 0.05).
Conclusions: Both glutamine and arginine treatments were effective in reducing inflammation following pulmonary contusion. However, combined treatment was less effective than arginine alone.

Keywords:  arginine; glutamine; inflammation; pulmonary contusion

DOI:  https://doi.org/10.5114/kitp.2025.154888
Biomed Pharmacother. 2025 Dec 03. pii: S0753-3322(25)01037-6. [Epub ahead of print]193 118843

Niosomal co-delivery of metformin and telaglenastat: A targeted nanotherapeutic strategy for breast cancer treatment and metastasis suppression in 2D and 3D models.

Ahlam Zaid Alkilani, Haneen A Basheer, Maram A Alhusban, Walhan Alshaer.

  Overexpression of glucose transporter-1 (GLUT-1) and glutaminase-1 (GLS-1) underlies the metabolic dependence of breast cancer cells on glucose and glutamine. Exploiting this vulnerability, a dual-drug niosomal delivery system was developed for the encapsulation of metformin (MET) and telaglenastat (TEL) to concurrently modulate these metabolic pathways. The optimized formulation, prepared at a cholesterol:Span 60 ratio of 1:1, exhibited nanosized vesicles (79.7-494.6 nm) with low polydispersity (PDI < 0.3), confirming a uniform and suitable size distribution for efficient cellular uptake. The encapsulation efficiency (EE%) was high for both agents, notably 84.34 % for TEL and 67.93 % for MET. Flow-cytometric profiling revealed elevated GLUT-1 and GLS-1 expression relative to unstained controls, validating the rationale for dual-pathway targeting. Functionally, the niosomal formulations outperformed free and single-drug treatments across both two- and three-dimensional models. In 3D spheroids, free TEL (200 µM) and free MET (200 mM) resulted in cell viabilities of 44.97 % and 54.00 %, respectively, whereas TEL-NP and MET-NP reduced viability to 9.49 % and 22.14 %, representing 4.7-and 2.4-fold enhancements in cytotoxic efficacy. The dual formulation promoted extensive spheroid disintegration and maintained intratumoral penetration for up to 72 h. In wound-healing assays, significant inhibition of migration was observed, with residual wound areas of 97.07 % (MET-NP), 87.43 % (TEL-NP), and 93.49 % (combined MET-NP + TEL-NP). Metabolic analyses further substantiated the mechanistic effect of dual inhibition. Glutamine-glutamate quantification demonstrated a marked shift from the untreated profile (glutamate 87.77 % / glutamine 12.23-59.89 % / 40.11 %) following combined nanoparticle treatment, consistent with suppression of GLS-1-mediated glutaminolysis. Correspondingly, ROS-Glo™ H₂O₂ assays revealed decreased intracellular hydrogen peroxide in all treated groups, with the most pronounced reduction observed in the dual-NP combination, indicating attenuation of oxidative stress and restoration of redox balance. In conclusion, coordinated inhibition of GLUT-1- and GLS-1-driven metabolism via MET/TEL-loaded niosomes achieves enhanced cytotoxicity, durable spheroid penetration, and strong anti-migratory and metabolic modulatory effects. This stable co-delivery platform represents a promising nanotherapeutic strategy to overcome metabolic adaptability and treatment resistance in breast cancer.

Keywords:  Breast cancer; Cytotoxicity; In vitro release; Metformin; Niosomes; Telaglenastat

DOI:  https://doi.org/10.1016/j.biopha.2025.118843
Front Immunol. 2025 ;16 1688995

Metabolic reprogramming of CAR T cells: a new frontier in cancer immunotherapy.

Tjaša Frlic, Mojca Pavlin.

  Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized hematological cancer treatment, but its efficacy in solid tumors remains limited by the immunosuppressive and metabolically hostile tumor microenvironment (TME). CAR T cells' functional compromise, exhaustion, and poor persistence are critically linked to their suboptimal metabolic fitness. This review highlights a paradigm shift: immunometabolism and its intricate interplay with epigenetics profoundly regulate T cell fate and function, establishing their reprogramming as a cornerstone for optimizing CAR T cell efficacy in diverse malignancies. We explore the intricate relationship between T cell differentiation and metabolic states, emphasizing that modulating CAR T cell metabolism ex vivo during manufacturing can drive differentiation towards less exhausted, more persistent memory phenotypes, such as stem cell central memory (Tscm) and central memory (Tcm) cells, which correlate with superior anti-tumor responses. Our analysis demonstrates that metabolic inhibitors offer significant potential to reprogram CAR T cells. Agents targeting glycolysis or the PI3K/Akt/mTOR pathway promote a memory-like phenotype by favoring oxidative phosphorylation (OXPHOS). Further strategies utilizing glutamine antagonists, mitochondrial modulators, or enzyme manipulation (e.g., IDH2, ACAT1) can epigenetically reprogram cells, fostering memory and exhaustion resistance. Similarly, nutrient level optimization during ex vivo expansion directly sculpts CAR T cell metabolic profiles. With approaches like glucose restriction/galactose substitution, or specific amino acid modulation (e.g., L-arginine, asparagine), persistence of CAR T cells in patients can be improved. The judicious selection and engineering of cytokines (e.g., IL-7, IL-15, IL-21) during manufacturing also plays a vital role in fostering desired memory phenotypes. In conclusion, metabolic engineering, leveraging its impact on epigenetic regulation during CAR T cell manufacturing, is crucial for generating potent, persistent, and functionally resilient products. This approach holds immense promise for expanding the curative potential of CAR T cell therapy to a broader range of cancers, particularly challenging solid tumors.

Keywords:  T cell differentiation; adoptive cell immunotherapy; chimeric antigen receptor (CAR); epigenetics; exhaustion; immunometabolism; metabolic modulation; persistence

DOI:  https://doi.org/10.3389/fimmu.2025.1688995
Dokl Biol Sci. 2025 Dec 02.

Generation of Long-Lived CHO Cells Suitable for Production of Afucosylated Antibodies and Fc-Fusion Proteins.

D E Kolesov, N A Orlova, I I Vorobiev.

  Using genome editing, we created a homozygous α-(1,6)-fucosyltransferase (FUT8-/-) knockout in apoptosis-resistant CHO 4BGD cells, yielding the new 4BGD-F cell line. Combining CRISPR/Cas9 with paired gRNAs and non-specific puromycin selection yielded a cell population with an exceptionally high FUT8 knockout frequency, obviating the need for metabolic enrichment with lentil lectin (Lens culinaris agglutinin, LCA). Despite impaired clonogenicity of the knockout cells, we successfully isolated multiple clonal cell lines harboring extensive biallelic FUT8 deletions. Isolated clones with biallelic deletions retained key parental line characteristics: viability >90% in 17-day fed-batch cultures at high densities (>15 × 106 cells/mL), and rapid selectability using both dihydrofolate reductase and glutamine synthetase systems. Mass spectrometric analysis of the test protein GLP1-Fc secreted by 4BGD-F cells confirmed the absence of N-glycan fucosylation. The CHO 4BGD-F cell line provides a valuable platform for producing afucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity.

Keywords:   FUT8 ; CHO cells; CRISPR/Cas9; afucosylation; lentil lectin selection

DOI:  https://doi.org/10.1134/S0012496625600587
Nat Commun. 2025 Dec 03.

USP16 S-nitrosylation aggravates coronary microembolization-induced myocardial injury via repressing KDM1A-mediated glutathione homeostasis.

Qiang Su, Jiao-Qin Qin, Yuan Huang, Ri-Xin Dai, Qing-Yun Wu, Li-Rong Mo, Qiang Wu, Wan-Zhong Huang, Hua-Feng Yang, Yang-Chun Liu, Di-Guang Pan.

Coronary microembolization (CME) is a serious cardiovascular complication that causes severe cardiac dysfunction and arrhythmias. Glutathione (GSH) exhaustion-induced oxidative stress is a key contributor to CME. Here, we explore the molecular mechanisms underlying GSH imbalance during CME. We show that CME induces myocardial injury by disturbing GSH homeostasis, which is ameliorated by glutamate-cysteine ligase modifier subunit (GCLM) or glutaminase (GLS) overexpression. Lysine-specific histone demethylase 1A (KDM1A) removes H3K9me1/2 from the promoter regions of GCLM and GLS to promote their epigenetic expression, thereby maintaining GSH homeostasis in CME. KDM1A is ubiquitinated at the K355 site during CME via inhibiting ubiquitin-specific peptidase 16 (USP16)-mediated deubiquitination. Inducible nitric oxide synthase (iNOS) facilitates S-nitrosylation (SNO) of USP16 at the C731 site, contributing to KDM1A ubiquitination and causing GSH imbalance during CME. Altogether, SNO-USP16 inhibition stabilizes the KDM1A protein to epigenetically activate GCLM and GLS, thus maintaining GSH homeostasis and relieving CME-induced myocardial injury.

DOI: https://doi.org/10.1038/s41467-025-66943-x
Exp Eye Res. 2025 Dec 02. pii: S0014-4835(25)00551-2. [Epub ahead of print]263 110778

Altered biopterin-related cofactor metabolism in the aqueous humor of glaucoma patients.

Arturs Zemitis, Liva Caikovska, Juris Vanags, Jingzhi Fan, Kristaps Klavins, Guna Laganovska.

  Glaucoma is a leading cause of irreversible blindness worldwide and is primarily managed through IOP reduction, though its underlying pathophysiology remains incompletely understood. This study investigates metabolic alterations in glaucoma via targeted metabolomic profiling to identify potential biomarkers and pathogenic mechanisms. Aqueous humor samples were collected from 191 patients at Pauls Stradins Clinical University Hospital immediately before the initiation of cataract surgery, ensuring preoperative conditions. Quantitative metabolite profiling was conducted using liquid chromatography coupled to a Thermo Orbitrap Exploris 120 mass spectrometer. A significant association was observed between open-angle glaucoma and the presence of PEXS (χ2(1) = 9.96, p = 0.002, Cramer's V = 0.228). Several metabolites, including tryptophan, leucine, phenylalanine, and glutamine, were significantly upregulated in glaucoma patients (all p < 0.003, FDR = 0.0358), with tyrosine showing a similar trend (p = 0.0034, FDR = 0.0358). These findings suggest dysregulation of aromatic amino acid metabolism and potential impairment of amino acid hydroxylases, possibly linked to reduced tetrahydrobiopterin (BH4) availability. Disruption in BH4 regeneration-driven by oxidative stress or MTHFR polymorphisms-may impair nitric oxide synthesis and contribute to disease progression. Elevated glutamine and leucine levels could reflect compensatory neuroprotective mechanisms against excitotoxic damage. Our findings suggest that altered biopterin-related cofactor metabolism in aqueous humor may disrupt nitric oxide production and exacerbate oxidative stress, both of which are key factors in glaucoma pathogenesis. These insights highlight the potential of oxidative stress-related biomarkers and antioxidant-based strategies for future glaucoma diagnosis and therapy.

Keywords:  Folic acid; Glaucoma; Metabolomics; Phenylalanine; Tetrahydrobiopterin; Tryptophan; Tyrosine

DOI:  https://doi.org/10.1016/j.exer.2025.110778
Bioorg Chem. 2025 Nov 24. pii: S0045-2068(25)01173-3. [Epub ahead of print]168 109293

Structure-enabled discovery of carboxylate esters prodrugs as potential potent inhibitors targeting Glutaminase C.

Hanyu Sun, Shize Li, Chengxia Mao, Xue Liu, Lisha Ye, Jingjie Yan, Xiaoguang Chen, Baolian Wang, Tingting Du, Xiaojian Wang.

  The role of glutaminase C (GAC) in regulating glutaminolysis has established it as a promising therapeutic target for cancer treatment, driving increased interest in GAC inhibitors in recent years. The mitochondrial localization of GAC presents a particular challenge for balancing high target binding affinity with effective delivery to its subcellular site. Our previous study identified a basic hotspot within the allosteric pocket of GAC, which could be leveraged to enhance binding affinity. Herein, a series of acidic derivatives targeting the basic hotspot were designed based on the scaffold of CB839. This was followed by the development of prodrugs based on carboxylic acid inhibitors 9 and 11 to improve their lipophilicity. Prodrug 16 showed pronounced antiproliferative activity in A549 cells (IC50 = 2.45 nM) alongside favorable stability, and additionally regulated cellular metabolites and increased reactive oxygen species by blocking glutamine metabolism. Ultimately, prodrug 16 exhibits strong in vivo antitumor activity in an A549 xenograft model, establishing it as a highly potent GAC inhibitor and suggesting a novel approach for the development of next-generation GAC-targeting therapeutics.

Keywords:  Allosteric inhibitor; Antitumor; GAC; Prodrug

DOI:  https://doi.org/10.1016/j.bioorg.2025.109293
NMR Biomed. 2026 Jan;39(1): e70171

In Vivo Glx Measurements From GABA-Edited HERMES at 3 T Are Not Consistent With Those From Short-TE PRESS Across Scanners, Brain Regions, Diagnostic and Age Groups.

Alice R Thomson, Viola Hollestein, Amy Goodwin, Anne Fritz, Beth Oakley, Declan Murphy, Edward Bullock, Ellen Demurie, Eva Loth, Giorgia Bussu, Herbert Roeyers, Isabel Yorke, Jan K Buitelaar, Julia Koziel, Laura Colomar, Manon A Krol, Matthew Bowdler, Nele Herregods, Pascal Aggensteiner, Pim Pullens, Rosemary Holt, Terje Falck-Ytter, Tony Charman, Tomoki Arichi, Nicolaas A Puts.

  1H-Magnetic resonance spectroscopy (1H-MRS) is a noninvasive technique for quantifying brain metabolites, including glutamate, glutathione (GSH), and γ-aminobutyric acid (GABA), which are essential for brain function and implicated in various neurodevelopmental conditions. As such, 1H-MRS methods that enable reliable and accurate measurement of these metabolites are of considerable clinical value. Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES; echo time [TE] = 80 ms) is a spectral editing technique that allows for the simultaneous quantification of GABA and GSH, using subtraction approaches to resolve these metabolites in a difference spectrum. Additionally, glutamate plus glutamine resonances (Glx) can be resolved either from the HERMES GABA-edited difference spectrum (GABA-DIFF) or from the sum of all HERMES transients (SUM spectrum). However, the reliability of 80-ms HERMES for quantification of Glx has not been systematically assessed. Here, we evaluate the agreement between Glx obtained from HERMES GABA-DIFF and SUM spectra with Glx derived from short-TE PRESS (TE = 35 ms), which is conventionally used for Glx estimation and has demonstrated reproducibility. Data were acquired from 139 participants across two brain regions (ACC and Thalamus voxels), three scanners, two diagnostic groups (autism and neurotypical development) and two age groups (adolescent/adult and preschooler). Comparisons were made using both creatine-scaled and tissue-corrected Glx estimates. Our findings demonstrate significant systematic and proportional bias between Glx estimates from HERMES (SUM and GABA-DIFF) and short-TE PRESS, consistent across scanners, voxels, age groups and diagnostic categories. These findings indicate that Glx estimates derived from HERMES are not directly comparable to those from short-TE PRESS, and this discrepancy is consistent across a multisite study setting. This underscores the importance of sequence selection and careful methodological consideration when integrating and interpreting data from 1H-MRS across different acquisition protocols.

Keywords:  1H‐MRS; ACC; Glx; HERMES; PRESS; Thalamus; agreement; edited 1H‐MRS

DOI:  https://doi.org/10.1002/nbm.70171
BMC Oral Health. 2025 Dec 01.

Saliva from oral squamous cell carcinoma patients promotes tumor progression via Inflammation, stromal remodeling, and metabolic reprogramming in a mouse model.

Xiao-Yan Zhang, Yuan-Tao Li, Jie Guo, Ying Feng, Qian Han, Shi-Han Zhang, Yu Gao, Hao-Tian Yin, Xiao-Xu Ding, Xiang-Jun Li, Bei-Bei Liang.

   BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy with increasing evidence implicating the oral microbiome and tumor microenvironment in its progression. However, the mechanistic impact of OSCC patient-derived saliva on tumor development remains poorly understood.
METHODS: We established an orthotopic OSCC mouse model and topically applied saliva collected from OSCC patients to assess its effects on tumor progression. Multi-omics analyses, including 16 S rRNA sequencing, tumor transcriptomics (RNA-seq), and metabolomics (LC-MS), were performed to explore changes in the oral microbiota, gene expression profiles, and metabolic pathways.
RESULTS: Treatment with OSCC patient saliva significantly accelerated tumor growth compared to controls. Saliva application altered the oral microbiota, most notably causing a significant enrichment of the genus Staphylococcus. Tumor transcriptomics revealed upregulation of genes associated with chronic neutrophilic inflammation (Mpo), cancer-associated fibroblast (CAF) activation, and extracellular matrix (ECM) remodeling (Angptl4, Col2a1). Metabolomic analysis demonstrated profound metabolic reprogramming within the tumors, including enhanced amino acid metabolism (tryptophan, glutamate), fatty acid oxidation, and accumulation of the oncometabolite succinate. Integrated analysis showed that Staphylococcus abundance was strongly correlated with these inflammatory and metabolic signatures.
CONCLUSIONS: This study demonstrates that saliva from OSCC patients promotes tumor progression in vivo through a multifactorial mechanism involving inflammation, stromal remodeling, and metabolic rewiring. These findings highlight the tumor-promoting potential of salivary and microbial components, suggesting new avenues for diagnostic and therapeutic strategies targeting the oral microenvironment in OSCC.

Keywords:  16S rRNA; Metabolomics; Oral squamous cell carcinoma; RNA-seq; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12903-025-07413-0