bims-glucam 2025-11-30 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–11–30
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

FOXA2 promotes glutamine metabolism to facilitate the malignant development of bladder cancer by transcriptionally increasing GLS1 expression.
Cdk5 regulates glutamine metabolism in colorectal cancer via the EZH2-GLS1 axis.
Glutamine synthetase modulates YAP activation by stabilizing LATS under glutamine homeostasis.
Revisiting the role of metabolic reprogramming as a contributor to prostate cancer disease progression.
Targeting METTL3 Induces a Metabolic Vulnerability in ER+ Breast Carcinoma Cells.
A pancancer analysis reveals the oncogenic role of glutaminase 1 (GLS1) in tumor metabolism and immune evasion: a bioinformatics analysis.
Potential glutamine metabolism-related biomarkers were identified in osteoarthritis by bioinformatics.
Conditional deletion of glutaminase 1 in Tnfrsf11a-expressing cells reduces bone mass and induces postnatal growth retardation in mice.
Directed rescue strategy for enhanced implant osteointegration in aged rats.
Mesoporous multimetallic PdPtBi nanozymes target redox imbalance and glutamine deprivation for immuno-chemodynamic therapy.
Metabolic plasticity drives mechanisms of PARP inhibitor persistence in ovarian cancer.
Glutamine-Dependent Biosynthetic Pathways Fuel Autoreactive T and B Cells in Foxp3 Deficiency-mediated Disease.
Amino acid metabolic reprogramming drives pathogenesis and therapy in hematologic malignancies.
Areca nut extract exposure disrupts myogenesis and metabolism in C2C12 cells.
Glutamine and allergic rhinitis: A bidirectional two-sample Mendelian randomization study.
From mechanism to targeted therapy: Advances in histone lactylation-driven cancer progression (Review).
Are HDAC and Glutamine Synthetase Expression Levels Associated with Ga68-DOTATATE PET/CT Data and Prognosis in Gastroenteropancreatic Neuroendocrine Tumours?

Mutat Res. 2025 Jul-Dec;831:pii: S0027-5107(25)00023-5. [Epub ahead of print]831 111920

FOXA2 promotes glutamine metabolism to facilitate the malignant development of bladder cancer by transcriptionally increasing GLS1 expression.

Quan Yuan, Bowen Liu, Wei Yan, Huifeng Li, Jinxian Pu.

   BACKGROUND: Forkhead box A2 (FOXA2) is found to be abnormally overexpressed in bladder cancer (BCa), but its role and underlying molecular mechanisms in BCa progression remain revealed.
METHODS: The expression levels of FOXA2, glutaminase 1 (GLS1), glutamine metabolism-related markers were examined using qRT-PCR and western blot. Glutamine metabolism was assessed by detecting glutamine uptake, intracellular glutamate, ATP, GSH and ROS levels. BCa cell proliferation, migration and invasion were analyzed by CCK8 assay, EdU assay, wound healing assay, and Transwell assay. The regulation of FOXA2 on GLS1 promoter was confirmed by dual-luciferase reporter assay and ChIP assay. Mice xenograft tumor models were constructed to evaluate the role of FOXA2 in BCa tumorigenesis.
RESULTS: FOXA2 expression was upregulated in BCa cells and its knockdown significantly decreased GLS1 expression. Silencing of FOXA2 inhibited BCa cell glutamine metabolism, thus suppressing cell proliferation and metastasis, and these effects were reversed by GLS1 overexpression. In terms of mechanism, FOXA2 increased the transcription and expression of GLS1 by binding to its promoter region. Animal study revealed that FOXA2 interference also reduced BCa tumorigenesis through decreasing GLS1 expression.
CONCLUSION: FOXA2 accelerated BCa cell proliferation and metastasis by promoting GLS1-mediated glutamine metabolism, providing a novel therapy target for BCa.

Keywords:  Bladder cancer; Forkhead box A2; Glutaminase 1; Glutamine metabolism

DOI:  https://doi.org/10.1016/j.mrfmmm.2025.111920
Cancer Metab. 2025 Nov 22.

Cdk5 regulates glutamine metabolism in colorectal cancer via the EZH2-GLS1 axis.

Qilong Wu, Xiaotong Zhu, Xinxin Wan, Xinjie Lu, Jiayan Chen, Zhe Ying, Yan Li, Xing Hu, Jiahai Lu, Yongliang Lou, Xiang Li.

  Colorectal cancer (CRC) is a globally prevalent malignancy that poses a substantial threat to human health. Despite advancements in prevention, diagnosis, and treatment, CRC remains a formidable clinical challenge due to the incomplete elucidation of its pathological mechanisms. Glutamine, an abundant amino acid, exerts pivotal roles in energy production, redox homeostasis, macromolecular biosynthesis, and signal transduction within cancer cells. Elucidating the role of glutamine in CRC pathogenesis is therefore of profound significance. In this study, we investigated the regulatory role of Cyclin-dependent kinase 5 (Cdk5) in glutamine metabolism in CRC, employing both human CRC cell models and murine models. Our findings demonstrated that Cdk5 knockdown accelerated glutamine uptake while suppressing the proliferation of CRC cells. Further exploration of the underlying molecular mechanisms revealed that Cdk5 physically interacts with EZH2. Besides, Cdk5 phosphorylates EZH2 at specific sites, and then the PRC2 complex (centered around EZH2) catalyzes the production of H3K27me3, an inhibitory marker, to regulate the expression of genes involved in glutamine metabolism. At the same time, we also found that modulation of the Cdk5-EZH2 axis alters the epigenetic landscape of genes associated with glutamine transporters and tricarboxylic acid cycle (TCA) enzymes, resulting in reduced mitochondrial activity, impaired glutamine utilization in the TCA cycle, and decreased ATP production-collectively impacting the global glutamine metabolic processes in CRC cells. In in vivo experiments utilizing a murine CRC model, we established five experimental groups. Results showed that Dinaciclib treatment suppressed tumor growth in the CRC model, with this inhibitory effect being further potentiated upon combination with glutamine deprivation. These findings not only uncover the intricate interplay between Cdk5, EZH2, and glutamine metabolism in CRC but also offer novel insights into the pathogenic mechanisms of CRC and identify potential therapeutic targets.

Keywords:  Colorectal cancer; Cyclin-dependent kinase 5; Glutaminase; Glutamine; Mitochondria; Tricarboxylic acid cycle

DOI:  https://doi.org/10.1186/s40170-025-00414-1
Cell Rep. 2025 Nov 25. pii: S2211-1247(25)01392-0. [Epub ahead of print]44(12): 116620

Glutamine synthetase modulates YAP activation by stabilizing LATS under glutamine homeostasis.

Siyi Li, Ting Ling, Yuhan Wang, Jing Shi, Qiuping Wang, Jing Lv, Jinghan Li, Yu Liu, Yi Zhang, Changhao Liu, Tian Xia, Di Chen, Wenqi Wang, Hong-Xu Liu, Hai-Long Piao.

  Glutamine homeostasis plays a crucial role in fundamental cellular processes and is often dysregulated in cancer cells; however, the underlying mechanisms governing this homeostasis remain unclear. Here, we demonstrate that enriched glutamine activates the Hippo pathway. Mechanistically, glutamine synthetase (GS) interacts with LATS1, leading to its downregulation via increased ubiquitin degradation. Glutamine supplementation reduces the expression of GS and stabilizes LATS1, leading to YAP phosphorylation and inhibition. Clinically, GS expression is associated with clinical outcomes and inversely correlated with LATS1 expression and YAP1 phosphorylation. Taken together, these results not only uncover a previously undescribed mechanism by which glutamine homeostasis regulates the Hippo pathway but also suggest a potential therapeutic strategy by targeting glutamine metabolism and key growth-related signaling pathways for cancer treatment.

Keywords:  CP: cancer; CP: metabolism; GS; Hippo pathway; LATS; cancer; glutamine

DOI:  https://doi.org/10.1016/j.celrep.2025.116620
Chin Med J (Engl). 2025 Nov 21.

Revisiting the role of metabolic reprogramming as a contributor to prostate cancer disease progression.

Hekang Ding, Qingwei Meng, Jun Zhou, Li Chen, Jiaoti Huang, Bing Zhao, Lingfan Xu.

   ABSTRACT: Prostate cancer (PCa) is one of the most common malignancies worldwide, and metabolic reprogramming plays a crucial role, particularly in tumor progression and therapeutic resistance. As PCa progresses into advanced stages, such as castration-resistant prostate cancer, significant alterations in tumor metabolic pathways, including glycolysis, amino acid utilization, and lipid acid metabolism, occur. These reprogrammed metabolic pathways support the survival and proliferation of tumor cells in altered tumor microenvironments. Glutamine metabolism is significant in advanced PCa because this pathway not only contributes to the tricarboxylic acid cycle by providing energy and carbon skeletons but also supports the synthesis of macromolecules such as nucleotides and lipids and acts as a key driver of therapeutic resistance. In addition, pioneer transcription factors, such as the androgen receptor, either regulate the activity of metabolic pathways or are influenced by specific signaling metabolites. Targeting metabolic vulnerability is an ideal therapeutic strategy for advanced PCa. The aim of this review was to describe distinct metabolic features in different stages of PCa and highlight how to improve therapeutic effects by targeting tumor metabolism.

Keywords:  Castration-resistant prostate cancer; Glutamine metabolism; Metabolic reprogramming; Prostate cancer; Targeted therapy

DOI:  https://doi.org/10.1097/CM9.0000000000003844
Endocr Relat Cancer. 2025 Nov 26. pii: ERC-25-0174. [Epub ahead of print]

Targeting METTL3 Induces a Metabolic Vulnerability in ER+ Breast Carcinoma Cells.

Mary H Sumlut, Jing Feng, Xiang Zhang, Susan Dougherty, Yoannis Imbert Fernandez, Carolyn M Klinge, Brian F Clem.

  Epitransciptomic marks, such as N6-methyladenosine (m6A) within RNA transcripts, have been implicated in multiple pro-tumorigenic activities. These modifications are controlled by writers, readers, and erasers, including the METTL3 m6A-methyltransferase. Recently, changes in expression or activity of epitranscriptomic enzymes have been shown to modulate metabolic pathways in multiple tumor types, including within endocrine-sensitive and -resistant estrogen receptor-positive (ERα+) breast cancer (ER+BC) cells. Yet, a broad analysis of metabolic alterations, specifically with respect to METTL3 inhibition, has not been explored in these BC subtypes. Herein, we investigated the magnitude of pharmacological targeting of METTL3 (STM2457) on overall cellular metabolism in endocrine-sensitive (MCF-7 and ZR-75-1) and -resistant (LCC9 and ZR-75-1-4-OHT) ER+BC cells. We found that STM2457 selectively decreased glycolytic activity in resistant cells and led to altered hexokinase 2 expression in LCC9 cells. STM2457 suppressed mitochondrial activity, while isotope tracing found diminished TCA glucose oxidation in MCF-7 and LCC9 cell lines. This was accompanied by increased glutamine uptake and glutaminolysis, which was more pronounced in the endocrine resistant LCC9 cells. We also observed differential expression of glutaminase 1 (GLS1) splice variants in the MCF-7 cells and an increase in the ASCT2 glutamine transporter. To determine combinatorial targeting potential, we co-treated cells with STM2457 and CB-839, which is a GLS1 inhibitor. CB-839 increased the potency of STM2457 only in the LCC9 and ZR-75-1-4-OHT endocrine-resistant cells. Our collective findings suggest that METTL3 inhibition leads to selective glycolytic and oxidative metabolic changes between these endocrine-sensitive and resistant BC cells that can be exploited for combinatorial therapy.

Keywords:  METTL3 inhibition; STM2457; epitranscriptomic; estrogen receptor-positive breast cancer; metabolism

DOI:  https://doi.org/10.1530/ERC-25-0174
Discov Oncol. 2025 Nov 24. 16(1): 2156

A pancancer analysis reveals the oncogenic role of glutaminase 1 (GLS1) in tumor metabolism and immune evasion: a bioinformatics analysis.

Jianjun Liu, Shikai Hong, Kangsheng Gu.

   BACKGROUND: Metabolic reprogramming is a significant factor that regulates the function and differentiation of immune cells, thereby influencing the progress of the immune response. The intricate interplay between glutamine metabolism and the immune microenvironment (TME) plays crucial roles in the pathogenesis of cancer. The initiation of glutamine metabolism is facilitated by the enzyme GLS1; however, its oncogenic role remains unclear.
METHODS: In this pancancer analysis, we aimed to investigate the potential oncogenic mechanism of GLS1 across various tumor types in The Cancer Genome Atlas (TCGA) dataset.
RESULTS: Our results revealed variable expression levels of GLS1 across different cancer types. Notably, higher expression levels of GLS1 were associated with worse prognosis in patients with kidney renal papillary cell carcinoma (KIRP, HR = 1.01; p < 0.01), liver hepatocellular carcinoma (LIHC, HR = 1.02; p < 0.01), and mesothelioma (MESO, HR = 1.01; p < 0.01). Additionally, we observed distinct associations between GLS1 expression levels and tumor methylation levels, tumor mutation burden (TMB), microsatellite instability (MSI), immune cell infiltration (IFL), and immune scores in several tumor types. We also detected the enrichment of GLS1 in key pathways, such as the mTOR, JAK, and KRAS pathways. Furthermore, we observed associations between GLS1 expression levels and a wide range of immune checkpoint genes, including both immunoinhibitors and immunostimulators, in most tumors.
CONCLUSIONS: Our study provides initial insights into the oncogenic roles of GLS1 across different tumors. These findings suggest that GLS1 can serve as a potential biomarker for determining prognosis and designing therapeutic strategies for various tumor types.

Keywords:  Epigenetic regulation; GLS1; Immunology; Metabolic enzyme; Pancancer analysis

DOI:  https://doi.org/10.1007/s12672-025-03779-3
Sci Rep. 2025 Nov 27.

Potential glutamine metabolism-related biomarkers were identified in osteoarthritis by bioinformatics.

Dongyun Li, Chen Wang, Yuelei Qing, Xitong Bao, Jingxiao Xu, Xinyu Wang, Wenping Bao, Xiaoying Wang.

  Osteoarthritis (OA) is a prevalent joint disorder. It is of great importance to identify efficacious therapeutic targets and biomarkers for the treatment of inflammatory joint diseases and the effective management of their condition. Glutamine metabolism is pivotal in regulating chondrocyte function, maintaining bone homeostasis and modulating the inflammatory response. This study aimed to identify glutamine metabolism-related genes that may serve as potential biomarkers for OA. The OA transcriptome dataset and the glutamine metabolism-related genes were obtained. Subsequently, consistency clustering was employed to differentiate between different disease types for the glutamine metabolism-related genes in the OA transcriptome dataset. Furthermore, differential expression analysis was conducted, and functional enrichment analysis was employed to elucidate the underlying mechanisms. A protein-protein interaction (PPI) network was constructed and candidate key genes were identified through Cytoscape's 7 algorithms. Valuation of the diagnostic ability of OA and prediction of transcription factors (TFs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) that were related. Subsequently, drug prediction and molecular docking were conducted. An OA mice model and cell model were established using the DMM and IL-1β methods, respectively, were employed to verify the expression. 1018 differentially expressed genes (DEGs1) were obtained in the OA transcriptome dataset. Subsequently, based on glutamine metabolism-related genes, the transcriptome dataset genes between two subtypes were further 385 differentially expressed genes (DEGs2) were obtained. An intersection of the DEGs1 and the DEGs2 revealed 102 intersecting genes, which were considered candidate genes. LRRFIP1 and MFSD11 as the key genes according to Cytoscape's 7 algorithms and expression levels verification, and with a better OA diagnostic ability. Subsequently, the OA mice model and cell model were established successfully, LRRFIP1 and MFSD11 both had a lower expression level. Glutamine metabolism-related genes LRRFIP1 and MFSD11 may be potential biomarkers for diagnosing and treating OA.

Keywords:  Glutamine metabolism; LRRFIP1; MFSD11; Osteoarthritis (OA); Transcriptome

DOI:  https://doi.org/10.1038/s41598-025-29541-x
Biochem Biophys Res Commun. 2025 Nov 25. pii: S0006-291X(25)01764-4. [Epub ahead of print]794 153048

Conditional deletion of glutaminase 1 in Tnfrsf11a-expressing cells reduces bone mass and induces postnatal growth retardation in mice.

Shintaro Terashita, Yasuhito Yahara, Jun-Dal Kim, Amane Mizutani, Hitoshi Uchida, Keisuke Yaku, Masakatsu Yamashita, Chihaya Imai, Takashi Nakagawa.

  Glutamine is a conditionally essential amino acid, and glutaminase 1 (GLS1) catalyzes its conversion to glutamate, which supports cellular energy metabolism and biosynthetic processes. GLS1 has been implicated in osteoclast differentiation in vitro; however, its physiological role in bone homeostasis remains incompletely understood. In this study, we generated Tnfrsf11aCre; Gls1flox/flox (cKO) mice to conditionally delete Gls1 in osteoclast-lineage cells and investigated its function in skeletal homeostasis. These mice exhibited reduced bone mass due to impaired osteoclast activity and decreased osteoblast numbers, suggesting disrupted bone remodeling dynamics. In vitro analyses revealed that Gls1-deficient osteoclasts displayed impaired differentiation and diminished bone resorption capacity, accompanied by significantly reduced intracellular levels of glutamate and α-ketoglutarate. In contrast, osteoblast function was preserved under monoculture and co-culture with osteoclasts, indicating that the in vivo reduction in osteoblast numbers was not due to intrinsic osteoblast dysfunction. While cKO mice appeared phenotypically normal at birth, they developed severe postnatal growth retardation and hypoglycemia, with elevated serum 3-hydroxybutyric acid levels at two weeks of age, indicative of systemic metabolic abnormalities. Since Tnfrsf11a is expressed not only in osteoclasts and their precursors but also in tissue-resident macrophages throughout the body, GLS1 deficiency in these cells may have contributed to postnatal nutritional deficits, leading to systemic growth impairments and compromised skeletal development.

Keywords:  Glutaminase 1; Glutamine metabolism; Growth retardation; Osteoclast differentiation; Tnfrsf11a

DOI:  https://doi.org/10.1016/j.bbrc.2025.153048
Nat Commun. 2025 Nov 24. 16(1): 10322

Directed rescue strategy for enhanced implant osteointegration in aged rats.

Xuan Li, Xiao Jiang, Ye He, Hongwei Xiong, Qian Huang, Kun Xu, Xin-Xin Luo, Kai Li, Bailong Tao, Kangkang Zha, Jing Wu, Peng Liu, Kaiyong Cai.

The elimination of senescent cells can enhance the osteointegration of implants in elderly patients. However, achieving specific clearance of senescent cells without adversely affecting the function of normal cells remains challenging. Here we show an implant surface modification technique to achieve specific clearance of locally senescent cells by modulating their metabolism. Our method involve modifying implants with BPTES, a glutaminase 1 (GLS1) inhibitor, through π-π stacking with dopamine. This modification effectively induces intracellular acidosis in senescent mesenchymal stem cells (MSCs) through suppression of glutaminolysis. Simultaneously, poly(γ-glutamate) (PGA), modified by a layer-by-layer method, serve as a high-density carbon source coating, continuously supporting glutamine metabolism in MSCs without ammonia production. Our results show that modified implants significantly reduce the senescence level around implants and promote osteointegration in aged rats. These findings provide promising insights into the design and application of orthopedic implants for elderly patients.

DOI: https://doi.org/10.1038/s41467-025-65284-z
J Nanobiotechnology. 2025 Nov 24.

Mesoporous multimetallic PdPtBi nanozymes target redox imbalance and glutamine deprivation for immuno-chemodynamic therapy.

Guanhua Qiu, Jie Long, Feng Lin, Zeyan Yu, Renchuan Liang, Jiaxin Luo, Xuezhong Mo, Duo Wang, Lei Jiao, Yunxi Huang.

  Therapeutic resistance remains a formidable challenge in oncology, mainly due to the chaotic tumor microenvironment (TME), which drive tumor progression and adaptive resistance via a self-sustaining metabolic-oxidative feedback loop. Herein, a multifunctional nanotherapeutic platform based on PdPtBi multimetallic nanozymes (PPB MMNs) is rationally engineered to address these challenges by simultaneously targeting reactive oxygen species (ROS) modulation and glutamine (Gln) metabolic disruption. Specifically, the PPB MMNs display cascade enzyme-mimicking activities resembling peroxidase (POD), catalase (CAT), and glutathione oxidase (GOD-SH). These activities effectively promote the generation of reactive oxygen species (ROS) and facilitate the decomposition of endogenous H₂O₂ into O₂, thereby alleviating hypoxia and inducing oxidative stress. Upon ultrasound (US) activation, their catalytic performance is further amplified, enabling deep-tissue therapeutic efficacy. Concurrently, PPB MMNs impair Gln metabolism, aggravating redox dyshomeostasis and undermining tumor metabolic flexibility. Both in vitro and in vivo studies validate the superior antitumor activity of PPB MMNs in suppressing primary and metastatic tumor growth by disrupting the redox-metabolic axis. Collectively, our study offers a robust framework for designing multimodal nanomedicines that reprogram the TME and overcome resistance, opening new avenues for precise, synergistic cancer therapy based on redox and metabolic vulnerabilities.

Keywords:  Glutamine metabolism; Immune activation; Immuno-Chemodynamic therapy; Mesoporous materials; Redox imbalance

DOI:  https://doi.org/10.1186/s12951-025-03856-3
bioRxiv. 2025 Oct 09. pii: 2025.10.08.681266. [Epub ahead of print]

Metabolic plasticity drives mechanisms of PARP inhibitor persistence in ovarian cancer.

Adriana Del Pino Herrera, Joon-Hyun Song, Karla Torres-Arciga, Susoma Halder, Kadin El Bakkouri, Mehdi Damaghi, Meghan C Ferrall-Fairbanks.

Ovarian cancer results in the death of 1 in 6 patients within the first three months of diagnosis, making it the fifth deadliest cancer in the United States. While clinicians have moved towards using targeted therapies, patients often stop responding to the treatment. In this study, we combined both experimental and computational techniques to explore this process by treating OVCAR3 cell line with Olaparib (a PARP inhibitor). We then performed single cell RNA sequencing on both naïve and persistent populations. RNA velocities analysis indicated that there was a trajectory of gene expressions adaptation toward the persister phenotype. To further investigate the persistence mechanism, metabolic pathways were scored on our single cell data, and persistence cells were found to have differentially expressed glutamine metabolism compared to naïve cells. To test these findings, both persistent and naïve cells where cultured in glutamine deprived media and we found persistent cells have higher viability than the naïve cells particularly under Olaparib treatment. We then found that these cells acquired glucose dependency that can be used as vulnerability. This finding suggested increased plasticity of cancer cells under long-term Olaparib treatment. We then built a math model that suggested treatment scheduling could be improved by considering metabolic plasticity in response to Olaparib treatment.
ONE SENTENCE SUMMARY: Ovarian cancer cells exploit metabolic plasticity to switch their glutamine/glucose metabolism to persist PARP inhibitor treatment.

DOI: https://doi.org/10.1101/2025.10.08.681266
bioRxiv. 2025 Nov 05. pii: 2025.11.04.686569. [Epub ahead of print]

Glutamine-Dependent Biosynthetic Pathways Fuel Autoreactive T and B Cells in Foxp3 Deficiency-mediated Disease.

Mohammad Adeel Zafar, Charlotte Nicole Hill Machado, Jyotirmaya Behera, Yuelin Zhong, Xiao Li, Shakchhi Joshi, Yassine El Fazaa, Virginia Camacho, Peter Georgiev, Kiran Kurmi, Marcia Carmen Haigis, Louis-Marie Charbonnier.

Foxp3 deficiency causes a profound loss of immune tolerance, unleashing autoreactive T and B cells, lymphoproliferation, cytokine-driven inflammation, and autoantibody production. This autoimmune pathology is fueled by increased glutamine usage, but it remains unresolved whether glutamine is necessary to produce energy, or for biosynthetic pathways leading to inosine and asparagine production. Here, we demonstrate that glutamine utilization supports Foxp3-deficiency mediated disease independently of pathogenic Foxp3-deficient Treg cell energetic reprogramming. Mechanistically, glutamine biosynthetic pathways sustain conventional T cell activation and proinflammatory cytokine production preventing inosine accumulation and signaling, thus implicating adenosine pathway modulation in autoreactive T cell dysregulation. Conversely, autoreactive B cell activation and autoantibody production depend on glutamine-dependent asparagine synthesis, which we reveal as a targetable vulnerability for autoantibody formation. These findings highlight glutamine-driven biosynthetic processes as critical drivers of autoimmunity and reveal distinct metabolic vulnerabilities in autoreactive T and B cells that can be targeted for therapeutic intervention.

DOI: https://doi.org/10.1101/2025.11.04.686569
Discov Oncol. 2025 Nov 24.

Amino acid metabolic reprogramming drives pathogenesis and therapy in hematologic malignancies.

Dexiang Ren, Rong Liu, Wei Li, Linzhou Li, Xueyin Lv, Xiaojun Xia, Xudong Lei.

  Hematological malignancies exhibit distinct patterns of amino acid metabolic reprogramming, which support uncontrolled proliferation, immune escape, and therapy resistance. Rather than merely fueling biosynthesis, amino acid metabolism intricately modulates tumor progression and therapeutic responses through interactions with signaling pathways such as mTOR, β-catenin/c-Myc, and NF-κB. This review emphasizes the rewired utilization of key amino acids-including glutamine, arginine, leucine, tryptophan, and phenylalanine-across leukemia, lymphoma, and multiple myeloma, and discusses how these changes orchestrate immune suppression and redox imbalance. Emerging studies reveal that metabolic vulnerabilities can be therapeutically exploited via enzyme depletion, transport inhibition, or combination regimens with immunotherapies and mTOR inhibitors. Moreover, amino acid-driven drug resistance mechanisms, particularly involving stromal support and transcriptional reprogramming, pose both challenges and opportunities for next-generation treatment design. By decoding the complex metabolic-immune-tumor network, we highlight strategic interventions that leverage amino acid metabolism as a therapeutic axis in hematological cancers.

Keywords:  Amino acid dependencies; Hematological malignancies; Metabolic reprogramming; Targeted metabolic therapies; Therapeutic resistance mechanisms; Tumor–Immune metabolic crosstalk

DOI:  https://doi.org/10.1007/s12672-025-04093-8
Curr Res Toxicol. 2025 ;9 100264

Areca nut extract exposure disrupts myogenesis and metabolism in C2C12 cells.

Chi-Wei Chen, Tsung-Teng Huang, Yan-Ru Chen, Chin-Hung Liu, Chia-Hsun Hsieh, Tai-Lin Chen, Kuo-Chu Lai.

  Areca nut (AN), which is commonly consumed in Southeast Asia, contains bioactive compounds that may influence cellular functions. Accumulating evidence has revealed several health impacts of AN consumption, but the toxicological effects of areca nut extract (ANE) on muscle cells remain largely unexplored. Myogenesis, a critical process for muscle development and regeneration, is closely tied to metabolic activity, which governs the differentiation and function of myocytes. This study aimed to evaluate the effects of ANE on myogenesis in murine C2C12 myoblasts and differentiated myotubes. In ANE-treated C2C12 myoblasts, we observed a significant decrease in the intracellular glutamine level that was accompanied by decreased GSH levels, decreased mTOR signaling, and increased autophagy in myoblasts but not in differentiated myotubes. ANE treatment decreased glutamine and 6-phosphogluconate levels in both myoblasts and myotubes, suggesting the widespread suppression of amino acid and redox-related metabolic pathways. Moreover, ANE significantly altered the metabolomic profile, upregulating the levels of glycolysis and TCA cycle intermediates but reducing ATP levels, indicating impaired energy metabolism in differentiated myotubes. ANE also downregulated the expression of key metabolic genes, including those involved in glycolysis (AKR1B3 and LDHA), glycerol metabolism (GPD1 and GPD2), and nitrogen metabolism (GLUD1, ARG1, GS, and GLS1), indicating that ANE disrupts critical pathways involved in muscle cell metabolism and myogenesis. This study provides new insights into the mechanisms by which AN consumption affects muscle development, emphasizing the need for further research into the dietary and environmental factors influencing myogenesis.

Keywords:  Areca nut extract; Autophagy; C2C12 myoblasts; Differentiated myotubes; Metabolomics; Muscle atrophy

DOI:  https://doi.org/10.1016/j.crtox.2025.100264
Medicine (Baltimore). 2025 Nov 21. 104(47): e45400

Glutamine and allergic rhinitis: A bidirectional two-sample Mendelian randomization study.

Shuhua Fan, Zhiwei Guan, Ying Ding, Wenxia Chen, Sujing Su, Han Bai, Le Li.

  Glutamine (Gln) has been implicated as a potential protective factor against allergic rhinitis (AR), with supplementation studies suggesting improved patient prognosis. However, the precise relationship between circulating Gln levels and AR risk remains unclear. To address this, we employed bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal association between Gln and AR. Genome-wide association study (GWAS) summary statistics for AR (FinnGen dataset finn-b-ALLERGY_RHINITIS; 217,914 samples; 16,380,461 single nucleotide polymorphisms [SNPs]) and circulating Gln levels (met-d-Gln; 114,750 samples; 12,321,875 SNPs) were obtained from the Integrative Epidemiology Unit Open GWAS database. MR analyses were performed, primarily using the inverse variance weighted (IVW; fixed-effects) method. Sensitivity analyses included the weighted median, simple median, MR-Egger, and maximum likelihood methods. Robustness of the MR findings was further assessed via heterogeneity tests, horizontal pleiotropy evaluation (MR-Egger intercept test), and leave-one-out (LOO) analysis. Additionally, phenotypic association scanning was conducted for both AR and Gln. Forward MR (Gln→AR) revealed a significant negative causal association, identifying Gln as a protective factor for AR (IVW OR < 1; P < .05). Reverse MR (AR→Gln) showed no causal effect (P > .05). Sensitivity analyses confirmed reliability: no significant heterogeneity (Q_P > .05) or horizontal pleiotropy (P > .05) was detected in either direction, and LOO analysis supported result stability. Phenotypic scanning corroborated Gln as a protective factor against AR (OR = 0.874, 95% CI = 0.77047-0.99093, P = .036). Our study suggests that Gln is a protective factor against AR and that AR is not causally associated with Gln.

Keywords:  Mendelian randomization; allergic rhinitis; causal relationship; glutamine; protective factor

DOI:  https://doi.org/10.1097/MD.0000000000045400
Oncol Lett. 2026 Jan;31(1): 28

From mechanism to targeted therapy: Advances in histone lactylation-driven cancer progression (Review).

Zhe Jia, Shan Lu, Zhenchuan Wang, Pengfei Ge.

  As a novel lactate-derived post-translational modification, histone lactylation links metabolic reprogramming and epigenetic regulation in cancer. Histone lactylation, particularly at histone H3 lysine 18 lactylation (H3K18la), has been implicated in tumor initiation, progression, metastasis, immune evasion and therapy resistance. It modulates oncogenic pathways (such as PI3K/Akt/mTOR, NF-κB, JAK/STAT) and metabolic pathways (such as glycolysis enhancement, fatty acid synthesis via stearoyl-CoA desaturase and glutamine metabolism) and by altering chromatin structure and gene transcription. In the tumor microenvironment, lactate-induced H3K18la polarizes macrophages toward an M2 phenotype, upregulates immune checkpoints and induces CD8+ T cells dysfunction, which promotes immunosuppression. However, CD8+ T cell-intrinsic lactylation may enhance antitumor immunity during checkpoint blockade. Histone lactylation also induces chemoresistance via autophagy activation, DNA repair and ferroptosis suppression. Therapeutic strategies targeting lactylation include inhibiting lactate transporters, glycolysis or regulation enzymes (such as E1A-binding protein, lysine acetyltransferase 2A and brahma-related gene 1). Furthermore, the clinical potential is emerging, with H3K18la and H4K5la serving as prognostic biomarkers in multiple types of cancer. However, key questions regarding the non-enzymatic modification mechanisms, identification of histone lactation regulatory enzymes and pan-cancer functional heterogeneity are yet to be elucidated. Future research should prioritize translational validation of lactylation-targeted therapies and their integration with existing regimens to overcome resistance and improve immunotherapy efficacy.

Keywords:  epigenetic regulation; histone lactylation; lactate metabolism; therapeutic targets

DOI:  https://doi.org/10.3892/ol.2025.15381
Medicina (Kaunas). 2025 Oct 30. pii: 1952. [Epub ahead of print]61(11):

Are HDAC and Glutamine Synthetase Expression Levels Associated with Ga68-DOTATATE PET/CT Data and Prognosis in Gastroenteropancreatic Neuroendocrine Tumours?

Ozge Ulas, Ramazan Oguz Yuceer, Zekiye Hasbek, Hatice Ozer, Kerim Seker, Mukaddes Yılmaz, Mahmut Uçar.

  Background and Objectives: Neuroendocrine neoplasms are heterogeneous tumours arising from endocrine gland cells and the neuroendocrine system. Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) constitute two-thirds of this tumour group. This study was aimed at investigating the relationship between histone deacetylase enzymes (HDAC) and glutamine synthetase (GS) positivity, and 68Ga-DOTATATE PET/CT data and their effect on prognosis in gastroenteropancreatic neuroendocrine tumours. Materials and Methods: Twenty-seven patients with Grade 1 and Grade 2 well-differentiated neuroendocrine tumours, diagnosed by biopsy and admitted to our nuclear medicine clinic for staging were included in the study. Results: There was no statistically significant correlation between HDAC and GS positivity in tumours and DOTATATE SUVmax value on PET/CT. There was no significant correlation between HDAC and GS positivity or negativity in the tumour and the presence or absence of metastasis on PET/CT. There was no statistically significant relationship between HDAC and GS positivity and survival. There was a statistically significant correlation between DOTATATE SUVmax value on PET/CT and survival (p = 0.039). Conclusions: According to the results of the present study, overall survival rates decreased in patients with high 68Ga-DOTATATE uptake on PET/CT and therefore, patients with high SUVmax on PET/CT should be followed closely and their prognosis may be poor. In addition, although not statistically significant, the mortality rate is higher in patients with HDAC-positive tumours compared to in patients with HDAC-negative tumours; thus, it should be kept in mind that the prognosis of such patients may also be poor. According to the results of the present study, GS levels were generally negative in NETs. In addition, there was no statistically significant relationship between GS levels and survival.

Keywords:  68Ga-DOTATATE; PET/CT; gastroenteropancreatic neuroendocrine tumours; glutamine synthetase; histone deacetylase enzymes

DOI:  https://doi.org/10.3390/medicina61111952