bims-glucam 2025-08-03 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–08–03
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Imaging the uptake and metabolism of glutamine in prostate tumor models using CEST MRI.
CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells, and is partially rescued by glutamine supplementation.
Multi-omics analysis revealed the addiction to glutamine and susceptibility to de novo lipogenesis of endometrial neoplasm.
DIO3 depletion attenuates ovarian cancer growth via reduced glycolysis and alterations in glutamine metabolism.
Rewiring cancer metabolism: oncogenic signaling pathways and targeted therapeutics.
Dysregulation of Mitochondrial Function in Cancer Cells.
Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease: Role in Cystogenesis and Novel Therapeutic Approaches.
Glucose metabolism and its direct action in cancer and immune regulation: opportunities and challenges for metabolic targeting.
Dynamic Mechanisms of Neutral Amino Acid Exchanger ASCT2 Transporting Substrate Glutamine.
Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer.
Deciphering enemy tactics - the narrow path to an optimal anti-cancer strategy targeting the Warburg effect.
Metabolic adaptations in cancer progression.
Metabolic Adaptations in Cancer Progression: Optimization Strategies and Therapeutic Targets.
Sympathetic nervous system in tumor progression and metabolic regulation: mechanisms and clinical potential.
Research advances on amino acid starvation interventions for hepatocellular carcinoma.
Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling.
Conservation and divergence of metabolic phenotypes between patient tumours and matched xenografts.

Npj Imaging. 2025 Aug 01. 3(1): 34

Imaging the uptake and metabolism of glutamine in prostate tumor models using CEST MRI.

Yuki Hodo, Caitlin M Tressler, Behnaz Ghaemi, Rebecca Thomas, Aliyah S Webster, Kirsten N Bains Williams, Yuguo Li, Martin G Pomper, Chi V Dang, Zaver M Bhujwalla, Jeff W M Bulte, Peter C M van Zijl, Aline M Thomas.

Glutamine metabolism is upregulated in many cancers. While multiple glutamine imaging agents have been developed and translated to clinical use, the short half-lives of their signal and instability in vivo limit the aspects of glutamine metabolism they capture. In phantoms at physiological pH, chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) contrast was observed at 11.7 T from glutamine, downstream metabolic products (glutamate and ammonia) and their co-substrates (alanine, aspartate, and cystine/cysteine). This contrast increased at lower pH. These results suggest that both uptake and metabolism of glutamine would increase CEST signal enhancement. We then investigated the feasibility of imaging the uptake (delivery, transport and metabolism) of naturally-occuring glutamine using CEST MRI in preclinical prostate cancer models, wherein key metabolic proteins are the glutamine transporter ASCT2 and as well as enzymes GLS1, ALT2 (GPT2), AST1 (GOT1), and GDH1 (GLUD1). The LNCaP prostate cancer line exhibited higher expression of ASCT2, GDH1, ALT2, and AST1 compared to DU-145 cells. CEST MRI enhancement upon administration of glutamine was consistently higher in LNCaP 3D spheres (phantoms) and tumors (in vivo) than their DU-145 counterparts. Mass spectrometry imaging confirmed higher uptake and metabolism of glutamine in LNCaP tumors. These findings demonstrate that CEST MRI of glutamine is capable of distinguishing preclinical prostate tumor models that differ in glutamine uptake and has potential for translation to clinical use.

DOI: https://doi.org/10.1038/s44303-025-00100-3
J Allergy Clin Immunol. 2025 Jul 28. pii: S0091-6749(25)00806-1. [Epub ahead of print]

CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells, and is partially rescued by glutamine supplementation.

Mona Kabha, Maya Liaks-Bohnick, Fadia Zagairy, Orna Atar, Mira Hamed, Michael Ziv, Nada Danial-Farran, Morad Khayat, Orly Ishach, Yael Dinur-Schejter, Vered Molho-Pessach, Ido Somekh, Shirly Frizinsky, Efrat Bar-Ilan, Shoshana Greenberger, NaserEddin Adeeb, Raz Somech, Polina Stepansky, Noga Ron-Harel, Eran Cohen-Barak.

   BACKGROUND: T-cell activation requires signaling through the T-cell receptor and costimulatory molecules, including CD28, triggering metabolic reprogramming to support growth and proliferation of the activating T -cell. CARMIL2, a scaffold protein, facilitates CD28-mediated signaling. Individuals with CARMIL2 mutations experience inborn errors of immunity, leading to T-cell dysfunction and severe infectious and inflammatory comorbidities. However, how CARMIL2 deficiency impacts T cell metabolic reprogramming remains unknown.
OBJECTIVE: To investigate how CARMIL2 deficiency affects activation-induced metabolic reprogramming in T-cells.
METHODS: CD4+ T-cells were isolated from patients with CARMIL2 deficiency and matched healthy controls (HC). Transcriptomic profile was analyzed by bulk RNA sequencing and whole-cell metabolomics by liquid chromatography-mass spectrometry (LC-MS/MS). Activation markers and signaling pathways were measured by flow cytometry. These approaches informed identification of specific amino acids for rescue experiments.
RESULTS: Nine patients with CARMIL2 deficiency and sixteen age-and sex-matched healthy controls were recruited. RNA sequencing of CD4+ T-cells revealed decreased expression of genes associated with metabolic activity, including mTOR signaling, glycolysis, one-carbon metabolism, and glutamine metabolism. Whole cell metabolomics reinforced these results and highlighted glutamine deficiency as a potential driver of the observed metabolic phenotype. Glutamine supplementation restored NF-kB and mTOR activity, as measured by p-65 and RPS phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells.
CONCLUSIONS: CARMIL2 deficiency disrupts T-cell metabolic reprogramming and was partially rescued ex-vivo with glutamine supplementation. These findings highlight a potential therapeutic approach targeting metabolism to improve immune function in individuals with CARMIL2 deficiency.

Keywords:  CARMIL2; Glutamine; Metabolism; T -cell; mTOR

DOI:  https://doi.org/10.1016/j.jaci.2025.07.018
Sci China Life Sci. 2025 Jul 24.

Multi-omics analysis revealed the addiction to glutamine and susceptibility to de novo lipogenesis of endometrial neoplasm.

Yuemeng Zhu, Yingxin Zheng, Qing Zhang, Leshi Chen, Yitong Ouyang, Zhiqiang Song, Bing Zhao, Chao Gu, Beihua Kong, He Huang, Jin Li.

  The endometrium is a proliferative tissue controlled by the menstrual cycle. Endometrial hyperplasia (EH) is a type of neoplastic disease that may develop into endometrial hyperplasia with atypia (EHA) or endometrial adenocarcinoma (EA). We performed a multi-omics analysis of a collection of endometrial tissues with four different proliferative statuses from two independent cohorts of patients. A positive association between the level of glutamine and malignancy, as well as addiction of EHA/EA neoplasms to glutamine, was identified. Further investigation revealed the dual mechanism by which glutamine influences the development of endometrial neoplasms. On one hand, glutamine regulates the level of c-MYC by controlling its translational process. On the other hand, glutamine is a major source of energy for endometrial neoplasms. Reprogramming the glutamine metabolism towards de novo lipogenesis affects the growth of endometrial adenocarcinoma in vitro, ex vivo and in vivo. Our study revealed the importance of maintaining metabolic homeostasis in endometrial tissues. The enhancement of de novo lipogenesis is a promising therapeutic strategy for treating endometrial adenocarcinoma.

Keywords:  endometrial cancer; glutamine; lipogenesis

DOI:  https://doi.org/10.1007/s11427-024-2761-y
Mol Metab. 2025 Jul 30. pii: S2212-8778(25)00132-2. [Epub ahead of print] 102225

DIO3 depletion attenuates ovarian cancer growth via reduced glycolysis and alterations in glutamine metabolism.

Dotan Moskovich, Daniel Beilinson, Amit Rosemarin, Aileen Cohen, Itai Fabian, Tzuri Lifschytz, Bernard Lerer, Govindasamy Mugesh, Maya Gottfried, Osnat Ashur-Fabian.

  Metabolic reprogramming emerges as a central driver of therapy resistance and survival disadvantage in ovarian cancer. We recently demonstrated that inhibiting the enzyme Deiodinase type 3 (DIO3) reduces ovarian cancer growth, although the underlying mechanism remains unclear. Here, we studied DIO3 role in metabolism in genetically manipulated ovarian cancer cells using protein expression analysis, integrative proteomics, endogenous and extracellular metabolomics, metabolic assays including lactate and glutamate secretion, reactive oxygen species (ROS) production and the Seahorse Cell Mito Stress test. We reveled that inhibiting DIO3 suppresses glycolysis while enhancing ATP production through oxidative phosphorylation (OXPHOS). We corroborated these findings using two models of ovarian cancer xenografts, demonstrating a marked reduction in glycolytic proteins upon silencing or inhibiting DIO3 using our first in class small molecule. Moreover, altered glutamine metabolism was also documented, favoring urea cycle and TCA cycle engagement over antioxidant production, accompanied by elevated ROS. Intriguingly, DIO3 depletion in fallopian tube cells, the precursor of HGSOC, displayed distinct metabolic adaptations, including enhanced glycolysis and lipid metabolism, suggesting tissue-specific roles for DIO3. These collective findings position DIO3 as a potential regulator of ovarian cancer metabolism, with implications for targeting this enzyme to disrupt tumor energetics as a novel therapeutic approach.

Keywords:  Deiodinase type 3; Thyroid hormones; gynecological malignancy; metabolism; ovarian cancer

DOI:  https://doi.org/10.1016/j.molmet.2025.102225
Sci China Life Sci. 2025 Jul 25.

Rewiring cancer metabolism: oncogenic signaling pathways and targeted therapeutics.

Siying Lyu, Nina Gildor, Qing Zhang, Chengheng Liao.

  Metabolic reprogramming is a hallmark of cancer, playing a critical role in tumorigenesis by supporting cancer cell survival, proliferation, metastasis, and immune evasion. Oncogenic signaling pathways regulate key metabolic processes by orchestrating gene expression and enhancing metabolic enzyme activity, ensuring cancer cells meet their bioenergetic and biosynthetic demands. Here, we highlight the roles of major oncogenic metabolic signaling pathways, including phosphoinositide 3-kinase (PI3K)/AKT, Myc, p53, and hypoxia-inducible factor (HIF), in driving metabolic rewiring. We provide a conceptual framework to understand why metabolic reprogramming occurs in tumor cells, how metabolic alterations contribute to tumorigenesis, metastasis, and immune evasion, and the therapeutic implications of targeting these metabolic vulnerabilities in cancer.

Keywords:  cancer metabolism; cell proliferation; immune evasion; metastasis; oncogenic signaling pathways; target therapy

DOI:  https://doi.org/10.1007/s11427-025-2979-3
Int J Mol Sci. 2025 Jul 14. pii: 6750. [Epub ahead of print]26(14):

Dysregulation of Mitochondrial Function in Cancer Cells.

Ahmed Mahmoud Ahmed Mahmoud Awad, Norwahidah Abdul Karim.

  In addition to their well-known role in ATP production, mitochondria are vital to cancer cell metabolism due to their involvement in redox regulation, apoptosis, calcium signaling, and biosynthesis. This review explores how cancer cells drive the extensive reprogramming of mitochondrial structure and function, enabling malignant cells to survive hostile microenvironments, evade therapy, and proliferate rapidly. While glycolysis (the Warburg effect) was once thought to be the dominant force behind cancer metabolism, recent updates underscore the pivotal contribution of mitochondrial oxidative phosphorylation (OXPHOS) to tumor development. Cancer cells often exhibit enhanced mitochondrial ATP production, metabolic flexibility, and the ability to switch between energy sources such as glucose, glutamine, and pyruvate. Equally important are changes in mitochondrial morphology and dynamics. Due to disruptions in fusion and fission processes, regulated by proteins like Drp1 and MFN1/2, cancer cells often display fragmented mitochondria, which are linked to increased motility, metastasis, and tumor progression. Moreover, structural mitochondrial alterations not only contribute to drug resistance but may also serve as biomarkers for therapeutic response. Emerging evidence also points to the influence of oncometabolites and retrograde signaling in reshaping mitochondrial behavior under oncogenic stress. Collectively, these insights position mitochondria as central regulators of cancer biology and attractive targets for therapy. By unraveling the molecular mechanisms underlying mitochondrial reprogramming-from energy production to structural remodeling-researchers can identify new approaches to disrupt cancer metabolism and enhance treatment efficacy.

Keywords:  OXPHOS; bioenergetics; cancer metabolism; mitochondria; mitochondrial dynamics

DOI:  https://doi.org/10.3390/ijms26146750
Biomedicines. 2025 Jun 30. pii: 1596. [Epub ahead of print]13(7):

Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease: Role in Cystogenesis and Novel Therapeutic Approaches.

Jingyuan Gao, Xiaoyong Yu.

  Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent hereditary renal disorder characterized by the progressive formation of numerous fluid-filled cysts, ultimately leading to end-stage kidney disease. The results of recent studies have demonstrated that metabolic reprogramming plays a crucial role in cystogenesis and disease progression, including enhanced aerobic glycolysis, impaired fatty acid oxidation, glutamine dependence, and mitochondrial dysfunction; these metabolic alterations are regulated by signaling pathways such as mTOR, cAMP/PKA, and HIF-1α, which can modulate cell proliferation, fluid secretion, and energy metabolism. Furthermore, hypoxia and the oxidative microenvironment also promote the growth of cysts. In this review, we summarized the complex interactions between metabolic pathway alterations and key signaling cascades in ADPKD, in addition to exploring new therapeutic strategies targeting these metabolic pathways, including drug and dietary interventions. A comprehensive understanding of these mechanisms may contribute to the development of innovative treatment methods aiming to slow the disease progression of patients with ADPKD.

Keywords:  ADPKD; autosomal dominant polycystic kidney disease; fatty acid oxidation; glutamine metabolism; glycolysis; metabolic reprogramming; mitochondrial dysfunction; novel therapeutic

DOI:  https://doi.org/10.3390/biomedicines13071596
J Biomed Sci. 2025 Jul 29. 32(1): 71

Glucose metabolism and its direct action in cancer and immune regulation: opportunities and challenges for metabolic targeting.

Bo-Syong Pan, Che-Chia Hsu, Hsin-En Wu, Yuan-Ru Chen, Xiaobo Zhou, Shu-Chi Wang, Chia-Yang Li, Hui-Kuan Lin.

  Glucose metabolism is a pivotal hub for cellular energy production and the generation of building blocks that support cell growth, survival, and differentiation. Cancer cells undergo metabolic reprogramming to sustain rapid proliferation, survive in harsh microenvironments, and resist therapies. Beyond producing energy and building blocks to meet cancer cell demands, glucose metabolism generates numerous metabolites that serve as signaling molecules, orchestrating signaling pathways and epigenetic modifications that regulate cancer cell phenotypes and immunity. In this review, we discuss how glucose, through its metabolism and direct actions, influences diverse biological processes driving cancer progression and therapeutic resistance, while also exploring metabolic vulnerabilities in cancer for therapeutic strategies.

Keywords:  Cancer therapy; Glucose metabolism; Glucose sensor; Immune regulation; Immunotherapy resistance; Metabolic targeting; Tumor microenvironment; Warburg effect

DOI:  https://doi.org/10.1186/s12929-025-01167-1
J Chem Inf Model. 2025 Jul 28.

Dynamic Mechanisms of Neutral Amino Acid Exchanger ASCT2 Transporting Substrate Glutamine.

Huamin Zhang, Mingyu Zhang, Huining Hou, Yingqing Chen, Weibing Sun, Qianqian Wang.

Tumor cells rely on the high expression of transporter proteins to meet their nutrient demands, with alanine-serine-cysteine transporter 2 (ASCT2) being a key player in glutamine (Gln) uptake. Glutamine, a conditionally essential amino acid abundant in protein-rich foods, such as meat, dairy, and legumes, serves as a critical nitrogen and carbon source for cellular biosynthesis. ASCT2-mediated Gln transport not only fuels cancer progression but also plays a role in nutrient absorption in healthy tissues, particularly the gut, where dietary amino acids are assimilated. Despite its dual significance in physiology and pathology, the molecular mechanisms of Gln transport by ASCT2 remain poorly understood, hindering the development of targeted therapies and dietary interventions. In this study, microsecond classical and Gaussian accelerated molecular dynamics (CMD/GaMD) were conducted to investigate the dynamic mechanism of glutamine transportation by ASCT2. A Markov State Model (MSM) was built based on the enhanced sampling trajectories to search for the communication pathways and critical transition states during the allosteric movement of helical hairpin 2 (HP2), a structural gatekeeper of transport. Additionally, the C467R mutation was found to disrupt HP2 dynamics, impair Gln binding, and hinder Gln transport. Intriguingly, substrate-bound ASCT2 exhibited prolonged HP2 opening compared to its unloaded state, suggesting that food-derived Gln may stabilize transporter conformations. The important transition states of the transporter opening process were also identified from the MSM. The key pathway from the "close" to "open" state is S2 → S15 → S10 → S6 → S5 → S7 → S19, with a maximum probability of 16.76%. These findings not only advance ASCT2-targeted drug discovery but also offer a framework for designing functional foods or nutraceuticals that modulate amino acid bioavailability, potentially leveraging natural compounds to fine-tune ASCT2 activity for cancer prevention or metabolic health optimization.

DOI: https://doi.org/10.1021/acs.jcim.5c00710
Cancer Cell. 2025 Jul 15. pii: S1535-6108(25)00271-5. [Epub ahead of print]

Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer.

Yijuan Zhang, Li Ling, Rabi Murad, Swetha Maganti, Ambroise Manceau, Hannah A Hetrick, Madelaine Neff, Cheska Marie Galapate, Shea F Grenier, Florent Carrette, Karen Duong-Polk, Anindya Bagchi, David A Scott, Yoav Altman, Jennifer L Hope, Andrew M Lowy, Linda M Bradley, Cosimo Commisso.

  Pancreatic ductal adenocarcinoma (PDAC) tumors are glutamine deficient, and both tumor cells and cancer-associated fibroblasts (CAFs) rely on this amino acid to maintain fitness and induce macropinocytosis as an adaptive response. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis sustains the myCAF phenotype under glutamine limitation by preventing inflammatory reprogramming. Our data demonstrate that metabolic stress induces an intrinsic inflammatory CAF (iCAF) program through MEK-ERK signaling. We find that blocking macropinocytosis in vivo promotes myCAF-to-iCAF transitions, remodeling the tumor stroma. Importantly, stromal remodeling driven by macropinocytosis inhibition-including iCAF enrichment, collagen reduction, immune cell infiltration, and vascular expansion-sensitizes PDAC tumors to immunotherapy and chemotherapy. Our findings reveal that inhibiting macropinocytosis promotes an inflammatory, less fibrotic tumor microenvironment that can be leveraged to improve therapeutic responses in PDAC.

Keywords:  CAF heterogeneity; chemotherapy; drug delivery; immunotherapy; macropinocytosis; metabolic stress; pancreatic cancer; plasticity; stromal architecture; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2025.06.021
Pharmacol Rep. 2025 Aug 01.

Deciphering enemy tactics - the narrow path to an optimal anti-cancer strategy targeting the Warburg effect.

Kinga A Kocemba-Pilarczyk, Barbara Ostrowska, Sonia E Trojan, Paulina Dudzik.

  Metabolic changes in cancer cells are crucial for maintaining their high growth and proliferation rate. As a result, many tumors are characterized by high glucose consumption and intensified aerobic glycolysis, a phenomenon known as the Warburg effect. Through the Warburg effect, cancer cells can rapidly acquire energy, obtain intermediates for biosynthesis, and ensure a source of NAD+ for oxidized biomass synthesis. Altered metabolism and the Warburg effect are characteristic features not only of most transformed proliferating cells but also of normal, rapidly dividing cells, thus posing a challenge for potential anticancer strategies disrupting cellular metabolism. Therefore, targeting the Warburg effect requires a carefully considered strategy so as not to affect the basal metabolism of normal cells and prevent the various side effects in the patient commonly observed with classical chemotherapies targeting DNA replication. On the other hand, strategies/agents that slow metabolic rate are likely to be less toxic to normal cells than to highly metabolically deregulated cancer cells. The aim of this work is to discuss the most optimal approach for inhibiting these favorable metabolic changes in cancer cells while ensuring specificity. The work discusses proteins, enzymes and pathways that, according to the current state of knowledge, can be optimal candidates for cancer specific targeting such as: HK2, PKM2, PFKFB3, PFKFB4, NAD+ de novo metabolism, NADH oxidation, MCT4, MCT1, LDHA and LDHB. In the era of rapid progress in diagnostic tools providing more and more data on molecular changes, the therapeutic strategy should take into account not only the specificity of the cancer, but also a personalized, optimal approach for each individual patient. This article presents an overview, including available databases, showing the heterogeneity of expression of genes involved in metabolic reprogramming among various cancer patients, which clearly suggests the need to develop a specific theranostic approach for targeting the Warburg effect in a personalized manner. Clinical trial number Not applicable.

Keywords:  Cancer metabolism; Metabolic reprogramming; Warburg effect

DOI:  https://doi.org/10.1007/s43440-025-00768-9
Physiol Rev. 2025 Jul 28.

Metabolic adaptations in cancer progression.

Yiming Peng-Winkler, Sarah-Maria Fendt.

  Cancer cells reprogram their metabolism as they travel to distant organs to establish metastases, the leading cause of cancer-related mortality. While the metabolic state of primary tumors has been extensively studied, the specific metabolic alterations associated with metastases have only recently garnered significant attention. The metabolic dependencies that arise during the metastatic cascade, along with the adaptive metabolic shifts required for growth in a new microenvironment, present promising therapeutic targets. In this review, we provide an overview of cancer metabolism, followed by a detailed exploration of the metabolic changes occurring at each stage of metastasis and within common organs of metastatic spread. Lastly, we examine the potential and challenges of targeting metabolic pathways in cancer therapy.

Keywords:  Cancer; Metabolism; Metabolism-based therapy; Metastasis; Organ microenvironment

DOI:  https://doi.org/10.1152/physrev.00037.2024
Cancers (Basel). 2025 Jul 15. pii: 2341. [Epub ahead of print]17(14):

Metabolic Adaptations in Cancer Progression: Optimization Strategies and Therapeutic Targets.

Agnieszka Dominiak, Beata Chełstowska, Grażyna Nowicka.

  As tumor research has deepened, the deregulation of cellular metabolism has emerged as yet another recognized hallmark of cancer. Tumor cells adapt different biochemical pathways to support their rapid growth, proliferation, and invasion, resulting in distinct anabolic and catabolic activities compared with healthy tissues. Certain metabolic shifts, such as altered glucose and glutamine utilization and increased de novo fatty acid synthesis, are critical early on, while others may become essential only during metastasis. These metabolic adaptations are closely shaped by, and in turn remodel, the tumor microenvironment, creating favorable conditions for their spread. Anticancer metabolic strategies should integrate pharmacological approaches aimed at inhibiting specific biochemical pathways with well-defined dietary interventions as adjunctive therapies, considering also the role of gut microbiota in modulating diet and treatment responses. Given the established link between the consumption of foods rich in saturated fatty acids and sugars and an increased cancer risk, the effects of diet cannot be ignored. However, current evidence from controlled and multicenter clinical trials remains insufficient to provide definitive clinical recommendations. Further research using modern omics methods, such as metabolomics, proteomics, and lipidomics, is necessary to understand the changes in the metabolic profiles of various cancers at different stages of their development and to determine the potential for modifying these profiles through pharmacological agents and dietary modifications. Therefore, clinical trials should combine standard treatments with novel approaches targeting metabolic reprogramming, such as inhibition of specific enzymes and transporters or binding proteins, alongside the implementation of dietary restrictions that limit nutrient availability for tumor growth. However, to optimize therapeutic efficacy, a precision medicine approach should be adopted that balances the destruction of cancer cells with the protection of healthy ones. This approach, among others, should be based on cell type-specific metabolic profiling, which is crucial for personalizing oncology treatment.

Keywords:  amino acids utilization; anticancer metabolic strategies; dietary interventions; fatty acid synthesis; glucose metabolism; gut microbiota; metabolic reprogramming; precision oncology; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers17142341
J Transl Med. 2025 Jul 25. 23(1): 836

Sympathetic nervous system in tumor progression and metabolic regulation: mechanisms and clinical potential.

Chen Sun, Yuqing Shen, Fuhua Wang, Tian Lu, Jianqiong Zhang.

  Tumor progression is characterized by profound metabolic alterations and dynamic interactions within the tumor microenvironment (TME), which enable rapid proliferation, immunoinvasion, and metastasis. The sympathetic nervous system (SNS), which has been best known for its role in stress regulation, has emerged as a critical regulator of tumor metabolism. The SNS influences glucose, lipid and glutamine metabolism in tumor cells and stromal components by releasing neurotransmitters such as norepinephrine (NE), creating a pro-tumor metabolic and immunosuppressive microenvironment. SNS signaling enhances glycolysis via upregulation of glucose transporter 1 (GLUT1) and glycolytic enzymes, and supports lipid metabolism through fatty acid synthesis and oxidation. In immune cells, SNS-driven metabolic shifts promote immunosuppressive phenotypes, particularly in T cells and macrophages. Concurrently, SNS signaling enhances glycolysis in endothelial cells, thereby facilitating angiogenesis within the TME. Together, these processes collectively sustain tumor growth, invasion, and resistance to therapy. Therapeutic strategies targeting SNS signaling, such as adrenergic receptors (ARs) blockers, show promise in disrupting these tumor-supportive networks. However, challenges such as the non-specific nature of SNS blockade and the complexity of TME interactions necessitate further research into ARs subtypes, tumor-specific metabolic vulnerabilities, and predictive biomarkers. This review highlights the therapeutic potential of targeting SNS signaling to reshape tumor metabolism and the microenvironment. By elucidating the metabolic impacts of its systemic and local arms, it provides a framework for integrating SNS-directed strategies with existing treatments to improve clinical outcomes.

Keywords:  Cancer therapy; Metabolic reprogramming; Sympathetic nervous system; Tumor microenvironment; Tumor progression

DOI:  https://doi.org/10.1186/s12967-025-06657-2
Biochim Biophys Acta Rev Cancer. 2025 Jul 24. pii: S0304-419X(25)00142-8. [Epub ahead of print]1880(5): 189400

Research advances on amino acid starvation interventions for hepatocellular carcinoma.

Yanqi Li, Lin Li, Yongyong Hou, Xueqiang Peng, Hangyu Li.

  Hepatocellular carcinoma (HCC) is an aggressive malignancy associated with high mortality. Numerous endeavors have been undertaken to develop more effective pharmaceutical interventions. Metabolic reprogramming is recognized as a hallmark of cancer for adapting to heightened bioenergetic and biosynthetic demands. Amino acid (AA) metabolism dysregulation plays a crucial role in the tumor initiation and progression of HCC, resulting in high reliance on AA availability. This makes HCC cells vulnerable to AA starvation, implying that restricting AA supply and utilization may offer a promising nutritional strategy in HCC therapy. We delineate the pivotal physiological functions and aberrant alterations of various AA metabolisms in HCC. We systematically summarize the recent advances in agents, targets, antineoplastic effects, and mechanisms of various AA starvation strategies in HCC, including dietary restriction, circulating depletion, transporter blockade, and metabolic enzyme inhibition. We further discussed a suite of adaptive responses that enable HCC cells to survive with AA shortage. Targeting these adaptive pathways in combination with AA starvation may enhance the efficacy of HCC treatment. This review aims to provide a comprehensive overview of progress in the field of AA starvation for HCC therapy and to explore novel therapeutic opportunities and strategies through nutritional intervention for HCC therapy.

Keywords:  Amino acid metabolism; Amino acid starvation; Cancer nutrition; Hepatocellular carcinoma

DOI:  https://doi.org/10.1016/j.bbcan.2025.189400
Cancer Discov. 2025 Jul 31.

Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling.

Hsi-Wen Yeh, Nicole Lauren DelGaudio, Beste Uygur, Alon Millet, Artem Khan, Gokhan Unlu, Michael Xiao, Rebecca C Timson, Caifan Li, Kerem Ozcan, Karl W Smith, Luiza Martins Nascentes Melo, Gabriele Allies, Olca Basturk, Albert Sickmann, Erol C Bayraktar, Richard Possemato, Alpaslan Tasdogan, Kivanc Birsoy.

Cancer cells require substantial metabolic adaptations to metastasize to distant organs, but the metabolites essential for successful colonization remain poorly defined. Here, we used a mitochondrial metabolomics approach to compare primary and metastatic breast cancer cells. This analysis revealed accumulation of mitochondrial glutathione (GSH) during lung metastasis, driven by elevated expression of SLC25A39, a mitochondrial GSH transporter. Loss of SLC25A39 impairs metastatic colonization in genetic screens, cell line models, and patient-derived xenografts, without affecting primary tumor growth. Mitochondrial GSH import is specifically required during early colonization and functions independently of its canonical antioxidant role. CRISPR activation screens identified ATF4, a stress-induced transcription factor, as a bypass mechanism that restores metastatic potential in SLC25A39-deficient cells. Mechanistically, SLC25A39 is required for optimal ATF4 activation during metastasis and under hypoxia, linking mitochondrial GSH availability to integrated stress response signaling. These findings identify mitochondrial GSH as a necessary and limiting metabolite for metastatic progression.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1556
Nat Metab. 2025 Jul 29.

Conservation and divergence of metabolic phenotypes between patient tumours and matched xenografts.

Aparna D Rao, Ling Cai, Marelize Snyman, Rachel E Walsdorf, Xiangyi Li, Sophia N Wix, Gabrielle Gard, Ariel B Brown, Juliana Kim, Joao Santos Patricio, Sarah Muh, Misty Martin Sandoval, Lauren G Zacharias, Kristen A Heimdal, Wen Gu, Jade Homsi, Brittny Tillman, Rohit Sharma, Travis W Vandergriff, Ashley Solmonson, Brandon Faubert, Thomas P Mathews, Sean J Morrison, Ralph J DeBerardinis, Jennifer G Gill.

Patient-derived xenografts (PDXs) are frequently used as preclinical models, but their recapitulation of tumour metabolism in patients has not been closely examined. We developed a parallel workflow to analyse [U-13C]glucose tracing and metabolomics data from patient melanomas and matched PDXs. Melanomas from patients have substantial TCA cycle labelling, similar to levels in human brain tumours. Although levels of TCA cycle labelling in PDXs were similar to those in the original patient tumours, PDXs had higher labelling in glycolytic metabolites. Through metabolomics, we observed consistent alterations of 100 metabolites among PDXs and patient tumours that reflected species-specific differences in diet, host physiology and microbiota. Despite these differences, most of nearly 200 PDXs retained a 'metabolic fingerprint' largely durable over six passages and often traceable back to the patient tumour of origin. This study identifies both high- and low-fidelity metabolites in the PDX model system, providing a resource for cancer metabolism researchers.

DOI: https://doi.org/10.1038/s42255-025-01338-2