bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2026–04–19
twenty papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Unraveling glutamine metabolism in ovarian carcinoma: signaling cross-talk, positron emission tomography utility, and therapeutic boundaries.
  2. Glutamine metabolism in ovarian carcinoma: disentangling tumor aggressiveness from chemoresistance.
  3. Targeting the amino acid metabolic axis: the Achilles' heel of tumor cells.
  4. SNAT1 (SLC38A1) Is Not the Main Glutamine Transporter in Melanoma, but Controls Metabolism via Glutamine-Dependent Activation of P62 (SQSTM1)/cMYC-Axis.
  5. Amino acid metabolism modulates macrophage polarization: implications for autoimmune-related diseases.
  6. Targeting glutamine metabolism combined with a nanoradioenhancer in radioresistant hepatocellular carcinoma.
  7. SLC1A5 prevents aortic aneurysm and dissection by glutaminolytic-epigenetic orchestration of vascular smooth muscle cell homeostasis.
  8. Chronic Stress Promotes Oral Squamous Cell Carcinoma Progression via GLUD1-Mediated Metabolic Reprogramming.
  9. Dissecting the prognostic role of metabolic markers in lung neuroendocrine Tumors: The MONET study.
  10. Hypoxic microenvironment in cancer: role in metabolic reprogramming.
  11. Enteral Nutrition: What Happened to Immune-Enhancing Diets?
  12. Therapeutic strategies of metabolic reprogramming in non-small cell lung carcinoma.
  13. Lactate-driven pyrimidine synthesis promotes ferroptosis resistance in hepatocellular carcinoma.
  14. Immunomodulatory functions of glutaminyl cyclases QPCTL and QPCT.
  15. Sugar Storm: O-GlcNAc signaling amid the clouds of cancer complexity.
  16. V9302, an inhibitor of glutamine transport, suppresses proliferation and migration, and induces apoptosis in non-small cell lung cancer cells through ROS-mediated mTOR/p70S6K pathway.
  17. A "DUBTAC" targeting GLUL deubiquitination promotes BMSC osteogenic differentiation and implant osseointegration in type 2 diabetes.
  18. Dual inhibition of glycolysis and glutaminolysis by targeting FOXO3 for hepatocellular carcinoma treatment.
  19. Hepatic IFRD1 suppresses metabolic dysfunction-associated fatty liver disease via GLUD1/α-KG axis.
  20. Oncolytic virus hijacks GOT1 and pyrimidinosomes to fuel pyrimidine synthesis for replication in tumor cells.
  1. Transl Cancer Res. 2026 Mar 31. 15(3): 222
    Unraveling glutamine metabolism in ovarian carcinoma: signaling cross-talk, positron emission tomography utility, and therapeutic boundaries.
    Jiajia Tong.
      
    Keywords:  Glutamine metabolism; ovarian carcinoma; tumor aggressiveness
    DOI:  https://doi.org/10.21037/tcr-2025-1-2920
  2. Transl Cancer Res. 2026 Mar 31. 15(3): 223
    Glutamine metabolism in ovarian carcinoma: disentangling tumor aggressiveness from chemoresistance.
    Siegfried Hélage.
      
    Keywords:  Ovarian carcinoma; chemoresistance; glutamine; glutaminolysis; metabolic imaging
    DOI:  https://doi.org/10.21037/tcr-2026-1-0162
  3. Amino Acids. 2026 Apr 17.
    Targeting the amino acid metabolic axis: the Achilles' heel of tumor cells.
    Zheyu Hu, Yiwei Wang, Qian Ma.
      Cancer is characterized by profound reprogramming of its metabolic programs, with the unending demand for exogenous amino acids by tumor cells serving as a hallmark manifestation. While this high dependency supports rapid proliferation, it exposes a critical vulnerability: disruption of amino acid supply can specifically trigger metabolic catastrophe in cancer cells. Furthermore, tumor cells exploit this metabolic reprogramming to deplete key amino acids in the microenvironment, thereby suppressing T-cell function and facilitating immune evasion. This review systematically elucidates therapeutic strategies targeting four critical amino acid metabolic axes (glutamine, arginine, tryptophan, and methionine). We delve into how inhibition of glutamine metabolism disrupts tumor bioenergetics, how arginine deprivation selectively targets cells with synthetic defects, and how methionine restriction interferes with key epigenetic regulation. Additionally, we explore interventions for these four amino acid metabolic axes to reverse immunosuppression. Convincing preclinical and clinical evidence demonstrates that these strategies, whether as monotherapy or rational combinations with conventional treatments, exhibit significant antitumor efficacy and substantial clinical translation potential. By integrating metabolic and immunological perspectives and critically assessing translational challenges, this review aims to provide a roadmap for future development of precision combination strategies capable of overcoming drug resistance and reshaping the immune microenvironment.
    Keywords:  Amino acid metabolic reprogramming; Combination therapy; Immunosuppression; Metabolic addiction; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s00726-026-03522-4
  4. Cancers (Basel). 2026 Mar 25. pii: 1068. [Epub ahead of print]18(7):
    SNAT1 (SLC38A1) Is Not the Main Glutamine Transporter in Melanoma, but Controls Metabolism via Glutamine-Dependent Activation of P62 (SQSTM1)/cMYC-Axis.
    Sandra Lörentz, Ines Böhme-Schäfer, Jörg König, Heinrich Sticht, Anja Katrin Bosserhoff.
      Background: Tumor cells can reprogram their metabolism, constituting a hallmark of cancer that plays a crucial role in tumor progression. As tumor cells exhibit an increased demand for nutrients, e.g., amino acids, they rely on extracellular sources and show deregulation of transport proteins. Among these, SNAT1 (SLC38A1) is described as the loader for glutamine that is responsible for the main influx of this amino acid. The aim of this study was to assess the molecular function of SNAT1 in melanoma regarding its role in amino acid transport and regulation of cellular metabolism. Methods: siPool-mediated downregulation of SNAT1 expression in melanoma cell lines was used to investigate the molecular function of this protein. Glutamine transport was assessed by measuring the intracellular and extracellular concentrations of glutamine. Regulation of downstream effectors was evaluated with qRT-PCR and Western Blot. Metabolism was investigated by performing Seahorse flux analysis. Mitochondrial staining was examined via flow cytometry. Protein interaction was assessed with Co-IP, and in silico modeling of protein interaction was performed with AlphaFold3. Results: In this study, we uncovered the new finding that SNAT1 is not primarily implicated in glutamine influx into melanoma cells but in signaling in response to extracellular glutamine. We identified P62 and cMYC as downstream effectors of SNAT1. By activating the P62/cMYC-axis and target genes of cMYC, SNAT1 modulates the metabolism of melanoma cells depending on the glutamine level. SNAT1 and P62 are interaction partners. Conclusions: This finding newly suggests that SNAT1 may function as a sensor or receptor ("transceptor") for glutamine rather than being a direct and primary glutamine transporter, and could open up new therapeutic options targeting melanoma cells.
    Keywords:  SNAT1 (SLC38A1); glutamine transport; melanoma; transceptor; tumor metabolism
    DOI:  https://doi.org/10.3390/cancers18071068
  5. Front Immunol. 2026 ;17 1736082
    Amino acid metabolism modulates macrophage polarization: implications for autoimmune-related diseases.
    Yuzhe Yin, Chaosheng Yan, Xinyu Pei, Jingjing Rao, Ling Wu, Yuzheng Xue, Haowen Sun, Yingyue Sheng.
      Amino acid metabolic reprogramming is an important component of immunometabolism. In addition to providing biosynthetic substrates and energetic support for macrophages, distinct amino acid metabolic pathways can also reshape the inflammatory and reparative functional states of macrophages by regulating redox homeostasis, epigenetic modifications, signal transduction, and the accumulation of metabolic intermediates. Despite rapid progress in this field, there remains a lack of systematic integration regarding how key metabolic axes, including arginine metabolism, tryptophan catabolism, and glutamine metabolism, coordinately or antagonistically drive macrophage functional reprogramming, as well as the conservation, heterogeneity, and translational significance of these changes across different autoimmune-related diseases. This review summarizes the roles of arginine, tryptophan, glutamine, branched-chain amino acid, serine/glycine/threonine, aspartate/asparagine, and sulfur-containing amino acid metabolism in the dynamic spectrum of macrophage polarization, and further outlines recent advances in systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes mellitus, psoriasis, autoimmune hepatitis, and vasculitis. This review emphasizes that amino acid metabolism is not an isolated regulatory module, but rather part of an interconnected network that, together with glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle anaplerosis, one-carbon metabolism, and lipid metabolism, determines macrophage fate. Given the existing differences in evidence strength and metabolic phenotypes among in vitro systems, animal models, and human studies, caution is still required when extrapolating these conclusions to clinical settings. Overall, therapeutic interventions targeting amino acid metabolism may provide novel biomarkers and treatment strategies for autoimmune-related diseases, but their clinical translation still depends on higher-resolution human validation and mechanism-oriented precision studies.
    Keywords:  arginine metabolism; glutamine metabolism; immunometabolism; metabolic reprogramming; therapeutic targeting; tryptophan catabolism
    DOI:  https://doi.org/10.3389/fimmu.2026.1736082
  6. Nanoscale. 2026 Apr 14.
    Targeting glutamine metabolism combined with a nanoradioenhancer in radioresistant hepatocellular carcinoma.
    Chia-Chun Kuo, Yao-Chen Chuang, Ping-Hsiu Wu, Wei-Min Chang, Leu-Wei Lo, Hsuan-Yu Chen, Kuen-Haur Lee, Hsin-Lun Lee, Jeng-Fong Chiou, Yao-An Shen.
      Radiotherapy (RT) remains one of the curative modalities for localized hepatocellular carcinoma (HCC), exerting its therapeutic effect primarily through irradiation-induced oxidative stress and DNA damage in tumor cells. However, its efficacy is often constrained by intrinsic tumor resistance mechanisms and radiotoxicity in non-tumorous liver tissue. Metabolic reprogramming is a defining hallmark of tumor progression and therapeutic resistance. Recent advances in nanotechnology have facilitated integrated treatment approaches, particularly those combining RT with metabolic modulation, thereby achieving synergistic outcomes. Herein, we developed a nanoplatform using gold nanodandelions (GNDs@gelatin) as a nanoradioenhancer (NRE), loaded with 6-diazo-5-oxo-L-norleucine (DON), to form matrix metalloproteinase-triggered dual-functional RT/metabolic reprogramming nanoplatform, termed GNDs@gelatin/DON. This platform disrupts cellular redox homeostasis via dual mechanisms: enhancement of reactive oxygen species (ROS) generation and suppression of glutathione (GSH) biosynthesis. Cell proliferation inhibition was assessed using the Cell Counting Kit-8 (CCK-8) assay, while drug-radiation interactions were quantified using the CompuSyn software. In the HepG2/C3a RR cell line, the combination index (CI) of RT/GNDs@gelatin/DON (CI = 0.126) was markedly lower than that of RT/DON (CI = 0.395). A similar trend was observed in Huh7 RR cells (CI = 0.294 vs. CI = 0.462). These findings indicate that RT/GNDs@gelatin/DON achieved strong synergism (CI < 0.3), whereas RT/DON exhibited only moderate synergy (0.3 < CI < 0.7). Mechanistically, this dual-functional strategy not only augmented DNA damage, but also triggered mitochondrial dysfunction, leading to greater inhibition of cell proliferation in radioresistant HCC cells than either treatment alone. Importantly, GNDs@gelatin/DON demonstrated controlled DON release and reduced gastrointestinal (GI) toxicity compared with free DON. Collectively, our physical and biological evidence suggests that the synergistic inhibition of glutamine metabolism and GND-enhanced ROS production, in conjunction with MV photon irradiation, holds promise for improving the therapeutic efficacy of clinical radiotherapy.
    DOI:  https://doi.org/10.1039/d5nr04366b
  7. Nat Commun. 2026 Apr 15.
    SLC1A5 prevents aortic aneurysm and dissection by glutaminolytic-epigenetic orchestration of vascular smooth muscle cell homeostasis.
    Pinglian Yang, Zhechang Gao, Weile Ye, Chunhong Zhou, Zhihua Zheng, Meiming Su, Yu He, Zhuoming Li, Jaroslav Pelisek, Ke He, Suowen Xu, Jiaojiao Wang, Zhiping Liu.
      Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with limited preventive pharmacotherapies based on angiotensin II receptor blockade. However, the underlying pathomechanisms of AAD are still unknown. Here, we find that glutamine transporters, particularly solute carrier family 1 member 5 (SLC1A5), in vascular smooth muscle cells (VSMCs) from both patients and mice with AAD are significantly downregulated. VSMC-specific Slc1a5 deficiency exacerbates experimental AAD formation, with a marked increase in VSMC phenotypic switch and inflammation. Mechanistically, SLC1A5 preserves contractile phenotype by facilitating glutamine metabolite acetyl-CoA production and subsequent histone H3 lysine 9 and 27 acetylation, and ameliorates inflammation by promoting acetylated STAT3 mitochondrial translocation, hence inhibiting its nuclear translocation. Intriguingly, enforced SLC1A5 expression in VSMCs in vivo largely alleviates experimental AAD. These findings reveal a metabolic link between SLC1A5-driven glutamine transport and vascular homeostasis, suggesting SLC1A5 may be a promising therapeutic target for AAD.
    DOI:  https://doi.org/10.1038/s41467-026-71856-4
  8. Carcinogenesis. 2026 Apr 13. pii: bgag022. [Epub ahead of print]
    Chronic Stress Promotes Oral Squamous Cell Carcinoma Progression via GLUD1-Mediated Metabolic Reprogramming.
    Huiqing Long, Yu Zhang, Yuqi Qin, Fangzhi Lou, Yiyun Liu, Juncai Pu, Xiaogang Zhong, Li Yan, Shihong Luo, Ping Ji, Bing Yang, Xin Jin.
      Stress is a risk factor for the development of various types of cancer. However, its impact and related underlying mechanisms in oral squamous cell carcinoma (OSCC) progression remain unclear. Therefore, the present study aimed to investigate how chronic stress affects OSCC progression. We assessed mitochondrial metabolism by investigating tumor growth and performing behavioral analysis and molecular assessment, including non-targeted metabolomics and U-13C5-glutamine isotope metabolic flow analysis. We knocked down glutamate dehydrogenase 1 (GLUD1) using lentiviral vectors and investigated it both in vitro (HSC3 and HN6 cells) and in vivo (xenograft models). Our results indicated that chronic stress enhanced glutamate oxidative deamination and tricarboxylic acid cycle metabolism in OSCC cells. It also increased α-ketoglutarate (α-KG) levels, adenosine triphosphate synthesis, and oxygen consumption. Notably, GLUD1-knockdown suppressed these metabolic pathways and significantly inhibited tumor growth both in vitro and in vivo. Furthermore, under chronic stress, GLUD1 regulated OSCC progression through histone H3 trimethylation at lysine 4. However, α-KG supplementation partially reversed GLUD1-knockdown-induced OSCC progression inhibition. Collectively, our results indicate the glutamate-dependent metabolic phenotype regulated by the GLUD1-α-KG metabolic axis is involved in the progression of OSCC under chronic stress.
    Keywords:  Chronic stress; Energy metabolism; Epigenetic regulation; Glutamate dehydrogenase 1; Oral squamous cell carcinoma
    DOI:  https://doi.org/10.1093/carcin/bgag022
  9. Lung Cancer. 2026 Apr 10. pii: S0169-5002(26)00465-4. [Epub ahead of print]216 109404
    Dissecting the prognostic role of metabolic markers in lung neuroendocrine Tumors: The MONET study.
    Giulia Pasello, Giulia Pigato, Cristiana Mulargiu, Federica Ferrarini, Federica Pezzuto, Marco Schiavon, Alessandra Ferro, Daniela Scattolin, Alessandro Dal Maso, Stefano Frega, Laura Bonanno, Fiorella Calabrese, Andrea Dell'Amore, Valentina Guarneri, Stefano Indraccolo.
       BACKGROUND: Lung neuroendocrine tumors (LNETs) span well-differentiated typical/atypical carcinoids (TC/AC) to poorly differentiated large-cell neuroendocrine carcinoma (LCNEC). Robust biomarkers for grading and prognostication are lacking. We hypothesized that differential metabolic pathways activation, reflected by protein expression, holds prognostic relevance. We conducted a monocentric translational study on resected LNETs to characterize biomarkers involved in glycolysis, fatty acid, and amino acid pathways across different grades of LNETs. Secondary endpoints included assessing clinical outcomes and correlating biomarker expression with patient prognosis.
    METHODS: Digital FFPE sections underwent standardized immunohistochemistry (IHC) and quantitative image analysis. Biomarkers included glycolysis (MCT1, MCT4, CD147), amino-acid metabolism (SLC1A5, SLC7A5, GLS), and fatty-acid synthesis (FAS, ACC). Expression was summarized by H-score and dichotomized. Associations with clinicopathologic variables, recurrence-free survival (RFS), and overall survival (OS) were tested using median and maximally selected rank statistics.
    RESULTS: Overall, 49 LNETs were included: 11 TC, 19 AC; 19 LCNEC. LCNEC showed marked upregulation of glycolytic and amino-acid transport markers versus TC/AC. Fatty-acid markers were generally low across subtypes. High MCT1 and SLC7A5 predicted shorter OS; MCT1 and CD147 predicted shorter RFS. In multivariable analysis, MCT1 remained independently associated with RFS. Notably, a subset of ACs with elevated glycolysis/amino-acid markers showed LCNEC-like outcomes, independent of Ki-67. GLS peaked in AC, suggesting divergent glutamine utilization along the spectrum.
    CONCLUSION: Quantitative digital pathology reveals distinct metabolic signatures in LNETs. MCT1 and SLC7A5 emerge as prognostic biomarkers, with MCT1 independently predicting RFS. Integrating metabolic immunophenotyping with histopathology refines risk stratification-especially for AC-and highlights potentially actionable metabolic axes for future therapeutic interventions in LNETs.
    Keywords:  Amino acids; Fatty acids; Glycolysis; Lung neuroendocrine tumors; Metabolism
    DOI:  https://doi.org/10.1016/j.lungcan.2026.109404
  10. Front Oncol. 2026 ;16 1771365
    Hypoxic microenvironment in cancer: role in metabolic reprogramming.
    Niti Sureka, Rashi Maheshwari, Amit Agravat, Shweta Singhal, Shamsuz Zaman, Bhavika Rishi, Fouzia Siraj, Sufian Zaheer, Aroonima Misra.
      Hypoxia, a defining hallmark of solid tumors, arises from structurally and functionally abnormal vasculature, rapid cellular proliferation, and impaired perfusion, resulting in chronic and cycling oxygen deprivation within the tumor massThe hypoxic tumor microenvironment orchestrates extensive molecular reprogramming primarily through stabilization and activation of hypoxia-inducible factors (HIF-1α and HIF-2α), which regulate broad transcriptional networks governing metabolism, angiogenesis, stemness, invasion, and immune modulation. Under low oxygen tension, tumor cells shift toward aerobic glycolysis, enhance glutamine utilization, promote lipid synthesis and storage, suppress mitochondrial oxidative phosphorylation, and fine-tune redox balance through coordinated regulation of ROS-generating and antioxidant systems. These adaptations not only sustain proliferation and survival under metabolic stress but also facilitate epithelial-mesenchymal transition, extracellular matrix remodeling, and metastatic dissemination. Beyond malignant cells, hypoxia reprograms stromal compartments-including cancer-associated fibroblasts, endothelial cells, tumor-associated macrophages, and myeloid-derived suppressor cells-thereby establishing a metabolically cooperative, angiogenic, and profoundly immunosuppressive microenvironment. Hypoxia-induced acidosis, lactate accumulation, and HIF-driven cytokine signaling further impair cytotoxic T-cell and NK-cell activity, contributing to immune escape and resistance to radiotherapy, chemotherapy, and immunotherapy. Emerging evidence from single-cell multi-omics, spatial transcriptomics, metabolic imaging, and early-phase clinical trials targeting HIF signaling, angiogenic pathways, and metabolic enzymes has uncovered actionable vulnerabilities in hypoxia-driven malignancies. This review synthesizes the mechanistic foundations of hypoxia-induced metabolic reprogramming, its role in tumor progression and therapeutic resistance, and discusses innovative strategies aimed at exploiting hypoxia-associated metabolic dependencies to advance precision oncology.
    Keywords:  Warburg effect; hypoxia; hypoxia-inducible factors (HIFs); immune evasion; metabolic reprogramming; mitochondrial metabolism; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fonc.2026.1771365
  11. Surg Clin North Am. 2026 Apr;pii: S0039-6109(25)00132-X. [Epub ahead of print]106(2): 261-271
    Enteral Nutrition: What Happened to Immune-Enhancing Diets?
    Chavi Rehani, Stacy Pelekhaty, Rosemary A Kozar.
      Immunonutrition, once thought to reduce infections in critically ill patients, faced scrutiny in the early 2000s following large trials that showed limited benefits and potential harm, particularly from formulas supplemented with arginine and glutamine. Newer evidence on immune-enhancing diets (IEDs) has prompted a shift toward individualized, precision-based nutrition strategies. Omega-3 fatty acids remain promising, especially in patients with traumatic brain injury or critical illness-induced muscle-wasting. Current guidelines recommend selective use of IEDs, such as in patients with cancer or chronic inflammatory conditions.
    Keywords:  Arginine; Enteral nutrition; Glutamine; Immune-enhancing diets; Omega-3-fatty acids; Precision nutrition
    DOI:  https://doi.org/10.1016/j.suc.2025.12.003
  12. Ann Med. 2026 Dec;58(1): 2652110
    Therapeutic strategies of metabolic reprogramming in non-small cell lung carcinoma.
    Jiajun Liu, Fenhong Qian.
       BACKGROUND: Non-small cell lung carcinoma (NSCLC) remains a leading cause of cancer-related mortality worldwide, with existing therapies frequently hindered by drug resistance and immunosuppression. Metabolic reprogramming (glycolysis, lipid metabolism, and amino acid metabolism) has emerged as a core hallmark driving NSCLC progression, tumor microenvironment (TME) remodeling, and treatment failure, transcending the classical Warburg effect to involve intricate cross-talk between cancer cells and stromal components.
    DISCUSSION: This review systematically synthesizes the latest insights into the regulatory mechanisms of metabolic reprogramming in NSCLC, highlighting how dysregulated glycolytic flux, altered lipid synthesis/oxidation, and adaptive amino acid utilization collectively sustain tumor growth, invasion, and immune escape. We critically examine the interplay between metabolic reprogramming and driver gene mutations (EGFR/KRAS/ALK), unraveling how mutation-specific metabolic adaptations contribute to targeted therapy resistance, and explore the role of metabolic heterogeneity in shaping treatment responses. Furthermore, we dissect actionable therapeutic strategies that target metabolic vulnerabilities, including immunotherapy synergies (e.g. PD-1 inhibitors combined with PKM2/ferroptosis targeting, metabolically modified CAR-T cells), subtype-specific targeted interventions (e.g. DPP4/GFPT2/PFKFB3 inhibitors reversing mutation-driven metabolic resistance), and chemotherapy sensitization approaches (e.g. CPT1A/GLUD1 inhibitors overcoming cisplatin resistance via suppressing metabolic compensation).
    CONCLUSION: This review underscores the clinical potential of targeting metabolic reprogramming to address unmet therapeutic needs, proposing synergistic regimens and personalized metabolic therapy frameworks that hold promise for improving NSCLC patient outcomes.
    Keywords:  Metabolic reprogramming; NSCLC; tumor progression and metastasis
    DOI:  https://doi.org/10.1080/07853890.2026.2652110
  13. Mol Biomed. 2026 Apr 17. pii: 53. [Epub ahead of print]7(1):
    Lactate-driven pyrimidine synthesis promotes ferroptosis resistance in hepatocellular carcinoma.
    Mun-Ju Park, Sebin Lee, Dong-Ho Kim, Mi Kyung Kim, Byoung Kuk Jang, Ghilsuk Yoon, Mihyang Park, Gui-Hwa Jeong, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park.
      Hepatocellular carcinoma (HCC) remains highly lethal, and emerging therapeutic strategies increasingly focus on harnessing ferroptosis to overcome treatment resistance. However, ferroptosis resistance has emerged as a major barrier to these approaches, highlighting the need to identify metabolic cues in the tumor microenvironment that drive this evasion. Here, we identify lactate as a critical metabolite that mediates detrimental metabolic crosstalk between HCC cells and hepatic stellate cells (HSCs), coupling this interaction to pyrimidine biosynthesis and enhanced extracellular matrix (ECM) production within the tumor microenvironment. We show that tumor-derived lactate activates mechanistic target of rapamycin complex 1 (mTORC1)-carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) signaling, enhancing de novo pyrimidine biosynthesis and pre-ribosomal RNA synthesis, thereby promoting ECM protein translation. The resulting ECM deposition drives Yes-associated protein (YAP)/TEA domain family member (TEAD)-dependent upregulation of the cystine/glutamate antiporter (xCT) in HCC cells, conferring marked resistance to sorafenib-induced ferroptosis. Inhibition of dihydroorotate dehydrogenase, the rate-limiting enzyme in pyrimidine synthesis, disrupts ECM production and restores ferroptosis sensitivity in vitro and in vivo. Clinical data further support these findings, indicating that phosphorylated CAD (p-CAD) levels in HSCs are associated with both poor prognosis and lactate-associated ECM enrichment in HCC patients. Collectively, our study identifies lactate-fueled pyrimidine biosynthesis as a key driver of ECM remodeling and ferroptosis resistance in HCC. Targeting this metabolic axis offers a promising therapeutic strategy to overcome ECM-mediated drug resistance and improve outcomes with ferroptosis-based HCC therapies.
    Keywords:  Extracellular matrix; Ferroptosis; Hepatic stellate cells; Hepatocellular carcinoma; Lactate; Pyrimidine biosynthesis
    DOI:  https://doi.org/10.1186/s43556-026-00450-3
  14. Front Immunol. 2026 ;17 1760809
    Immunomodulatory functions of glutaminyl cyclases QPCTL and QPCT.
    Hannah Elaine Smid, Jana Colotti, Sophia Nölp, Nike Sophia Arlt, Sophie Weber, Amelie Gumann, Stephan von Hörsten, Axel Karow, Wolfgang Schuh.
      Glutaminyl-peptide cyclotransferase (QPCT, QC) and its isoenzyme glutaminyl-peptide cyclotransferase-like protein (QPCTL, isoQC) are zinc-dependent enzymes that post-translationally catalyze the conversion of N-terminal glutamine or glutamate residues into pyroglutamate (pGlu). The pGlu modification impacts protein-protein interactions, enhances protein stability, and protects proteins from proteolytic degradation. QPCTL and QPCT differ in their subcellular localization, with QPCTL being retained in the Golgi apparatus and QPCT being active in secretory vesicles. Current research focuses on the impact of QPCTL-mediated pGlu formation in cancer and neurodegenerative disorders such as Alzheimer's disease. In cancer, QPCTL is a promising immunotherapy target since QPCTL-mediated CD47 pyroglutamylation prevents macrophages from phagocytosing tumor cells. Moreover, QPCTL shapes the tumor microenvironment by modulating macrophage recruitment and polarization through modification of CCL2. However, QPCTL modulates Butyrophilins on tumor cells and thereby promote their detection and killing by γδ T cells. Hence, QPCTL significantly affects cancer progression, inflammatory processes, and immune regulation. These insights highlight QPCTL's potential as a therapeutic target in oncology, metabolic diseases, and immune-mediated disorders. In this review, we highlight the role of QPCTL in tumor evasion and immune modulation. Moreover, we provide a comprehensive overview about predicted and validated substrates of QPCT/L and about the relevance of QPCT/L in various diseases.
    Keywords:  IsoQC; QC; QPCT; QPCTL; glutaminyl cyclases; immune cells; pyroglutamate
    DOI:  https://doi.org/10.3389/fimmu.2026.1760809
  15. Glycobiology. 2026 Apr 09. pii: cwag026. [Epub ahead of print]
    Sugar Storm: O-GlcNAc signaling amid the clouds of cancer complexity.
    Nusaiba N Ahmed, Riley G Young, Jessica Merzy, Mauricio J Reginato.
      Cancer is a systemic disease driven not only by cell-intrinsic alterations, but also by system-wide factors that regulate its initiation and progression. Among the key regulators of these processes are nutrient-sensing pathways, which coordinate both cellular and systemic responses. One such pathway involves O-linked N-acetylglucosaminylation (O-GlcNAcylation), a nutrient-responsive and reversible post-translational modification that has emerged as a critical driver of cancer progression. Catalyzed by O-GlcNAc transferase (OGT), O-GlcNAcylation integrates signals from glucose, glutamine, and other nutrients to regulate the activity of cytoplasmic, nuclear, and mitochondrial proteins. Recent studies demonstrate that O-GlcNAcylation influences multiple dimensions of cancer progression, including metabolic adaptation, transcriptional plasticity, immune evasion, metastasis, cancer stem-like states, and therapy resistance. Beyond its cell-intrinsic effects, O-GlcNAcylation also interfaces with broader systemic processes. In this review, we position O-GlcNAcylation within the framework of the "clouds of cancer complexity," highlighting its roles across the metabolic effects, inception and promotion, pleiotropic immune responses, and aging systems and tissues clouds. We propose that O-GlcNAcylation functions as a systems-level integrator that embeds metabolic, environmental, and temporal signals into tumor evolution, revealing new conceptual and therapeutic opportunities.
    Keywords:  O-GlcNAc; OGT; cancer; metabolism; signaling
    DOI:  https://doi.org/10.1093/glycob/cwag026
  16. Neoplasma. 2026 Apr 16. pii: 251028N451. [Epub ahead of print]
    V9302, an inhibitor of glutamine transport, suppresses proliferation and migration, and induces apoptosis in non-small cell lung cancer cells through ROS-mediated mTOR/p70S6K pathway.
    Shuo Li, Xingyu Zhang, Teng Chen, Xiaofan Cong, Wenjing Feng, Xiaojin Sun, Cheng Zha, Surong Zhao, Pei Zhang.
      This study aimed to investigate the effects and underlying mechanisms of V9302, an inhibitor of glutamine transport, on non-small cell lung cancer (NSCLC) cells. Proliferation was assessed using the cell counting kit-8, colony formation, and EdU assays. Mitochondrial membrane potential was evaluated through JC-1 staining. Cell cycle distribution, apoptosis, and reactive oxygen species (ROS) levels were analyzed by flow cytometry, while migration was assessed using wound healing and Transwell assays. Western blotting was performed to determine protein expression levels. The antitumor efficacy of V9302 in vivo was evaluated using a xenograft mouse model with PC-9 cells. The results demonstrated that V9302 inhibited cell proliferation and induced G1-phase arrest in human lung adenocarcinoma PC-9 and A549 cells. Western blotting showed that V9302 significantly inhibited the ASCT2 protein expression in both PC-9 and A549 cells. Additionally, V9302 promoted apoptosis through a mitochondrial-dependent pathway, as evidenced by elevated levels of cleaved PARP, cleaved Caspase 3, cleaved Caspase 9, and Bax. V9302 also suppressed cell migration by downregulating N-cadherin and vimentin expression. Notably, V9302 triggered significant ROS accumulation and inhibited mTOR/p70S6K pathway activation, an effect that was partially restored by N-acetylcysteine, a ROS scavenger. Pretreatment with mTOR activator MHY1485 mitigated the inhibitory effects of V9302 on cell proliferation and migration, as well as its induction of apoptosis. Furthermore, V9302 inhibited tumor growth and induced apoptosis in a xenograft mouse model, without inducing detectable visceral toxicity. In conclusion, these findings demonstrate that V9302 reduces cell proliferation and migration, and causes apoptosis through the ROS-mediated mTOR/p70S6K pathway in NSCLC cells. These findings provide a novel theoretical foundation for advancing both academic and clinical research on NSCLC treatment.
    DOI:  https://doi.org/10.4149/neo_2026_251028N451
  17. J Adv Res. 2026 Apr 12. pii: S2090-1232(26)00338-3. [Epub ahead of print]
    A "DUBTAC" targeting GLUL deubiquitination promotes BMSC osteogenic differentiation and implant osseointegration in type 2 diabetes.
    Lingxiao Wang, Zhanqiu Diao, Wanqing Wang, Yishu Huang, Yang Liu, Zhenhua Gao, Pan Ma, Zhaochen Shan, Jun Li, Zhipeng Fan.
       INTRODUCTION: Osseointegration in patients with type 2 diabetes mellitus (T2DM) is poor, and overcoming osseointegration impairment safely and efficiently remains challenging.
    OBJECTIVES: To investigate the effect and process of GLUL on the osteogenic differentiation and osseointegration in T2DM by using BMSCs.
    METHODS: Human BMSCs were used for osteogenic differentiation in vitro and vivo, while C57BL/6 mice and GK male rats were used for in vivo osseointegration study. Cell transfection, western blotting, coimmunoprecipitation test, microscopic thermography, transcriptome sequencing and bioinformatic analysis favored in discovery of potential target protein and specific sites.
    RESULTS: The expression of glutamine synthetase (GLUL) is downregulated in the jawbone-derived BMSCs of T2DM patients. In this study, we found that GLUL protein homeostasis is important for the osteogenic differentiation of BMSCs and implant osseointegration. Synovial cell apoptosis inhibitor 1 (SYVN1) mediates the ubiquitination of GLUL protein at K259/334A, reducing GLUL protein expression and affecting the osteogenic differentiation of BMSCs. On this basis, we developed a GLUL-DUBTAC called HY-X3369, which is linked by the GLUL ligand HY-126351 and the covalent ligand of the deubiquitinase OTUB1 to target the GLUL ubiquitination site and reduce GLUL ubiquitination. Through pathway degradation, HY-X3369 maintains the protein homeostasis of GLUL in T2DM. HY-X3369 promotes the osteogenic differentiation of jawbone BMSCs from T2DM patients and inhibits GLUL degradation. In vivo evaluation further confirmed that HY-X3369 promotes osseointegration in GK rats.
    CONCLUSIONS: This study reveals a promising strategy involving HY-X3369 to promote the function of BMSCs and osseointegration in T2DM, providing a theoretical basis and candidate methods for improving osseointegration in T2DM patients.
    Keywords:  Bone marrow mesenchymal stem cells; DUBTAC; GLUL; SYVN1; Ubiquitination
    DOI:  https://doi.org/10.1016/j.jare.2026.04.034
  18. Oncogene. 2026 Apr 13.
    Dual inhibition of glycolysis and glutaminolysis by targeting FOXO3 for hepatocellular carcinoma treatment.
    Fan Wang, Meng Huang, Kaixuan Sheng, Yue Yan, Beibei Zhang, Xinlei Wang, Zhiyi Yang, Mengyi Li, Yuping Liu, Qi Qi, Yuejun Sun, Chenglin Li.
      Metabolic reprogramming is a hallmark of tumorigenesis and progression in hepatocellular carcinoma (HCC) and has emerged as a promising therapeutic strategy. Forkhead box O3 (FOXO3), a critical nuclear transcription factor, is dysregulated in multiple cancers; however, its precise role in HCC progression remains unclear. In this study, we demonstrate that enhanced glycolysis and glutaminolysis are pivotal metabolic features of HCC, with tumor cells heavily relying on both pathways for survival and proliferation. We identify FOXO3 as a tumor suppressor in HCC that inhibits key metabolic enzymes and metabolites involved in these pathways. This inhibitory effect is mediated through suppression of yes-associated protein (YAP). Mechanistically, FOXO3 directly binds to the GTGAACAT motif (-1824 to -1817) within the YAP promoter, leading to transcription repression of YAP and subsequent disruption of YAP-driven metabolic programs. Pharmacological activation of FOXO3 using specific inducers markedly reduced YAP expression, resulting in inhibition of glycolysis, glutaminolysis, and proliferation in HCC cells. In vivo, activation of the FOXO3/YAP axis effectively suppressed HCC progression through the coordinated inhibition of glycolysis and glutaminolysis. Moreover, FOXO3 inducers significantly impaired the growth and viability of patient-derived HCC organoid models. Hence, these findings identify FOXO3 as a key regulator of metabolic reprogramming in HCC and establish the FOXO3/YAP axis as a promising therapeutic target, suggesting potential strategies for metabolic-based interventions in HCC treatment.
    DOI:  https://doi.org/10.1038/s41388-026-03765-1
  19. Sci Bull (Beijing). 2026 Apr 06. pii: S2095-9273(26)00365-8. [Epub ahead of print]
    Hepatic IFRD1 suppresses metabolic dysfunction-associated fatty liver disease via GLUD1/α-KG axis.
    Mengya Geng, Fanzheng Meng, Hairui Li, Lijie Sun, Xuedan Sun, Yu Ding, Rongdongqing Shi, Zhihua Wang, Yabin Huang, Jizhou Wang, Yao Liu, Jiabei Wang, Peter J Little, Suowen Xu, Lianxin Liu, Jianping Weng, Sihui Luo.
      The mechanisms underlying metabolic remodeling in metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear. Targeting the process of de novo lipogenesis (DNL) in the liver has the potential to mitigate MASLD. Here we show that interferon-related developmental regulator 1 (IFRD1) expression negatively correlates with MASLD/metabolic-associated steatohepatitis (MASH) progression in human liver tissues. In multiple mouse models, Ifrd1-/- mice exhibit an exacerbated MASLD phenotype, while hepatocyte-specific IFRD1 expression suppresses MASH progression. Mechanistically, IFRD1 promotes GLUD1's mitochondrial localization via direct interaction, stabilizing the enzyme's activity to enhance α-ketoglutarate (α-KG) production. α-KG reduces H3K36me3 level at lipogenic genes, thereby inhibiting DNL and ameliorating MASH. α-KG supplementation reverses MASH exacerbation in Ifrd1-CKO mice. Collectively, our research establishes the IFRD1-GLUD1-α-KG axis as a critical metabolic-epigenetic regulatory hub, providing novel targets for inhibiting hepatic DNL and developing therapeutic agents for MASLD/MASH.
    Keywords:  GLUD1; H3K36me3; IFRD1; Mitochondria
    DOI:  https://doi.org/10.1016/j.scib.2026.04.016
  20. Tumour Virus Res. 2026 Apr 09. pii: S2666-6790(26)00006-6. [Epub ahead of print]21 200342
    Oncolytic virus hijacks GOT1 and pyrimidinosomes to fuel pyrimidine synthesis for replication in tumor cells.
    Ning Tang, Yabin Gong, Changrun Zhao, Yujia Niu, Lei Tan, Cuiping Song, Xusheng Qiu, Ying Liao, Shengqing Yu, Chan Ding, Shuhai Lin, Yingjie Sun.
      Oncolytic viruses selectively infect and kill tumor cells, but the metabolic adaptations that support their replication remain incompletely understood. Here, using oncolytic Newcastle disease virus (NDV) as a model, we identify glutamic-oxaloacetic transaminase 1 (GOT1) as a key metabolic enzyme required for efficient viral replication through its dual role in de novo pyrimidine synthesis. In NDV-infected tumor cells, GOT1 promotes aspartate production through the malate-aspartate shuttle to support pyrimidine biosynthesis, while also maintaining NAD+/NADH homeostasis to activate the mTOR-S6K-CAD signaling axis and further enhance pyrimidine synthesis. These GOT1-dependent metabolic and signaling adaptations sustain pyrimidine biosynthesis and viral replication. In addition, NDV infection promotes pyrimidinosome assembly, and GOT1 functions as a pyrimidinosome-associated component. Together, these findings reveal a mechanism by which oncolytic NDV rewires host pyrimidine metabolism to support its replication and provide a rationale for metabolic modulation of oncolytic virotherapy.
    Keywords:  CAD; GOT1; NAD(+)/NADH; Oncolytic newcastle disease virus; Pyrimidine synthesis; Pyrimidinosome
    DOI:  https://doi.org/10.1016/j.tvr.2026.200342
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