bims-glucam 2025-03-23 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–03–23
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Nutrient transporter-oriented nanoinhibitor counteracts intracellular metabolic reprogramming for RT-resistant HCC treatment.
Targeting ncRNAs to overcome metabolic reprogramming‑mediated drug resistance in cancer (Review).
CircPVT1 weakens miR-33a-5p unleashing the c-MYC/GLS1 metabolic axis in breast cancer.
A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity.
An innovative glutamine metabolism-related gene signature for predicting prognosis and immune landscape in cervical cancer.
Teriparatide facilitates osteogenic differentiation of bone mesenchymal stem cells to alleviate idiopathic osteoporosis via the circFNDC3B-miR-125a-5p-GLS axis.
Metabolic mechanisms of immunotherapy resistance.
Hafnium Metal-Organic Framework-Based Glutamine Metabolism Disruptor For Potentiating Radio-Immunotherapy in MYC-Amplified Hepatocellular Carcinoma.
Role of the sulfur-containing amino acid-ROS axis in cancer chemotherapeutic drug resistance.
Disrupted Minor Intron Splicing Activates Reductive Carboxylation-mediated Lipogenesis to Drive Metabolic Dysfunction-associated Steatotic Liver Disease Progression.
Metabolic regulation of amino acids provides an important basis for individualized nutritional therapy for patients with gastric cancer during the perioperative period.
Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.
Identification of metabolite biomarkers for pancreatic neuroendocrine tumors using a metabolomic approach.
The tumor microenvironment is an ecosystem sustained by metabolic interactions.

Mater Today Bio. 2025 Apr;31 101608

Nutrient transporter-oriented nanoinhibitor counteracts intracellular metabolic reprogramming for RT-resistant HCC treatment.

Yuehua Wang, Zhenjie Wang, Mengnan Liu, Chaojie Chen, Qiye Xi, Jingwen Tang, Zhiqiang Yu, Shengtao Wang, Ling Yu, Meng Yu.

  Radiotherapy (RT) is the primary treatment modality for hepatocellular carcinoma (HCC). Inevitably, the X-ray exposure also increases the metabolic stress and energy demands in surviving tumor cells, which leads to metabolic reprogramming that reduces the sensitivity of HCC to clinical treatments including RT. Nevertheless, the current research in tumor metabolic therapy predominantly focuses on inhibiting glycolytic pathways, and the consequent metabolic compensation behavior of tumor cells exacerbates the risks of drug resistance and recurrence. To address this challenge, we innovatively proposed a tumor-specific multi-metabolic pathway regulation strategy navigated by tumor cell surface nutrient transporter (2-DG/BP MRs), which can be triggered by X-ray radiation to achieve dual blockade of glycolysis and glutamine metabolism pathways. Thus, this nanosystem reconfigured metabolic pathways within tumor cells to counteract RT-induced metabolic reprogramming through dual metabolic inhibition (glycolysis and glutamine metabolism). This approach disrupted the essential energy supply required for cancer cell proliferation without causing metabolic disorders in normal cells, thereby sensitizing HCC to RT. This tumor cell-specific metabolic intervention strategy provides a safe and effective approach for combination therapy in clinically RT-resistant tumors.

Keywords:  Nanomedicine; ROS; Responsive drug release; Tumor microenvironment; Tumor therapy

DOI:  https://doi.org/10.1016/j.mtbio.2025.101608
Int J Oncol. 2025 May;pii: 35. [Epub ahead of print]66(5):

Targeting ncRNAs to overcome metabolic reprogramming‑mediated drug resistance in cancer (Review).

Junxin Li, Yanyu Li, Lin Fu, Huiling Chen, Fei Du, Zhongshu Wang, Yan Zhang, Yu Huang, Jidong Miao, Yi Xiao.

  The emergence of resistance to antitumor drugs in cancer cells presents a notable obstacle in cancer therapy. Metabolic reprogramming is characterized by enhanced glycolysis, disrupted lipid metabolism, glutamine dependence and mitochondrial dysfunction. In addition to promoting tumor growth and metastasis, metabolic reprogramming mediates drug resistance through diverse molecular mechanisms, offering novel opportunities for therapeutic intervention. Non‑coding RNAs (ncRNAs), a diverse class of RNA molecules that lack protein‑coding function, represent a notable fraction of the human genome. Due to their distinct expression profiles and multifaceted roles in various cancers, ncRNAs have relevance in cancer pathophysiology. ncRNAs orchestrate metabolic abnormalities associated with drug resistance in cancer cells. The present review provides a comprehensive analysis of the mechanisms by which metabolic reprogramming drives drug resistance, with an emphasis on the regulatory roles of ncRNAs in glycolysis, lipid metabolism, mitochondrial dysfunction and glutamine metabolism. Furthermore, the present review aimed to discuss the potential of ncRNAs as biomarkers for predicting chemotherapy responses, as well as emerging strategies to target ncRNAs that modulate metabolism, particularly in the context of combination therapy with anti‑cancer drugs.

Keywords:  drug‑resistant; ferroptosis; glutamine; glycolysis; lipid metabolism; mitochondrion; non‑coding RNA

DOI:  https://doi.org/10.3892/ijo.2025.5741
J Exp Clin Cancer Res. 2025 Mar 20. 44(1): 100

CircPVT1 weakens miR-33a-5p unleashing the c-MYC/GLS1 metabolic axis in breast cancer.

Alina Catalina Palcau, Claudio Pulito, Valentina De Pascale, Luca Casadei, Mariacristina Valerio, Andrea Sacconi, Valeria Canu, Daniela Rutigliano, Sara Donzelli, Federica Lo Sardo, Francesca Romana Auciello, Fulvia Pimpinelli, Paola Muti, Claudio Botti, Sabrina Strano, Giovanni Blandino.

   BACKGROUND: Altered metabolism is one of the cancer hallmarks. The role of circRNAs in cancer metabolism is poorly studied. Specifically, the impact of circPVT1, a well-known oncogenic circRNA on triple negative breast cancer metabolism is mechanistically underexplored.
METHODS: The clinical significance of circPVT1 expression levels was assessed in human breast cancer samples using digital PCR and the cancer genome atlas (TCGA) dataset. The oncogenic activity of circPVT1 was assessed in TNBC cell lines and in MCF-10 A breast cell line by either ectopic expression or depletion of circPVT1 molecule. CircPVT1 mediated metabolic perturbation was assessed by 1 H-NMR spectroscopy metabolic profiling. The binding of circPVT1 to miR-33a-5p and c-Myc recruitment onto the Glutaminase gene promoter were assessed by RNA immunoprecipitation and chromatin immunoprecipitation assays, respectively. The circPVT1/miR-33a-5p/Myc/GLS1 axis was functionally validated in breast cancer patients derived organoids. The viability of 2D and PDO cell models was assessed by ATP light assay and Opera Phenix plus high content screening.
RESULTS: We initially found that the expression of circPVT1 was significantly higher in tumoral tissues than in non-tumoral breast tissues. Basal like breast cancer patients with higher levels of circPVT1 exhibited shorter disease-free survival compared to those with lower expression. CircPVT1 ectopic expression rendered fully transformed MCF-10 A immortalized breast cells and increased tumorigenicity of TNBC cell lines. Depletion of endogenous circPVT1 reduced tumorigenicity of SUM-159PT and MDA-MB-468 cells. 1 H-NMR spectroscopy metabolic profiling of circPVT1 depleted breast cancer cell lines revealed reduced glycolysis and glutaminolitic fluxes. Conversely, MCF-10 A cells stably overexpressing circPVT1 exhibited increased glutaminolysis. Mechanistically, circPVT1 sponges miR-33a-5p, a well know metabolic microRNA, which in turn releases c-MYC activity promoting transcriptionally glutaminase. This activity facilitates the conversion of glutamine to glutamate. CircPVT1 depletion synergizes with GLS1 inhibitors BPTES or CB839 to reduce cell viability of breast cancer cell lines and breast cancer-derived organoids.
CONCLUSIONS: In aggregate, our findings unveil the circPVT1/miR-33a-5p/Myc/GLS1 axis as a pro-tumorigenic metabolic event sustaining breast cancer transformation with potential therapeutic implications.

Keywords:  Breast cancer; MYC; Metabolism; Non-coding RNAs; Patients derived organoids

DOI:  https://doi.org/10.1186/s13046-025-03355-1
Bioact Mater. 2025 Jun;48 493-509

A micro-metabolic rewiring assay for assessing hypoxia-associated cancer metabolic heterogeneity.

Jeong Min Oh, Tianze Guo, Hydari Masuma Begum, Saci-Elodie Marty, Liang Sha, Cem Kilic, Hao Zhou, Yali Dou, Keyue Shen.

  Cancer metabolism plays an essential role in therapeutic resistance, where significant inter- and intra-tumoral heterogeneity exists. Hypoxia is a prominent driver of metabolic rewiring behaviors and drug responses. Recapitulating the hypoxic landscape in the tumor microenvironment thus offers unique insights into heterogeneity in metabolic rewiring and therapeutic responses, to inform better treatment strategies. There remains a lack of scalable tools that can readily interface with imaging platforms and resolve the heterogeneous behaviors in hypoxia-associated metabolic rewiring. Here we present a micro-metabolic rewiring (μMeRe) assay that provides the scalability and resolution needed to characterize the metabolic rewiring behaviors of different cancer cells in the context of hypoxic solid tumors. Our assay generates hypoxia through cellular metabolism without external gas controls, enabling the characterization of cell-specific intrinsic ability to drive hypoxia and undergo metabolic rewiring. We further developed quantitative metrics that measure the metabolic plasticity through phenotypes and gene expression. As a proof-of-concept, we evaluated the efficacy of a metabolism-targeting strategy in mitigating hypoxia- and metabolic rewiring-induced chemotherapeutic resistance. Our study and the scalable platform thus lay the foundation for designing more effective cancer treatments tailored toward specific metabolic rewiring behaviors.

Keywords:  Hypoxia; Metabolic rewiring; Metabolism-targeting therapy; Tumor heterogeneity; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bioactmat.2025.02.030
Discov Oncol. 2025 Mar 20. 16(1): 368

An innovative glutamine metabolism-related gene signature for predicting prognosis and immune landscape in cervical cancer.

Hai-Ya Fang, Li-Mei Ji, Cui-Hua Hong.

   BACKGROUND: Cervical cancer (CC) is a major global malignancy affecting women. However, the precise mechanisms underlying glutamine's role in CC remain inadequately understood. This study systematically assessed the survival outcomes, immune landscape, and drug sensitivity profiles with CC patients by analyzing genes associated with glutamine metabolism.
METHODS: Transcriptomic data for the samples were sourced from the TCGA, GTEx, and GEO databases. Prognostic genes were identified through univariate, multivariate, and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses. The predictive accuracy of the model was assessed through the analysis of receiver operating characteristic (ROC) curves. A comprehensive nomogram was developed and evaluated for accuracy using calibration and Decision Curve Analysis (DCA) curves. Kaplan-Meier (K-M) survival curves were employed to estimate overall survival. The relationship between risk scores and immune infiltration was analyzed through Single-sample Gene Set Enrichment Analysis (ssGSEA) and CIBERSORT. Functional enrichment analysis and the construction of miRNA and transcription factors networks were conducted to explore the potential molecular mechanisms of the signature genes.
RESULTS: This investigation identified four signature genes associated with glutamine metabolism, UCP2, LEPR, TFRC, and RNaseH2A. We successfully developed a prognostic model with strong predictive performance. In the training set, the AUC values for 1-, 3-, and 5-year survival were 0.702, 0.719, and 0.721, respectively. In the validation set, the AUC values for these time points were 0.715, 0.696, and 0.739, respectively. Patients categorized as low-risk had notably improved survival rates than those identified as high-risk (P < 0.05). Additionally, a nomogram that combines clinical data and risk scores offered improved clinical net benefits over a broad range of threshold probabilities. Functional enrichment analysis revealed that these signature genes are strongly linked to the regulation of the cell cycle and intracellular oxygen levels. Furthermore, the gene signature displayed a significant negative correlation with the infiltration levels of most immune cell types.
CONCLUSION: This novel signature demonstrates robust predictive capability for prognostic survival probabilities and immune infiltration in CC patients, providing a fresh perspective for advancing precision treatment strategies in CC.

Keywords:  Cervical cancer; Glutamine metabolism; Prognosis; Risk score

DOI:  https://doi.org/10.1007/s12672-025-02109-x
BMC Musculoskelet Disord. 2025 Mar 17. 26(1): 268

Teriparatide facilitates osteogenic differentiation of bone mesenchymal stem cells to alleviate idiopathic osteoporosis via the circFNDC3B-miR-125a-5p-GLS axis.

Jiaxin Fu, Zhi Liu, Guangxin Zhang, Chun Zhang.

  Osteoporosis (OP), a systemic bone disease, is characterized by degeneration of bone microstructure and susceptibility to fracture. Teriparatide (TPD) is an active fragment of human endogenous parathyroid hormone which has been revealed to promote osteogenesis of mesenchymal stem cells (hMSCs) to alleviate osteoporosis. Currently, the underlying cellular and molecular mechanisms of TPD in treating OP were not fully understood. This study aimed to investigate the roles of non-coding RNA-regulated osteogenic differentiation of hMSCs under TPD treatments. Circular RNA FNDC3B was significantly downregulated, and miRNA-125a-5p was upregulated in primary hMSCs of osteoporosis patients. Moreover, during osteogenesis, expression of circFNDC3B and glutamine metabolism were gradually elevated and miR-125a-5p was suppressed. Silencing circFNDC3B or overexpression of miR-125a-5p remarkedly suppressed the TPD-induced osteogenic differentiation-related genes (ALP, RUNX2, osteocalcin, osteonectin) activity or expression and calcium deposition of hMSCs. Results from RNA pull-down, RNA IP and luciferase assays demonstrated that circFNDC3B sponged miR-125a-5p, which further targeted 3'UTR of glutaminase (GLS), a key enzyme in glutamine metabolism to form a ceRNA regulator network. Rescue experiments demonstrated under TPD treatment, silencing of circFNDC3B significantly upregulated miR-125a-5p expression, blocked GLS expression and inhibited osteogenic differentiation evidenced by the suppressed ALP activity and expressions of osteocalcin, osteonectin and RUNX2. These regulatory phenotypes were further overridden by miR-125a-5p inhibition. In summary, our study demonstrated that TPD treatment promoted osteogenic differentiation of hMSCs by regulating the circFNDC3B-miR-125a-5p-GLS pathway.

Keywords:  Circular RNA; Glutamine metabolism; Osteogenic differentiation; Osteoporosis; Teriparatide

DOI:  https://doi.org/10.1186/s12891-025-08505-2
Explor Target Antitumor Ther. 2025 ;6 1002297

Metabolic mechanisms of immunotherapy resistance.

Luis Cabezón-Gutiérrez, Magda Palka-Kotlowska, Sara Custodio-Cabello, Beatriz Chacón-Ovejero, Vilma Pacheco-Barcia.

  Immunotherapy has revolutionized cancer treatment, yet its efficacy is frequently compromised by metabolic mechanisms that drive resistance. Understanding how tumor metabolism shapes the immune microenvironment is essential for developing effective therapeutic strategies. This review examines key metabolic pathways influencing immunotherapy resistance, including glucose, lipid, and amino acid metabolism. We discuss their impact on immune cell function and tumor progression, highlighting emerging therapeutic strategies to counteract these effects. Tumor cells undergo metabolic reprogramming to sustain proliferation, altering the availability of essential nutrients and generating toxic byproducts that impair cytotoxic T lymphocytes (CTLs) and natural killer (NK) cell activity. The accumulation of lactate, deregulated lipid metabolism, and amino acid depletion contribute to an immunosuppressive tumor microenvironment (TME). Targeting metabolic pathways, such as inhibiting glycolysis, modulating lipid metabolism, and restoring amino acid balance, has shown promise in enhancing immunotherapy response. Addressing metabolic barriers is crucial to overcoming immunotherapy resistance. Integrating metabolic-targeted therapies with immune checkpoint inhibitors may improve clinical outcomes. Future research should focus on personalized strategies to optimize metabolic interventions and enhance antitumor immunity.

Keywords:  Immune resistance; cancer; metabolism; tumor microenvironment

DOI:  https://doi.org/10.37349/etat.2025.1002297
ACS Appl Mater Interfaces. 2025 Mar 21.

Hafnium Metal-Organic Framework-Based Glutamine Metabolism Disruptor For Potentiating Radio-Immunotherapy in MYC-Amplified Hepatocellular Carcinoma.

Haofan Hu, Shangwu Ning, Furong Liu, Ze Zhang, Weifeng Zeng, Yachong Liu, Zhibin Liao, Hongwei Zhang, Zhanguo Zhang.

  Hepatocellular carcinoma (HCC) with MYC oncogene amplification remains a serious challenge in clinical practice. Recent advances in comprehensive treatment strategies, particularly the combination of radiotherapy and immunotherapy, offer new hope. To further improve efficacy while lowering radiation doses, nanopharmaceuticals based on high-Z elements have been extensively studied in radio-immunotherapy. In this work, a hafnium-based metal-organic framework (Hf-MOF), UiO-66-Hf(2OH)-CB-839/BSO@HA (UiO-66-Hf(2OH)-C/B@HA), was designed to codeliver telaglenastat (CB-839) and buthionine sulfoximine (BSO), which synergistically inhibited glutamine metabolism and alleviated tumor hypoxia. Further modification with hyaluronic acid (HA) enhanced tumor targeting, ultimately strengthening the efficacy of radiotherapy in MYC-amplified HCC. Beyond increasing reactive oxygen species (ROS) generation, promoting DNA damage, and inducing tumor apoptosis, more importantly, UiO66-Hf(2OH)-C/B@HA triggered immunogenic cell death (ICD), driving the antitumor immune response. Combination with immune checkpoint blockade (ICB) further enhanced the efficacy, accompanied by increased infiltration of T cells with high granzyme B expression (GZMB+ T cells) within the tumor microenvironment (TME). In the orthotopic HCC model, established with MYC-amplified tumor cells, intravenous administration of UiO66-Hf(2OH)-C/B@HA significantly potentiated the efficacy of radio-immunotherapy, resulting in superior tumor regression. In summary, our study provides insights into the design of Hf-MOF for radio-immunotherapy and proposes a promising therapeutic approach for MYC-amplified HCC.

Keywords:  GLS1; MYC-amplified HCC; glutamine metabolism; radio-immunotherapy

DOI:  https://doi.org/10.1021/acsami.4c21998
Drug Resist Updat. 2025 Mar 12. pii: S1368-7646(25)00038-X. [Epub ahead of print]81 101238

Role of the sulfur-containing amino acid-ROS axis in cancer chemotherapeutic drug resistance.

Bingli Wu, Yinwei Cheng, Liyan Li, Zepeng Du, Qianlou Liu, Xinyue Tan, Xin Li, Guozhi Zhao, Enmin Li.

  Chemotherapeutic drug resistance remains a major barrier to effective cancer treatment. Drug resistance could be driven in part by adaptive redox remodeling of cancer cells. Paradoxically, drug-resistant malignancies exhibit elevated reactive oxygen species (ROS), as well as amplified antioxidant defenses, which enable cancer cell survival under therapeutic stress. Central to this adaptation is glutathione (GSH), the predominant cellular antioxidant, whose synthesis relies on sulfur-containing amino acids (SAAs) - methionine and cysteine. This review delineates the metabolic interplay between methionine and cysteine in the transsulfuration pathway, highlighting their roles as precursors in GSH biosynthesis. We systematically summarize the key enzymes that drive GSH production and their contributions to resistance against platinum-based drugs and other chemotherapeutics. In addition to GSH synthesis, we summarize the roles of GSH antioxidant systems, including glutathione peroxidases (GPXs), peroxiredoxins (PRDXs), and thioredoxins (TRXs), which are critical in chemotherapeutic drug resistance through ROS scavenging. Recent advances reveal that targeting these enzymes, by pharmacologically inhibiting transsulfuration enzymes or disrupting GSH-dependent antioxidant cascades, can sensitize resistant cancer cells to ROS-mediated therapies. These findings not only clarify the mechanistic links between SAA metabolism and redox adaptation but also provide practical approaches to overcome chemotherapeutic drug resistance. By analyzing metabolic and redox vulnerabilities, this review highlights the therapeutic potential to restore chemosensitivity, offering new options in precision oncology medicine.

Keywords:  Antioxidant proteins; Chemotherapeutic drug resistance; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.drup.2025.101238
J Clin Invest. 2025 Mar 18. pii: e186478. [Epub ahead of print]

Disrupted Minor Intron Splicing Activates Reductive Carboxylation-mediated Lipogenesis to Drive Metabolic Dysfunction-associated Steatotic Liver Disease Progression.

Yinkun Fu, Xin Peng, Hongyong Song, Xiaoyun Li, Yang Zhi, Jieting Tang, Yifan Liu, Ding Chen, Wenyan Li, Jing Zhang, Jing Ma, Ming He, Yimin Mao, Xu-Yun Zhao.

  Aberrant RNA splicing is tightly linked to diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we revealed that minor intron splicing, a unique and conserved RNA processing event, is largely disrupted upon the progression of metabolic dysfunction-associated steatohepatitis (MASH) in mice and humans. We demonstrated deficiency of minor intron splicing in the liver induces MASH transition upon obesity-induced insulin resistance and LXR activation. Mechanistically, inactivation of minor intron splicing leads to minor intron retention of Insig1 and Insig2, resulting in premature termination of translation, which drives proteolytic activation of SREBP1c. This mechanism is conserved in human patients with MASH. Notably, disrupted minor intron splicing activates glutamine reductive metabolism for de novo lipogenesis through the induction of Idh1, which causes the accumulation of ammonia in the liver, thereby initiating hepatic fibrosis upon LXR activation. Ammonia clearance or IDH1 inhibition blocks hepatic fibrogenesis and mitigates MASH progression. More importantly, the overexpression of Zrsr1 restored minor intron retention and ameliorated the development of MASH, indicating that dysfunctional minor intron splicing is an emerging pathogenic mechanism that drives MASH progression. Additionally, reductive carboxylation flux triggered by minor intron retention in hepatocytes serves as a crucial checkpoint and potential target for MASH therapy.

Keywords:  Amino acid metabolism; Fibrosis; Hepatology; Metabolism; RNA processing

DOI:  https://doi.org/10.1172/JCI186478
World J Surg Oncol. 2025 Mar 14. 23(1): 89

Metabolic regulation of amino acids provides an important basis for individualized nutritional therapy for patients with gastric cancer during the perioperative period.

Zhening Guo, Zheng Xiang, Wenzhao Su, Bo Lv, Qinhong Zhao, Wen Zhang, Rui Ren, Wei Peng, Cunjin Su, Yongyou Wu, Jie Pan.

   BACKGROUND: Gastric cancer is a prevalent malignancy worldwide, with early detection and treatment being vital to improving patient outcomes. Amino acids (AAs), as essential regulators in cancer cell metabolism, are implicated in the progression and response to treatment.
METHODS: This study aimed to investigate the dynamics of plasma AA levels in gastric cancer patients preoperatively, postoperatively, and following nutritional intervention, comparing them to healthy controls. We analyzed 22 AAs in plasma samples from 66 gastric cancer patients and 55 healthy individuals.
RESULTS: The results show that significant preoperative elevation of AAs, such as threonine (Thr), serine (Ser), proline (Pro), lysine (Lys), arginine (Arg), citrulline (Cit), glutamine (Gln), glycine(Gly), and alanine (Ala), with reductions in taurine (Tau), phenylalanine (Phe) and hydroxylysine (Hylys). Post-surgery, levels of many AAs decreased markedly, but were partially restored following nutritional intervention, with some exceeding preoperative values. Nevertheless, specific AAs, including methionine (Met) and Gln, remained lower than in healthy controls, suggesting potential benefit from targeted supplementation. Correlations between AA changes and postoperative recovery indicators were observed; notably, increased postoperative Thr, Ser, Tau, tyrosine (Tyr), glutamic acid (Glu), and Hylys levels were associated with quicker gastrointestinal recovery. Additionally, several AAs, such as Pro, Lys, Tyr, Met, Cit, and Glu, were linked to reduced inflammation, as reflected by C-reactive protein (CRP) and white blood cell (WBC) levels, suggesting roles in the postoperative immune response. Pathway enrichment analysis highlighted metabolic pathways involving Gly, Ser, Phe, Tyr, Lys, and Met as critical in the recovery process.
CONCLUSIONS: These findings underscore the potential of AA profiles as biomarkers for postoperative recovery and suggest nutritional interventions targeting specific AAs may improve outcomes.

Keywords:  Amino acids profiles; Biomarker; Gastric cancer; Nutritional intervention; Perioperative recovery

DOI:  https://doi.org/10.1186/s12957-025-03729-x
bioRxiv. 2025 Mar 07. pii: 2025.03.03.641255. [Epub ahead of print]

Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.

Ayşegül Erdem, Séléna Kaye, Francesco Caligiore, Manuel Johanns, Fleur Leguay, Jan Jacob Schuringa, Keisuke Ito, Guido Bommer, Nick van Gastel.

Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD+. We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry. Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD+ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD+/NADH ratio in AML cells. Continuous intracellular NAD+ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition. Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD+/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD+ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells.

DOI: https://doi.org/10.1101/2025.03.03.641255
Eur J Endocrinol. 2025 Mar 19. pii: lvaf055. [Epub ahead of print]

Identification of metabolite biomarkers for pancreatic neuroendocrine tumors using a metabolomic approach.

Arnaud Jannin, Sophie Dabo-Niang, Christine Do Cao, Amandine Descat, Stéphanie Espiard, Catherine Cardot-Bauters, Marie-Christine Vantyghem, Benjamin Chevalier, Jean François Goossens, Benjamin Marsac, Jimmy Vandael, Sophie Dominguez, Robert Caiazzo, François Pattou, Camille Marciniak, Medhi El Amrani, Isabelle Van Seuningen, Nicolas Jonckheere, Anne-Frédérique Dessein, Lucie Coppin.

   OBJECTIVE: Metabolic flexibility, a key hallmark of cancer, reflects aberrant tumor changes associated with metabolites. The metabolic plasticity of pancreatic neuroendocrine tumors (pNETs) remains largely unexplored. Notably, the heterogeneity of pNETs complicates their diagnosis, prognosis, and therapeutic management. Here, we compared the plasma metabolomic profiles of patients with pNET and non-cancerous individuals to understand metabolic dysregulation.
DESIGN AND METHODS: Plasma metabolic profiles of 76 patients with pNETs and 38 non-cancerous individuals were analysed using LC-MS/MS and FIA-MS/MS (Biocrates AbsoluteIDQ p180 kit). Statistical analyses, including univariate and multivariate methods, were performed along with the generation of receiver operating characteristic (ROC) curves for metabolomic signature identification.
RESULTS: Compared to non-cancerous individuals, patients with pNET exhibited elevated levels of phosphoglyceride metabolites and reduced acylcarnitine levels, indicating an upregulation of fatty acid oxidation (FAO), which is crucial for the energy metabolism of pNET cells and one-carbon metabolism metabolites. Elevated glutamate levels and decreased lipid metabolite levels have been observed in patients with metastatic pNETs. Patients with the germline MEN1 mutations showed lower amino acid metabolites and FAO, with increased metabolites related to leucine catabolism and lipid metabolism, compared to non-MEN1 mutated patients. The highest area under the ROC curve (AUC) was observed in patients with pNET harbouring MEN1 mutations.
CONCLUSION: This study highlights the distinct plasma metabolic signatures of pNETs, including the critical role of FAO and elevated glutamate levels in metastasis, supporting the energy and biosynthetic needs of rapidly proliferating tumour cells. Mapping of these dysregulated metabolites may facilitate the identification of new therapeutic targets for pNETs management.

Keywords:  MEN1; acylcarnitine; diagnosis biomarkers; glutathione; glycerophospholipid; metabolism; metabolomics; pNET; pancreatic neuroendocrine tumor; sphingolipid

DOI:  https://doi.org/10.1093/ejendo/lvaf055
Cell Rep. 2025 Mar 13. pii: S2211-1247(25)00203-7. [Epub ahead of print]44(3): 115432

The tumor microenvironment is an ecosystem sustained by metabolic interactions.

Emily Jane Kay, Sara Zanivan.

  Cancer-associated fibroblasts (CAFs) and immune cells make up two major components of the tumor microenvironment (TME), contributing to an ecosystem that can either support or restrain cancer progression. Metabolism is a key regulator of the TME, providing a means for cells to communicate with and influence each other, modulating tumor progression and anti-tumor immunity. Cells of the TME can metabolically interact directly through metabolite secretion and consumption or by influencing other aspects of the TME that, in turn, stimulate metabolic rewiring in target cells. Recent advances in understanding the subtypes and plasticity of cells in the TME both open up new avenues and create challenges for metabolically targeting the TME to hamper tumor growth and improve response to therapy. This perspective explores ways in which the CAF and immune components of the TME could metabolically influence each other, based on current knowledge of their metabolic states, interactions, and subpopulations.

Keywords:  CAFs; CP: Cancer; CP: Metabolism; immune cells; metabolism; stroma immune; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2025.115432