bims-glucam 2025-10-05 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–10–05
fifteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting glutaminase C, a splice variant of glutaminase 1, suppresses smooth muscle cell phenotypic modulation and neointimal hyperplasia.
Cancer Metabolism Meets DNA Repair: The Hidden Link to Therapy Resistance.
Glutamine modulates cellular size by regulating Wee1 expression.
Glutamine metabolism and ammonia death: targeted modulation for enhanced cancer immunotherapy.
Panoramic analysis of the biological function and clinical value of SLC38A2 in human cancers: a study based on pan-cancer and single-cell analysis.
Crosstalk Between Metabolic Reprogramming and Epigenetic Modifications in Colorectal Cancer: Mechanisms and Clinical Applications.
Inhibition of microglial glutaminase alleviates chronic stress-induced neurobehavioral and cognitive deficits.
Metabolic plasticity drives specific mechanisms of chemotherapy and targeted therapy resistance in metastatic colorectal cancer.
Genetic variations in amino acid metabolism-related genes are associated with risk of papillary thyroid carcinoma: a case-control study.
Serum metabolic disparity between patients with lymph node tuberculosis and patients with sarcoidosis: towards differential diagnosis.
Clinicopathological analysis of GLUT-1, GLS1, and GLS2 expression in breast cancer tissues from Jordanian patients.
Systematic metabolomic study on the plasma and urine of a mouse model of Alport syndrome.
Role of LXRβ in oligodendrocytes in neuronal survival.
Biallelic variants in BCAT1 impair mitochondrial function and are associated with a candidate neurometabolic disorder.
Proteomic subtyping highlights tumor heterogeneity of human HCC.

Exp Cell Res. 2025 Sep 26. pii: S0014-4827(25)00377-5. [Epub ahead of print]452(2): 114777

Targeting glutaminase C, a splice variant of glutaminase 1, suppresses smooth muscle cell phenotypic modulation and neointimal hyperplasia.

Ankan Sarkar, Bhavneesh Kumar, Ashok K Yadav, Sandip V Pawar, Kanwaljit Chopra, Manish Jain.

  Smooth muscle cell (SMC) phenotypic modulation plays a pivotal role in vascular proliferative disorders. During proliferation, SMCs utilize glutamine to fulfill their energy, biosynthesis, and redox needs. Glutaminase C (GAC), a splice variant of glutaminase (GLS), catalyzes the hydrolysis of glutamine to glutamate, which is ultimately used in the TCA cycle. Although GAC is known to stimulate the proliferation of human cancer cells, endothelial cells, and fibroblasts, its role in SMC proliferation and neointimal hyperplasia remains elusive. This study explores the role of the therapeutic potential of targeting GAC during SMC proliferation and neointimal hyperplasia. To assess the role of GAC on the proliferation of SMCs, murine aortic SMCs were treated with CB-839 (selectively inhibits GAC activity; 10 μM) for 60 min. SMCs were stimulated with Platelet-Derived Growth Factor-BB (PDGF-BB; 20 ng/ml) for 24 h. Using Western blotting and immunofluorescence, we report that GAC expression was significantly higher in SMCs stimulated by PDGF-BB and in the neointima of wire-injured mice as compared to the control. Deprivation of glutamine in the media impeded the proliferation and migration of SMCs. Pretreatment of SMCs with GAC inhibitor reduces PDGF-BB-induced SMC migration, proliferation, and phenotypic switching. GAC inhibition was associated with decreased phosphorylation of ERK and mTOR. GAC translocated to mitochondria and induced oxidative stress. The perivascular application of a GAC inhibitor attenuated injury-induced neointimal hyperplasia. The present study demonstrates that targeting glutamine metabolism by inhibiting GAC reduces SMC proliferation and may be a potential target for reducing neointimal hyperplasia.

Keywords:  Glutaminase C; Glutamine; Neointimal hyperplasia; Restenosis; Smooth muscle cells

DOI:  https://doi.org/10.1016/j.yexcr.2025.114777
Bioessays. 2025 Sep 28. e70073

Cancer Metabolism Meets DNA Repair: The Hidden Link to Therapy Resistance.

Chunzhang Yang.

  Cancer cells exhibit reprogrammed metabolic pathways to sustain aggressive phenotypes, including continuous cell division, stemness, invasion, and metastasis. Emerging evidence suggests that these metabolic adaptations profoundly impact DNA repair pathways, which contribute to the responses to therapy and influence overall outcomes. Metabolic processes such as the Warburg effect, nicotinamide adenine dinucleotide (NAD) metabolism, glutamine metabolism, and one-carbon metabolism support DNA repair by expanding the metabolite pool and facilitating post-translational modifications. Conversely, oncometabolites impair DNA repair pathways through epigenetic reprogramming, thereby promoting genomic instability. This review highlights recent discoveries that elucidate the intricate connections between metabolic hallmarks in cancer cells and DNA repair mechanisms, offering insights into potential therapeutic targets for future cancer treatments.

Keywords:  DNA repair; Warburg effect; cancer metabolism; molecular targeting; oncometabolite

DOI:  https://doi.org/10.1002/bies.70073
Sci Rep. 2025 Oct 03. 15(1): 34513

Glutamine modulates cellular size by regulating Wee1 expression.

Didhiti Singha, Meghna Mondal, Debopriya Choudhury, Pushkar Malakar.

  Glutamine plays a vital role in cellular biomass synthesis, serving as a key nutrient. Cancer profoundly impacts cellular size, promoting rapid proliferation and enhanced survival. Understanding the molecular mechanisms that regulate cell size in cancer is essential for designing interventions that can disrupt these processes and inhibit tumor progression. Polyploid giant cancer cells (PGCCs) represent a distinct subpopulation of tumor cells that are implicated in tumor initiation, immortality, invasion, metastasis, and resistance to chemotherapy and radiotherapy. These cells are characterized by their markedly increased size and polyploidy, underscoring the significance of cell size regulation in cancer biology. Although glutamine is known to influence cell growth, its role in regulating cell size remains poorly understood. Wee1, a key cell cycle regulator, controls the timing of mitotic entry, and is known to modulate cell size by preventing premature division. However, the potential link between glutamine, Wee1, and cell size has not been previously explored. In the present study, we investigated the role of glutamine in regulating cellular size. We found that glutamine depletion results in a significant reduction in cell size, along with decreased Wee1 expression at both mRNA and protein levels. Additionally, transient knockdown of Wee1 also led to a reduction in cellular size, reinforcing its role as a regulator of cell size. Moreover, we observed that cytochalasin-B-induced polyploidy was diminished under glutamine-deprived conditions, further affirming the importance of glutamine in maintaining polyploidy and cell size. Overall, our findings clearly indicate that glutamine is a key mediator of cellular size, and that glutamine regulates cell size at least in part through its influence on Wee1. These insights contribute to a better understanding of metabolic control of cell size in cancer and may offer novel therapeutic opportunities.

Keywords:  And cancer; Cellular size; Glutamine; Polyploidy; Wee1

DOI:  https://doi.org/10.1038/s41598-025-17687-7
Front Immunol. 2025 ;16 1643017

Glutamine metabolism and ammonia death: targeted modulation for enhanced cancer immunotherapy.

Fei Du, Linlin Xiao, Wang Guojun, Qian Dai, Junxin Li, Xin Zhao, Qimin Zhang, Lan Yang, Yujie Liu, Yidan Hu, Bo Wen, Jingqiu Zhou, Jie Dai, Wenhao Zhang, Zhuo Zhang.

  Immunotherapy has rapidly emerged as a transformative advancement in cancer treatment, becoming essential for managing diverse malignancies. Despite the remarkable clinical efficacy of immunotherapies, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR)-T cells, across various tumor types, patient responses remain heterogeneous, with some tumors developing resistance through immune evasion strategies. Presently, the investigation of cell death mechanisms is gaining momentum as a promising avenue for immunotherapy optimization. Recent studies underscore that integrating cell death pathways with immunotherapy can significantly amplify anti-tumor immune responses. Ammonia, a metabolic byproduct within the tumor microenvironment (TME), has garnered increasing interest. Specifically, emerging research suggests that ammonia, accumulating in effector T cells as a result of glutamine metabolism, induces cell death. This distinct form of cell death, termed "ammonia death," diverges from previously characterized mechanisms. This review examines the metabolic role of glutamine in various TME cells, explores the potential regulatory links between glutamine metabolism and ammonia-induced cell death, and evaluates the feasibility of targeting ammonia-induced cell death to enhance anti-tumor immunity and improve immunotherapy outcomes.

Keywords:  CD8+ T cell; ammonia death; glutamine; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1643017
Front Genet. 2025 ;16 1658299

Panoramic analysis of the biological function and clinical value of SLC38A2 in human cancers: a study based on pan-cancer and single-cell analysis.

Mao Liao, Yuqing Rao, Molan Li, Jiayang Guo, Kun Guo, Kaiyue Li, Rui Zheng, Yifan Liu, Qianyi Wang, Manni Wang, Duo Chen, Meng Zhang, Yongfeng Wang, Yanzong Zhao, Sheng Li.

   Background: Glutamine metabolic reprogramming is a hallmark of tumor progression and is highly correlated with poor clinical outcomes. The excessive uptake of glutamine by tumor cells is a key factor contributing to widespread invasion, metastasis, and immune suppression. SLC38A2, an amino acid transporter widely expressed on the surface of tumor cells, has not been thoroughly studied regarding its function and prognostic significance in tumor progression. Our objective is to employ bioinformatics methods to conduct a comprehensive and in-depth analysis of SLC38A2 across various cancers, aiming to elucidate its role and prognostic value in tumor biology.
Methods: By comprehensively incorporating gene expression and clinical data from the TCGA tumor database, GTEx database, Human Protein Atlas, and GEO database, we analyzed the expression profile, mutations, and established prognostic models for SLC38A2 across various cancers. Additionally, we investigated the enrichment of SLC38A2 at the single-cell level in 12 types of cancer and analyzed its temporal expression patterns in different cell subgroups in breast and pancreatic cancer. We also studied the correlation between SLC38A2 and glutathione metabolism.
Results: Compared to normal tissues, SLC38A2 exhibits significant differential expression in 15 types of cancer and serves as a prognostic risk factor in BRCA (HR = 1.597, p < 0.05), LUAD (HR = 1.650, p < 0.01), MESO (HR = 2.007, p < 0.05), and PAAD (HR = 1.761, p < 0.05), while acting as a protective factor in KIRC (HR = 0.625, p < 0.05). Furthermore, SLC38A2 is positively correlated with tumor and stromal cells, negatively correlated with immune cell infiltration, and associated with immune exhaustion. In BRCA, SLC38A2 is highly expressed during early differentiation of malignant and stromal cells, and enriched in late differentiation of immune cells. Moreover, the expression of SLC38A2 shows a general positive correlation with glutathione metabolism genes in BRCA, LUAD, MESO, and PAAD, demonstrating diagnostic value.
Conclusion: SLC38A2 shows widespread changes in expression patterns within tumor tissues, making it an effective diagnostic and prognostic biomarker. It is enriched in malignant cells and tumor-infiltrating stromal cells, while negatively correlated with the infiltration of many cells involved in anti-tumor immunity. Targeting SLC38A2 presents a viable therapeutic strategy by inhibiting glutamine competition and relieving immune suppression in the tumor microenvironment.

Keywords:  cancer; glutamine; metabolic reprogramming; prognosis; single-cell; slc38a2

DOI:  https://doi.org/10.3389/fgene.2025.1658299
Curr Issues Mol Biol. 2025 Sep 12. pii: 751. [Epub ahead of print]47(9):

Crosstalk Between Metabolic Reprogramming and Epigenetic Modifications in Colorectal Cancer: Mechanisms and Clinical Applications.

Yu-Hui Sun, Jing-Xian Zhang, Han-Shu Jin, Jin Huang.

  Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract in developing countries. It exhibits significant metabolic reprogramming and epigenetic abnormalities during its development. These two changes interact at the molecular level and jointly promote the progression of tumor cells. Cancer cells reprogram metabolites such as glucose, glutamine, and lipids to meet their energy and biological substrate requirements for survival. Concurrently, abnormalities in epigenetic modifications drive imbalances in gene expression and sustain the malignant phenotype. More importantly, metabolites can serve as substrates or cofactors for epigenetic enzymes, and changes in metabolic status can induce epigenetic remodeling. Correspondingly, epigenetic mechanisms regulate the transcription and function of metabolism-related genes, leading to adaptive alterations in tumor metabolic pathways. This review systematically summarizes the characteristics of major metabolic pathway reprogramming and the mechanisms underlying key epigenetic abnormalities in CRC. Furthermore, it elaborates on the mechanisms of their mutual influence in signaling pathways, key factors, immunometabolism, and the tumor microenvironment. It also discusses recent advances in novel diagnostic technologies (such as multi-omics integrated diagnostics) and therapeutic strategies (including targeting metabolism, epigenetic therapy, and combination therapies). In the future, research focusing on the interaction between metabolic reprogramming and epigenetics will provide new insights and targets for the early diagnosis and precision treatment of CRC.

Keywords:  CRC; diagnosis; epigenetic modifications; metabolic reprogramming; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.3390/cimb47090751
Neurotherapeutics. 2025 Sep 26. pii: S1878-7479(25)00237-5. [Epub ahead of print] e00759

Inhibition of microglial glutaminase alleviates chronic stress-induced neurobehavioral and cognitive deficits.

Meixiang Huang, Yannan Li, Ajit G Thomas, Anjali Sharma, Wathsala Liyanage, Tomáš Tichý, Lukáš Tenora, Yu Su, Jisu Ha, Niyada Hin, Mizuho Obayashi, Pavel Majer, Rangaramanujam M Kannan, Takashi Tsukamoto, Gianluca Ursini, Rana Rais, Barbara S Slusher, Xiaolei Zhu.

  Major depressive disorder (MDD) is a prevalent and debilitating psychiatric condition with significant societal and economic impacts. Many patients are resistant to current antidepressant therapies, underscoring the need for novel treatments targeting underlying mechanisms. We previously discovered that glutaminase (GLS1), an enzyme converting glutamine to glutamate, is upregulated specifically in activated microglia in mice exposed to Chronic Social Defeat Stress (CSDS). Importantly, GLS1 mRNA was also upregulated in microglia within postmortem brain tissue of MDD patients, highlighting a potential role for microglial GLS1 in MDD pathophysiology. However, existing GLS1 inhibitors lack brain penetrance and/or cause gastrointestinal toxicities, limiting their translational potential. To address this, we utilized a hydroxyl-terminated poly(amidoamine) dendrimer nanoparticle system to selectively target microglial GLS1. Using structurally distinct GLS1 inhibitors, we synthesized two hydroxyl-dendrimer-GLS1 inhibitor conjugates: dendrimer-TTM020 (D-TTM020) and dendrimer-JHU29 (D-JHU29). In the murine CSDS model, we evaluated their microglial target engagement, safety, and efficacy using immunofluorescence, GLS1 activity assays, gastrointestinal histopathology, and a battery of behavioral tests. Using a Cy5 fluorescently labeled hydroxyl-dendrimer (D-Cy5), we confirmed that systemically administered D-Cy5 crossed the blood-brain barrier and was selectively engulfed by activated microglia in mice after CSDS. D-TTM020 and D-JHU29 attenuated CSDS-induced microglial GLS1 activity elevation without affecting non-microglial cells. Furthermore, D-TTM020 and D-JHU29 both alleviated CSDS-induced social avoidance, and D-TTM020 additionally reduced anxiety-like behavior and improved recognition memory. Both conjugates were well tolerated, with no overt or gastrointestinal toxicities. Collectively, these findings suggest that microglia-targeted GLS1 inhibition is a promising therapeutic approach for chronic stress-associated depression.

Keywords:  Chronic social defeat stress; Dendrimer; Depression; Glutaminase; Microglia

DOI:  https://doi.org/10.1016/j.neurot.2025.e00759
Explor Target Antitumor Ther. 2025 ;6 1002337

Metabolic plasticity drives specific mechanisms of chemotherapy and targeted therapy resistance in metastatic colorectal cancer.

Mariam Rojas, Malena Manzi, Sergio Madurga, Fernando Enrique García Velásquez, Maira Alejandra Romero, Silvia Marín, Marta Cascante, Joan Maurel.

  Microsatellite-stable metastatic colorectal cancer (MSS mCRC) is currently treated with chemotherapy and targeted agents based on RAS and BRAF mutational status. Although these therapies offer initial benefit, most patients rapidly develop resistance, with fewer than 20% remaining progression-free at two years. This review aims to synthesize emerging evidence on the metabolic mechanisms driving treatment resistance in MSS mCRC, with a particular focus on the immune-metabolic signature (IMMETCOLS) classification. We conducted a comprehensive review of preclinical models, transcriptomic datasets, and clinical trial results addressing metabolic adaptations to chemotherapy and targeted therapies in MSS mCRC. The IMMETCOLS framework defines three metabolic subtypes-IMC1, IMC2, and IMC3-each associated with distinct resistance mechanisms. IMC1 exhibits glycolysis and transforming growth factor-β (TGF-β)-dependent signaling enriched in inflammatory fibroblasts, conferring resistance to chemotherapy. IMC2 relies on oxidative phosphorylation and glutamine metabolism, supporting antioxidant defenses and resistance to both cytotoxic agents and anti-EGFR therapies. IMC3 demonstrates lactate-fueled respiration and pentose phosphate pathway activation, contributing to redox balance, DNA repair, and resistance to targeted therapies such as anti-BRAF or KRAS inhibitors. All subtypes display metabolic plasticity under therapeutic pressure. Emerging clinical data support tailoring targeted therapy combinations based on IMMETCOLS subtype, particularly in BRAF- and HER2-positive populations. Understanding subtype-specific metabolic rewiring in MSS mCRC offers novel opportunities to overcome drug resistance. Targeting the metabolic vulnerabilities defined by the IMMETCOLS signature may improve response durability and inform precision treatment strategies.

Keywords:  IMMETCOLS; chemotherapy resistance; colorectal cancer; metabolic subtypes; targeted therapy

DOI:  https://doi.org/10.37349/etat.2025.1002337
BMC Endocr Disord. 2025 Sep 30. 25(1): 214

Genetic variations in amino acid metabolism-related genes are associated with risk of papillary thyroid carcinoma: a case-control study.

Hongjing Meng, Zhifu Xiao, Qiang Wang, Dewei Li, Zhuyan Li.

   BACKGROUND: Abnormal amino acid metabolic pathways, especially those of glutamine, serine and proline, are crucial to tumourigenesis and the development of papillary thyroid carcinoma (PTC). However, genetic variants in key genes regulating these metabolic pathways remain poorly characterized in PTC.
METHODS: Seven SNPs in the SLC1A5, SLC1A3, SHMT1, and PRODH genes were genotyped in 620 patients with PTC and 620 controls using a flight mass spectrometry platform.
RESULTS: The frequency of the minor allele A of SLC1A5-rs2070246 was significantly greater in the PTC group than in the control group, thereby increasing the risk of PTC by 1.587 times (p < 0.0001). Similarly, the minor alleles C, T and A of SLC1A3-rs16903247, SHMT1-rs4925166 and PRODH-rs372055 increased susceptibility to PTC by 2.584, 1.346 and 1.349 times, respectively (prs16903247 < 0.0001, prs4925166 = 0.00024, and prs372055= 0.001, respectively). Moreover, carriers of the rs2070246-GA/AA genotype had a 1.77- and 2.35-fold increased risk of PTC, and the rs16903247-PTC/CC genotype was associated with a 2.42- and 9.46-fold increased risk of PTC (p < 0.0001). In addition, carriers of the TG or TT genotypes of rs4925166 and the AA genotype of rs372055 all presented a greater risk of PTC (prs4925166 = 0.0005, prs372055= 0.0021). Genetic model data further confirmed that the above four SNPs indeed increased the individual's sensitivity to PTC, as these SNPs were all associated with an elevated disease risk under different models (Bonferroni p < 0.0014).
CONCLUSION: Our results revealed significant associations between amino acid metabolism gene polymorphisms and PTC risk, suggesting potential biomarkers for PTC susceptibility.

Keywords:  PRODH; Papillary thyroid carcinoma (PTC); Polymorphisms; SHMT1; SLC1A3; SLC1A5

DOI:  https://doi.org/10.1186/s12902-025-02034-8
BMC Pulm Med. 2025 Oct 03. 25(1): 448

Serum metabolic disparity between patients with lymph node tuberculosis and patients with sarcoidosis: towards differential diagnosis.

Alok Nath, Sachin Yadav, Kritika Singh, Vikas Agarwal, Ajmal Khan, Zia Hashim, Mansi Gupta, Dinesh Kumar.

   BACKGROUND AND HYPOTHESIS: Sarcoidosis (SAR) and lymph-node tuberculosis (LNTB) are granulomatous diseases that present diagnostic challenges, especially in TB-endemic regions. We hypothesized that serum-metabolic profiles would help in differentiating SARs from LNTBs.
OBJECTIVE: This study aimed to identify serum metabolic biomarkers to distinguish SAR from LNTB using NMR-based metabolomics analysis.
METHODS: Serum samples were collected from 26 SAR and 22 LNTB patients. The serum metabolic profiles were measured using 800 MHz NMR spectroscopy and quantified using the commercial software CHENOMX. The serum metabolic profiles were compared using multivariate partial least squares discriminant analysis (PLS-DA), and potential discriminatory metabolites were identified using variable importance in projection (VIP) scores and subsequently evaluated for statistical significance using a volcano plot. The diagnostic potential of the discriminatory metabolites was evaluated using receiver operating characteristic (ROC) curve analysis.
RESULTS: PLS-DA demonstrated significant metabolic disparity between the SAR and LNTB groups. The key metabolic features identified included elevated levels of glutamate, pyroglutamate, acetate, and leucine and a decreased glutamate-to-glutamine ratio (EQR) and decreased levels of glutamine, pyruvate, and myo-inositol in TB patients. These metabolic changes suggest that TB-infection involves activated glutaminolysis and elevated host lipid metabolism. ROC curve analysis revealed several metabolites with high diagnostic potential (AUC > 0.8), including glutamate, pyroglutamate, and glutamine (AUC > 0.98).
CONCLUSION: In conclusion, this study underscores the potential of serum metabolic profiling as a noninvasive tool for distinguishing SARs from LNTBs. However, further studies are imperative to validate these findings on independent patient cohorts and to facilitate their integration into routine clinical practice.

Keywords:  Clinical metabolomics; Lymph node tuberculosis; Metabolic biomarkers; NMR; Sarcoidosis

DOI:  https://doi.org/10.1186/s12890-025-03756-0
Sci Rep. 2025 Oct 01. 15(1): 34135

Clinicopathological analysis of GLUT-1, GLS1, and GLS2 expression in breast cancer tissues from Jordanian patients.

Haneen A Basheer, Ahlam Zaid Alkilani, Samir Al Bashir, Maram A Alhusban, Lina Elsalem, Sura Bilal AlOmari, Qosay Mahmoud Sharqiah, Kamyar Afarinkia.

  Breast cancer remains the most common malignancy among women, with significant heterogeneity in molecular subtypes and clinical outcomes. This study examines the clinicopathological significance of GLUT-1, GLS1, and GLS2 expression in breast cancer tissues from Jordanian patients, focusing on their role in metabolic reprogramming and potential as therapeutic targets. Using tissue microarray analysis and immunohistochemistry, we evaluated 306 invasive breast cancer cases and 52 normal tissue samples. Overexpression of all three markers was observed in tumor tissues compared to normal samples (p ≤ .01). GLUT-1 and GLS2 showed significant associations with higher tumor grades and triple-negative breast cancer (TNBC) subtypes, highlighting their potential role in aggressive tumor biology. Conversely, GLS1 expression was consistently elevated in cancer tissues but did not vary significantly across grades or subtypes. Strong correlations between high GLUT-1/GLS2 expression and Ki-67 proliferative index underscore their contributions to tumor proliferation and metabolic adaptation. Population-specific patterns, such as the higher GLS2 expression in HER2-negative cases, reflect potential genetic or environmental influences unique to Jordanian patients. These findings emphasize the critical role of metabolic reprogramming in breast cancer progression and underscore the translational potential of targeting GLUT-1 and GLS2, particularly in aggressive subtypes like TNBC. Further research is warranted to explore functional mechanisms and validate these markers in diverse populations. This study provides novel insights into the metabolic dynamics of breast cancer, offering a foundation for regionally tailored therapeutic strategies.

Keywords:  Breast cancer; GLUT-1; Glutaminases; Metabolic reprogramming; Triple-negative breast cancer

DOI:  https://doi.org/10.1038/s41598-025-03123-3
Sci Rep. 2025 Oct 02. 15(1): 34452

Systematic metabolomic study on the plasma and urine of a mouse model of Alport syndrome.

Hong Sang Choi, Songjin Oh, Moongi Ji, Byeongchan Choi, Sang Heon Suh, Chang Seong Kim, Seong Kwon Ma, Soo Wan Kim, Man-Jeong Paik, Eun Hui Bae.

  Chronic kidney disease (CKD) progression involves metabolic alterations that remain poorly understood. We conducted a comprehensive metabolomic study by using an Alport syndrome (AS) mouse model, which is a hereditary form of CKD characterized by progressive nephropathy and hearing loss, to identify key metabolic disturbances associated with disease progression. Plasma and urine samples were collected from male Col4a3 knockout (AS) and wild-type mice at 4 and 7 weeks and analyzed using gas chromatography-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry. We identified 28 plasma and 42 urine metabolites that differed significantly (p < 0.05, VIP > 1.0 by PLS-DA) between AS and wild-type groups. At 4 weeks, the levels of metabolites involved in glycolysis/gluconeogenesis and the TCA cycle increased in the AS mice. By 7 weeks, the pathways related to amino acid metabolism (e.g., tryptophan metabolism and alanine, aspartate, and glutamate metabolism) and ketone body metabolism were significantly disrupted. Notably, palmitic acid and 5-methylcytidine emerged as potential biomarkers of disease progression. Our study provided novel insights into metabolic dysregulation and highlighted specific metabolites as potential biomarkers for early diagnosis and disease monitoring of CKD. These results might facilitate the development of targeted metabolic interventions for CKD.

Keywords:  Alport syndrome; Disease progression; Metabolic profile; Metabolomics; Renal insufficiency

DOI:  https://doi.org/10.1038/s41598-025-17620-y
Mol Psychiatry. 2025 Oct 01.

Role of LXRβ in oligodendrocytes in neuronal survival.

Xiaoyu Song, Wanfu Wu, Mukesh Varshney, Andrew Roman, Jan-Åke Gustafsson, Margaret Warner.

We have reported that mice in which the liver X receptor β (LXRβ) gene is inactivated lose dopaminergic neurons in the substantia nigra and motor neurons in the ventral horn of the spinal cord. These mice develop progressive hind limb paralysis starting at 6 months of age. Since LXRβ is not expressed in either dopaminergic neurons or motor neurons, we have focused on LXRβ-expressing cells whose function is essential for neuron survival. We now report defects in oligodendrocyte maturation in the absence of LXRβ. At 4 months of age, long before motor neuron loss occurs, there was reduction in expression of the four following genes in oligodendrocytes: The monocarboxylate transporter 1 (MCT1), which is essential for metabolic support of motor neurons; BDNF, a motor neuron trophic factor; 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis; glutamine synthetase (GS), an enzyme crucial for the elimination of neurotoxic glutamate from synapses. Differentiation of ES cells from WT and LXRβ-/- mice into motor neurons/oligodendrocytes revealed that LXRβ-/- cultures showed less arborization of motor neurons and a reduced proportion of mature oligodendrocytes. Our study suggests that defects in glial cells can have profound effects on neuronal survival and that early defective oligodendrocyte maturation can lead to motor neuron death. The expression of LXRβ in oligodendrocytes should be investigated as a target for preventing neuronal loss in diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson's disease.

DOI: https://doi.org/10.1038/s41380-025-03278-5
HGG Adv. 2025 Sep 29. pii: S2666-2477(25)00128-9. [Epub ahead of print] 100525

Biallelic variants in BCAT1 impair mitochondrial function and are associated with a candidate neurometabolic disorder.

Brianna L DiSanza, Giulia S Porcari, Livia Sertori Finoti, Leonardo Ramos-Rodriguez, Devin M Burris, Justin A McDonough, Gang Ning, Grace Fagan, Guy T Helman, Erin Weiss, Ryan J Taft, Amy Pizzino, Matthew T Whitehead, Amy Waldman, Cas Simons, Xilma Ortiz-Gonzalez, William C Skarnes, Adeline Vanderver, Elizabeth J Bhoj, Rebecca C Ahrens-Nicklas.

Branched-chain amino acid transaminase-1 (BCAT1) initiates the catabolism of branched-chain amino acids (BCAA), which are essential for neurologic function. However, the role of BCAT1 in neurodevelopment is largely unknown. Here, we identify compound heterozygous BCAT1 variants in a patient with a severe progressive neurodevelopmental syndrome. To investigate the functional consequences, we established patient variant (BCAT1: c.792T>A p.(Phe264Leu); c.1042G>A p.(Glu348Lys)) and BCAT1 knockout hiPSC models. Both disease models show profound defects in cortical neuron differentiation and neurite outgrowth. Furthermore, metabolic analysis revealed evidence of mitochondrial dysfunction associated with increased levels of tricarboxylic acid (TCA) cycle intermediates, glutamate, and glutamine. This increase is linked to altered oxygen consumption rates, superoxide production, and upregulation of UCP2 in BCAT1-disease neurons, suggesting a downstream impact on electron-transport chain homeostasis. These findings establish a regulatory role for BCAT1 in mitochondrial function and further define a role for genomic variants in BCAT1 in neurometabolic disorders.

DOI: https://doi.org/10.1016/j.xhgg.2025.100525
Virchows Arch. 2025 Oct 03.

Proteomic subtyping highlights tumor heterogeneity of human HCC.

Thomas Ritz, Jovan Tanevski, Jana Baues, Sven H Loosen, Tom Luedde, Ulf Neumann, Peter Boor, Peter Schirmacher, Julio Saez-Rodriguez, Thomas Longerich.

  Hepatocellular carcinoma (HCC) has a poor prognosis. While molecular profiling has identified subclasses with potentially druggable pathways, implementation in routine diagnostics remains challenging. Although immunohistology may aid HCC classification, multiplexed protein-based approaches have not yet been established. Proteomic heterogeneity in HCC tissue also remains poorly understood. Tissue microarrays from 58 HCC patients were analyzed using a multispectral imaging platform, enabling the detection of multiple protein biomarkers on a single tissue slide. A machine learning-based algorithm facilitated single-cell expression analysis, clustering, and spatial distribution assessment. A 4-plex immunofluorescence marker panel was designed and applied to interrogate altered signaling pathways in HCC. Unsupervised analysis revealed four factors corresponding to three HCC clusters defined by the overexpression patterns of p-S6/CRP (Cluster A), glutamine synthetase (Cluster B), and EpCam (Cluster C). Single-cell resolution uncovered substantial intratumoral heterogeneity. Only one third of HCCs showed a ≥ 0.95 purity of tumor cells in the predominant cluster. Clinically, Cluster C was associated with reduced median overall survival, while the other clinico-pathological features were not significantly different between the clusters. A protein-based subclassification of human HCC was established, characterized by three distinct subclasses (inflammation, beta-catenin/WNT signaling, progenitor-like) that align with known molecular categories. Cases with dominant progenitor features tended to have a shorter survival probability. The intratumoral heterogeneity observed in most cases may promote therapy resistance and underscores the need for precise molecular stratification to improve treatment outcomes.

Keywords:  HCC; Intratumoral heterogeneity; Multiplexed immunofluorescence; Multispectral imaging

DOI:  https://doi.org/10.1007/s00428-025-04260-w