bims-glucam 2025-08-10 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–08–10
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Asparagine synthetase modulates glutaminase inhibitor sensitivity through metabolic reprogramming and serves as a prognostic biomarker in hepatocellular carcinoma.
Mitochondrial metabolism and cancer therapeutic innovation.
Microcystin-LR facilitates pubertal bone retardation by interfering with glutamine metabolism to accelerate stem cell senescence through Hippo/GLS pathway.
OPPORTUNITIES AND CHALLENGES FOR TARGETING CANCER METABOLISM.
Metabolic Adaptation Study of Tumor Cells during Lung Cancer Bone Metastasis in Mice Based on Single-Cell Metabolome Analysis.
TGF-β Coordinates Alanine Synthesis and Import for Myofibroblast Differentiation in Pulmonary Fibrosis.
Tumor glucose reprogramming suppresses cuproptosis: A review.
Surface avidity of anionic polypeptide coatings target nanoparticles to cancer-associated amino acid transporters.
Inferring Metabolic Flux from Gene Expression Data Using METAFlux.
Alanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer.
Reprogramming of amino acid metabolism in breast cancer.
Differentiation of Toxoplasma into latent forms is linked to central carbon metabolism and requires a GID/CTLH-type E3 ubiquitin ligase.
Cancer stem cells: landscape, challenges and emerging therapeutic innovations.
Metabolic Reprogramming in Pheochromocytoma and Paraganglioma: Insights From Untargeted NMR Metabolomics Presurgical and Postsurgical intervention.
Integrated Transcriptome and Metabolome Analysis Reveals a Disturbance in Antioxidant Metabolism Associated With the Progression of Bronchopulmonary Dysplasia.
Untargeted metabolomic analysis of the therapeutic effects of Pholiota adiposa in H22 hepatocellular carcinoma tumor-bearing mice.

Redox Biol. 2025 Aug 05. pii: S2213-2317(25)00326-X. [Epub ahead of print]86 103813

Asparagine synthetase modulates glutaminase inhibitor sensitivity through metabolic reprogramming and serves as a prognostic biomarker in hepatocellular carcinoma.

Benjian Gao, Dongning Zheng, Hong Liu, Yu Guo, Yuntao Ye, Zhou Chen, Fengyi Yang, Jie Liu, Guangnian Zhang, Guoying Feng, Yongfa Liu, Qiang Wang, Song Su, Xiaoli Yang, Bo Li.

  Glutamine addiction represents a metabolic vulnerability in hepatocellular carcinoma (HCC), making glutaminase inhibitor CB-839 therapy a promising approach. However, effective therapeutic strategies are not yet available. In this study, we aim to investigate the potential role of asparagine synthetase (ASNS) as a target for HCC therapy during CB-839 treatment. CB-839 suppressed HCC cell growth, triggered apoptosis, and induced oxidative stress along with the disruption of amino acid metabolism. Moreover, ASNS was induced by CB-839 treatment through the activation of the amino acid response pathway. ASNS was significantly upregulated in HCC tumor tissues and was positively associated with poor prognosis; indeed our results revealed that its overexpression facilitated the proliferation, migration, and invasion of HCC cells. Furthermore, ASNS increased glutaminolysis and glutathione synthesis through reprogramming glutamine metabolism to maintain intracellular redox homeostasis, thereby activating the mTOR pathway that contributed to HCC progression. ASNS knockdown sensitized HCC cells to CB-839 both in vitro and in vivo. Overall, ASNS modulated the sensitivity to CB-839 in HCC through metabolic reprogramming, potentially serving as a biomarker for CB-839 response and a promising therapeutic target for HCC.

Keywords:  Asparagine synthetase; CB-839; Glutamine metabolism; Hepatocellular carcinoma; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.redox.2025.103813
Signal Transduct Target Ther. 2025 Aug 04. 10(1): 245

Mitochondrial metabolism and cancer therapeutic innovation.

Hongxiang Du, Tianhan Xu, Sihui Yu, Sufang Wu, Jiawen Zhang.

Mitochondria are dynamic organelles that are essential for cellular energy generation, metabolic regulation, and signal transduction. Their structural complexity enables adaptive responses to diverse physiological demands. In cancer, mitochondria orchestrate multiple cellular processes critical to tumor development. Metabolic reprogramming enables cancer cells to exploit aerobic glycolysis, glutamine metabolism, and lipid alterations, supporting uncontrolled growth, survival, and treatment resistance. Genetic and epigenetic alterations in mitochondrial and nuclear DNA disrupt oxidative phosphorylation, tricarboxylic acid cycle dynamics, and redox homeostasis, driving oncogenic progression. Mitochondrial dysfunction in tumors is highly heterogeneous, influencing disease phenotypes and treatment responses across cancer types. Within the tumor microenvironment, mitochondria profoundly impact immune responses by modulating T-cell survival and function, macrophage polarization, NK cell cytotoxicity, and neutrophil activation. They also mediate stromal cell functions, particularly in cancer-associated fibroblasts and tumor endothelial cells. Although targeting mitochondrial function represents a promising therapeutic strategy, mitochondrial heterogeneity and adaptive resistance mechanisms complicate interventional approaches. Advances in mitochondrial genome editing, proteomics, and circulating mitochondrial DNA analysis have enhanced tumor diagnostic precision. This review synthesizes the developmental landscape of mitochondrial research in cancer, comprehensively summarizing mitochondrial structural dynamics, metabolic plasticity, signaling networks, and interactions with the tumor microenvironment. Finally, we discuss the translational challenges in developing effective mitochondria-based cancer interventions.

DOI: https://doi.org/10.1038/s41392-025-02311-x
Environ Pollut. 2025 Aug 01. pii: S0269-7491(25)01304-1. [Epub ahead of print] 126931

Microcystin-LR facilitates pubertal bone retardation by interfering with glutamine metabolism to accelerate stem cell senescence through Hippo/GLS pathway.

Chun Pan, Tingting Liu, Zhencheng Fan, Biao Ma, Kehan Wang, Xinglong Wang, Yao Zhang, Runyang Hong, Hao Chen.

  Microcystin-leucine-arginine (MC-LR) is a natural toxin produced by freshwater cyanobacteria that can cause pubertal growth retardation. As bone tissues are the supporting organ of the body, it remains unknown whether MC-LR interferes with adolescent growth and development by targeting bone tissue. In the present study, MC-LR accumulated in bones and caused increased loss of trabecular bone and incomplete bone microstructure, leading to bone retardation in adolescent mice. Moreover, the accumulation of reactive oxygen species (ROS) in the bone marrow cavity of MC-LR-treated femurs led to the presence of massive numbers of senescent bone marrow mesenchymal stem cells (BMSCs), which was responsible for enhanced adipogenic differentiation of BMSCs rather than osteogenic differentiation. MC-LR-treated BMSCs presented an obvious decrease in the expression of glutaminase (GLS), a key gene for glutamine metabolism, accompanied by a decrease in glutamate content and GSH synthesis, which was the main cause of ROS accumulation. Activation of GLS reversed MC-LR-induced BMSCs senescence by promoting glutamine metabolism and reducing ROS release. Moreover, transcriptome sequencing data from BMSCs exposed to MC-LR indicated that the Hippo pathway was enriched, and endogenous levels of Yes-associated protein (YAP) were markedly decreased under MC-LR exposure. The overexpression of YAP promoted GLS transcription by facilitating its promoter, which then reversed MC-LR-induced disturbance of glutamine metabolism and BMSCs senescence. After MC-LR exposure, decreased protein phosphatase 2A (PP2A) activity can activate the Hippo pathway. These findings suggest that MC-LR binds to and inhibits PP2A activity, causes activation of the Hippo pathway, blocks GLS-mediated glutamine metabolism, and accelerates BMSCs senescence, which is the key to delaying MC-LR-induced adolescent bone development retardation.

Keywords:  BMSCs; GLS; Hippo/YAP pathway; Microcystin-LR; Senescence

DOI:  https://doi.org/10.1016/j.envpol.2025.126931
Trans Am Clin Climatol Assoc. 2025 ;135 196-205

OPPORTUNITIES AND CHALLENGES FOR TARGETING CANCER METABOLISM.

Chi V Dang.

Otto Warburg sparked the field of cancer metabolism in the 1920s through his observations that human and animal cancer tissues converted significant amounts of glucose to lactate with an elusive underlying mechanism. The discovery of oncogenes led to the notion that neoplasia results from deregulated cell division control with metabolism at the margin, standing by to support cell growth. Studies over the past several decades have linked oncogenes to the direct regulation of metabolism, such as the myelocytomatosis (MYC) oncogene, driving glycolysis and other central metabolic pathways, necessary for cell growth and proliferation. Deregulated oncogenic drive of metabolism renders tumor cells addicted to glucose and other nutrients, such that nutrient deprivation can trigger cancer cell death. The revelation of this addiction stimulated pharmaceutical companies to target metabolism for cancer therapy, but due to several failed clinical studies, this exuberance fizzled commercially. However, the transformative impact of cancer immunotherapy ushered in an interest in understanding the hostile metabolic tumor microenvironment that limits the function of anti-tumor T cells and clinical responses to immunotherapy. This interest drives the convergence of immunometabolism and cancer cell metabolism research to provide a richer understanding of tumor metabolic vulnerability. Herein, I discuss the historical and current context of opportunities and challenges to targeting cancer metabolism.
J Am Soc Mass Spectrom. 2025 Aug 06.

Metabolic Adaptation Study of Tumor Cells during Lung Cancer Bone Metastasis in Mice Based on Single-Cell Metabolome Analysis.

Xuesen Hu, Tianrun Xu, Shengkai Xia, Yang Xu, Yao Chen, Liliang Wen, Wangshu Qin, Xianzhe Shi, Xinyu Liu, Qi Wang, Chunxiu Hu, Guowang Xu.

  Lung cancer metastasis, the leading cause of patient mortality, is driven by circulating tumor cells (CTCs), which act as direct mediators of metastatic spread. To elucidate the metabolic heterogeneity across lung cancer metastatic stages, a panoramic single-cell metabolomics study in a mouse lung cancer bone metastasis model was performed using a concentric hybrid nanoelectrospray ionization-atmospheric pressure chemical ionization source. This platform enables high-coverage detection of polar and nonpolar metabolites, overcoming limitations in sensitivity and metabolite diversity. Unsupervised clustering and dimensionality reduction (t-SNE) of single-cell metabolic profiles distinguished primary tumor cells, CTCs, and bone metastatic cells, revealing stage-specific metabolic reprogramming. Machine learning identified key metabolites (e.g., aminobenzoic acid, 2-methyl-3-ketovaleric acid, pantothenic acid) that robustly discriminated metastatic stages with high accuracy (AUC > 0.96). CTCs exhibited dynamic metabolic adaptions at different stages: during blood circulation, amino acid and glutamine metabolism dominated to counteract nutrient deprivation, while during bone colonization, the tricarboxylic acid cycle and one-carbon metabolism were upregulated to support proliferation. This study provides important data to shed light on the metabolic heterogeneity of tumor cells and the metastasis mechanism of lung cancer.

Keywords:  Circulating Tumor Cells; Hybrid Ionization Source; Lung Cancer Bone Metastasis; Metabolic Adaptation; Single-Cell Metabolomics

DOI:  https://doi.org/10.1021/jasms.5c00177
bioRxiv. 2025 Jul 24. pii: 2025.07.23.666333. [Epub ahead of print]

TGF-β Coordinates Alanine Synthesis and Import for Myofibroblast Differentiation in Pulmonary Fibrosis.

Fei Li, Niv Vigder, David R Ziehr, Mari Kamiya, Hung N Nguyen, Matthew L Steinhauser, Edy Y Kim, William M Oldham.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease marked by aberrant fibroblast-to-myofibroblast differentiation, a process that requires metabolic reprogramming. We identify alanine as a critical metabolite that confers metabolic flexibility to support differentiation. TGF-β increases alanine by activating both its synthesis and import in normal and IPF lung fibroblasts. Alanine is synthesized primarily by GPT2, which is regulated by a glutamine-glutamate-α-ketoglutarate axis. Inhibiting GPT2 depletes alanine and suppresses TGF-β-induced expression of α-SMA and COL1A1, an effect reversed by alanine supplementation. We also identify SLC38A2 as a key transporter of both alanine and glutamine that is upregulated by TGF-β and alanine deprivation. Together, SLC38A2 and GPT2 activities converge to maintain intracellular alanine levels to support myofibroblast differentiation. Mechanistically, alanine deficiency suppresses glycolysis and depletes tricarboxylic acid cycle intermediates, while supplementation provides carbon and nitrogen for intracellular glutamate and proline biosynthesis, particularly in the absence of glutamine. Combined inhibition of GPT2 and SLC38A2 suppresses fibrogenic responses in fibroblasts and in human precision-cut lung slices, highlighting a potential therapeutic strategy for fibrotic lung disease.

DOI: https://doi.org/10.1101/2025.07.23.666333
Biomol Biomed. 2025 Aug 06.

Tumor glucose reprogramming suppresses cuproptosis: A review.

Xiao-Hang Song, Yi-Hang Ding, Jing-Song Chen.

Cuproptosis is a copper-dependent form of regulated cell death that begins when ferredoxin 1 (FDX1) reduces Cu²⁺ to Cu¹⁺, allowing the ion to bind lipoylated enzymes of the tricarboxylic-acid (TCA) cycle, drive protein aggregation, dismantle iron-sulphur clusters and trigger fatal proteotoxic stress. Most tumours, despite accumulating copper, evade this fate through glucose-metabolic rewiring. First, oncogenic stabilisation of hypoxia-inducible factor-1 alpha (HIF-1α) and MYC increases pyruvate dehydrogenase kinase (PDK) activity, which phosphorylates and inactivates the pyruvate dehydrogenase complex (PDC), shrinking the lipoylated target pool in mitochondria and cutting the feed into the TCA cycle. Second, glycolytic signalling suppresses cuproptosis-promoting genes such as FDX1 and dihydrolipoamide S-acetyltransferase while inducing the negative regulator glutaminase (GLS), further lowering copper sensitivity. Third, diversion of glycolytic intermediates into the pentose-phosphate pathway (PPP) supplies abundant nicotinamide adenine dinucleotide phosphate (NADPH), whereas enhanced glutamine catabolism furnishes glutamate; together these fuels expand reduced glutathione (GSH) and metallothionein (MT) pools that chelate Cu¹⁺ and quench reactive oxygen species exactly where cuproptosis is executed. Consequently, glycolysis-dependent cancer cells are far less sensitive to copper-ionophore drugs such as elesclomol or disulfiram than respiration-dependent counterparts, and clinical datasets consistently link high PDK and low PDC-subunit expression with poor prognosis. These insights highlight rational combination strategies: re-activating the TCA cycle with PDK inhibitors, draining PPP- or GLS-driven NADPH/GSH supply, and concurrently delivering copper ionophores could reopen the cuproptotic trap in tumours. Validating such approaches in vivo, charting upstream regulators of FDX1 and mapping crosstalk between cuproptosis and other lethal programmes remain key steps toward exploiting this copper-centred vulnerability in cancer therapy.

DOI: https://doi.org/10.17305/bb.2025.12751
bioRxiv. 2025 Jul 31. pii: 2025.07.28.667320. [Epub ahead of print]

Surface avidity of anionic polypeptide coatings target nanoparticles to cancer-associated amino acid transporters.

Ivan S Pires, Margaret M Billingsley, Ezra Gordon, Andrew J Pickering, Eva Cai, Gonzalo J Esparza, Mae L Pryor, Alexander D Stoneman, Darrell J Irvine, Paula T Hammond.

Tumor-targeted drug delivery enhances therapeutic efficacy while minimizing toxicity. Layer-by-layer nanoparticles (LbL-NPs) coated with anionic polypeptides selectively bind to cancer cells, though the mechanisms have been unclear. Here, we integrated in silico and in vitro approaches-including gene expression analysis, receptor inhibition, and AI-based protein modeling-to show that poly(L-glutamate) (PLE)-coated LbL-NPs bind with high avidity to SLC1A5, a glutamine transporter overexpressed in cancer. We also discovered that PLE clusters SLC1A5 on the cell membrane, promoting prolonged cell surface retention. Poly(L-aspartate) (PLD)-coated NPs similarly bind SLC1A5 but also interact with faster internalizing transporters of anionic amino acids. Correlation analyses across cancer cell lines confirmed a strong link between transporter expression and nanoparticle association. These findings demonstrate that dense glutamate or aspartate presentation through electrostatically adsorbed polypeptides enables selective targeting of overexpressed transporters, providing a mechanistic framework for receptor-targeted delivery that leverages metabolic characteristics of a range of solid tumor types.

DOI: https://doi.org/10.1101/2025.07.28.667320
Methods Mol Biol. 2025 ;2932 187-202

Inferring Metabolic Flux from Gene Expression Data Using METAFlux.

Yuchen Pan, Yuefan Huang, Vakul Mohanty, Ken Chen.

  Metabolic dysregulation is a hallmark of malignant cells, which contributes significantly to tumor proliferation, persistence, and therapeutic resistance. Further, metabolic interplay between malignant cells and cells in the tumor microenvironment (TME) has a significant impact on tumor phenotype. Examining the reconfiguration of metabolic pathways within tumors and TME is therefore critical to understand cancer biology and improve patient care. Current limitations of metabolomic techniques, however, restrict broad and deep characterization of tumor metabolome. To address this gap, we developed METAFlux (METAbolic Flux balance analysis), a computational technique that uses flux balance analysis (FBA) to infer activity or flux of metabolic reactions from bulk and single-cell RNA sequencing data (scRNA-seq). Here, we describe the workflow along with a detailed step-by-step explanation for calculating metabolic fluxes using METAFlux from bulk RNA-seq and scRNA-seq data and the extension to characterize metabolic heterogeneity and metabolic interaction among cell types.

Keywords:  Bulk RNA-seq; Flux balance analysis; Metabolism; Single-cell RNA-seq; Tumor microenvironment

DOI:  https://doi.org/10.1007/978-1-0716-4566-6_10
bioRxiv. 2025 Aug 01. pii: 2025.07.29.667471. [Epub ahead of print]

Alanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer.

Tonatiuh Montoya, Joyce V Lee, Longhui Qiu, Abigail Krall, Nedas Matulionis, Yurim Seo, Brian N Finck, Robin K Kelley, Heather Christofk, Andrei Goga.

Liver cancer is a leading cause of cancer-related death world-wide in part due to the shortage of effective therapies, and MYC overexpression defines an aggressive and especially difficult to treat subset of patients. Given MYC's ability to reprogram cancer cell metabolism, and the liver's role as a coordinator of systemic metabolism, we hypothesized that MYC induces metabolic dependencies that could be targeted to attenuate liver tumor growth. We discovered that MYC-driven liver cancers catabolize alanine in a GPT2-dependent manner to sustain their growth. GPT2 is the predominant alanine-catabolizing enzyme expressed in MYC-driven liver tumors and genetic ablation of GPT2 limited MYC-driven liver tumorigenesis. In vivo isotope tracing studies uncovered a role for alanine as a substrate for a repertoire of pathways including the tricarboxylic acid cycle, nucleotide production, and amino acid synthesis. Treating transgenic MYC-driven liver tumor mouse models with L-Cycloserine, a compound that inhibits GPT2, was sufficient to diminish the frequency of mouse tumor formation and attenuate growth of established human liver tumors. Thus, we identify a new targetable metabolic dependency that MYC-driven liver tumors usurp to ensure their survival.

DOI: https://doi.org/10.1101/2025.07.29.667471
Biochim Biophys Acta Rev Cancer. 2025 Aug 06. pii: S0304-419X(25)00154-4. [Epub ahead of print] 189412

Reprogramming of amino acid metabolism in breast cancer.

Meijin Wang, Yunlu Zhang, Zhenhua Li, Li Fu.

  Breast cancer is one of the most prevalent malignant tumours, representing a significant health risk for women. Subtyping of breast cancer is based on gene expression profiles, with five distinct subtypes identified Luminal A, Luminal B, HER2-positive, basal-like and normal-like. The heterogeneity of breast cancer represents a significant challenge to its treatment, while drug resistance limits the effectiveness of existing therapies. There is widespread amino acid metabolic reprogramming in breast cancer, and the altered amino acid metabolism observed in breast cancer cells exhibits a heterogeneous metabolic phenotype that differs from normal cells. Consequently, targeting the metabolic differences between breast and normal cells may represent a promising novel anti-cancer strategy. In this article, we review the alterations in the metabolism of amino acids such as glutamine, cystine, serine, glycine, tryptophan and arginine in breast cancer and explore the specific mechanisms by which the aberrant expression of various amino acid metabolism-related enzymes leads to alterations in the proliferative, invasive and metastatic capacities of cancer cells. Finally, we summarise the drugs targeting amino acid metabolism in breast cancer that are currently in preclinical and clinical trials, providing a theoretical basis for targeted therapy of amino acid metabolism.

Keywords:  Amino acid metabolic reprogramming; Breast cancer; Targeted therapy

DOI:  https://doi.org/10.1016/j.bbcan.2025.189412
bioRxiv. 2025 Jul 28. pii: 2025.07.27.667068. [Epub ahead of print]

Differentiation of Toxoplasma into latent forms is linked to central carbon metabolism and requires a GID/CTLH-type E3 ubiquitin ligase.

Alessandro D Uboldi, Sachin Khurana, Amalie A Jaywickrama, Sai Prasanna Lekkala-Lethakula, Amber Simonpietri, Karan Singh, Vinzenz Hofferek, Ushma Ruparel, Lachlan L Whitehead, Kelly L Rogers, Alexandra L Garnham, Nichollas Scott, Nicholas J Katris, Malcolm J McConville, David Komander, Simon A Cobbold, Christopher J Tonkin.

Toxoplasma and other Apicomplexan parasites, switch between different developmental stages to persist in and transmit between hosts. Toxoplasma can alternate between systemic tachyzoites and encysted bradyzoite forms found in the CNS and muscle tissues. How parasites sense these tissue types and trigger differentiation remains largely unknown. We show that Toxoplasma differentiation is induced under glucose-limiting conditions and using a CRISPR screen identify parasite genes required for growth under these conditions. From ∼25 identified genes important for differentiation we show that lactate and glutamine metabolism is linked to differentiation and demonstrate the importance of an E3 ubiquitin ligase complex, orthologous to glucose induced degradation deficient (GID) complex in yeast and CTLH complex in humans. We show that TgGID likely regulates translational repression of a key transcription factor required for differentiation, BFD1, through its 3' utr. Overall, this work provides important new insight into how these divergent parasites sense different host cell niches and trigger stage conversion through a ubiquitination-dependent program.

DOI: https://doi.org/10.1101/2025.07.27.667068
Signal Transduct Target Ther. 2025 Aug 05. 10(1): 248

Cancer stem cells: landscape, challenges and emerging therapeutic innovations.

Haksoo Lee, Byeongsoo Kim, Junhyeong Park, Sujin Park, Gaeun Yoo, Soomin Yum, Wooseok Kang, Jae-Myung Lee, HyeSook Youn, BuHyun Youn.

Cancer stem cells (CSCs) constitute a highly plastic and therapy-resistant cell subpopulation within tumors that drives tumor initiation, progression, metastasis, and relapse. Their ability to evade conventional treatments, adapt to metabolic stress, and interact with the tumor microenvironment makes them critical targets for innovative therapeutic strategies. Recent advances in single-cell sequencing, spatial transcriptomics, and multiomics integration have significantly improved our understanding of CSC heterogeneity and metabolic adaptability. Metabolic plasticity allows CSCs to switch between glycolysis, oxidative phosphorylation, and alternative fuel sources such as glutamine and fatty acids, enabling them to survive under diverse environmental conditions. Moreover, interactions with stromal cells, immune components, and vascular endothelial cells facilitate metabolic symbiosis, further promoting CSC survival and drug resistance. Despite substantial progress, major hurdles remain, including the lack of universally reliable CSC biomarkers and the challenge of targeting CSCs without affecting normal stem cells. The development of 3D organoid models, CRISPR-based functional screens, and AI-driven multiomics analysis is paving the way for precision-targeted CSC therapies. Emerging strategies such as dual metabolic inhibition, synthetic biology-based interventions, and immune-based approaches hold promise for overcoming CSC-mediated therapy resistance. Moving forward, an integrative approach combining metabolic reprogramming, immunomodulation, and targeted inhibition of CSC vulnerabilities is essential for developing effective CSC-directed therapies. This review discusses the latest advancements in CSC biology, highlights key challenges, and explores future perspectives on translating these findings into clinical applications.

DOI: https://doi.org/10.1038/s41392-025-02360-2
Magn Reson Chem. 2025 Aug 05.

Metabolic Reprogramming in Pheochromocytoma and Paraganglioma: Insights From Untargeted NMR Metabolomics Presurgical and Postsurgical intervention.

Jashanpreet Kaur, Rakhi Pooja, Gurvinder Singh, Sanniya Middha, Ankit Tandon, Dinesh Kumar, Rama Walia.

  The aim of this study is to investigate the metabolic alterations associated with pheochromocytomas and paragangliomas (PPGLs) and the impact of surgical resection on the serum metabolome using untargeted nuclear magnetic resonance (NMR) metabolomics. For this, the study included 34 patients diagnosed with PPGLs. Pre-operative and postoperative serum samples were analyzed using 1D-proton NMR spectroscopy, and NMR spectral data were processed using Bruker software Topspin. The quantitative metabolic profiles were estimated using CHENOMX NMR-Suite, and multivariate data were analyzed using partial least squares discriminant analysis (PLS-DA) and orthogonal PLS-DA followed by random forest (RF) classification method (a machine learning approach). The multivariate analysis revealed distinct metabolic differences between pre-operative and postoperative samples with respect to normal control (NC) samples, indicating a metabolic shift following tumor resection. RF classification, with an out-of-bag error rate of 0.186, effectively distinguished between NC, presurgery, and postsurgery groups, underscoring the distinct metabolic states in PPGL and the restorative effect of surgical intervention. Pre-operative serum profiles of PPGL patients were characterized by decreased levels of key metabolites, including glucose, citrate, amino acids (glutamine, glycine, leucine, valine, tyrosine, and alanine), histidine, myo-inositol, and creatinine, suggesting altered energy metabolism, and amino acid catabolism induced by catecholamine excess. Postsurgical profiles showed partial metabolic restoration, with significant increases in proline, glutamate, and 3-hydroxybutyrate (3-HB) (p < 0.01), indicating normalization involving lipid oxidation and amino acid metabolism. Although plasma metanephrines normalized postsurgery, full biochemical recovery lagged, as metabolic profiles of postoperative patients remained distinct from healthy controls. In conclusion, the present untargeted NMR metabolomics revealed significant metabolic reprogramming in PPGL patients and captured the partial normalization of metabolic pathways following tumor resection. Metabolites such as proline, glutamate, and 3-HB emerged as potential biomarkers of treatment response. These findings underscore the utility of metabolomics to identify biomarkers for monitoring disease progression, assessing postsurgical recovery, and improving our understanding of PPGL pathophysiology.

Keywords:  NMR based metabolomics; metabolic signatures; neuroendocrine tumors; paraganglioma; pheochromocytoma

DOI:  https://doi.org/10.1002/mrc.70019
FASEB J. 2025 Aug 15. 39(15): e70874

Integrated Transcriptome and Metabolome Analysis Reveals a Disturbance in Antioxidant Metabolism Associated With the Progression of Bronchopulmonary Dysplasia.

Xianxian Jia, Miao Yang, Bo Wu, Kai You, Wei Xu.

  Hyperoxia-induced bronchopulmonary dysplasia (BPD) is associated with the abnormal development of lungs in preterm infants. However, its molecular pathogenesis remains unclear. This study aimed to evaluate the genetic and metabolic consequences of hyperoxic lung injury in neonatal rats with BPD and determine the underlying molecular mechanisms. Hyperoxia treatment was used to establish BPD in neonatal rats. Histopathological analysis of the lung tissues was performed using hematoxylin and eosin staining. An integrated transcriptomic and metabolomic analysis was performed to identify the associated molecular functions and pathways. Histopathological analysis revealed that hyperoxia reduced the number of alveolar cells and increased their interval and volume. Transcriptomic and metabolomic analyses identified differentially expressed genes and metabolites in the lung tissue of neonatal rats with BPD, which were related to metabolic pathways modulating antioxidant activity, particularly glutathione metabolism; alanine, aspartate, and glycine metabolism; taurine and hypotaurine metabolism; and arginine and proline metabolism. We observed a decrease in metabolites and an increase in genes involved in antioxidant metabolic pathways in neonatal rats with BPD, indicating the concurrent upregulation of oxidative stress responses. Our findings indicate that BPD progression is linked to oxidative stress and disrupted amino acid metabolism, particularly in glutathione, taurine/hypotaurine, and arginine/proline pathways. This integrated multi-omics approach reveals potential therapeutic targets for BPD treatment.

Keywords:  bronchopulmonary dysplasia; differentially accumulated metabolite; differentially expressed gene; disorder of amino acid metabolism; transcriptome and metabolome analysis

DOI:  https://doi.org/10.1096/fj.202500394RR
J Bioenerg Biomembr. 2025 Aug 07.

Untargeted metabolomic analysis of the therapeutic effects of Pholiota adiposa in H22 hepatocellular carcinoma tumor-bearing mice.

Xiao-Yan Wang, Le Dai, Yan Liu, Gang Li.

  Pholiota adiposa is a traditional Chinese medicine "Huangsan". Huangsan is rich in proteins, polysaccharides, which has been documented to be used in the treatment of cancer. However, the pharmacological mechanism of Huangsan in the treatment of cancer remains unclear. This research examined the anticancer mechanisms of the ethanol extract of P. adiposa (EPA) in hepatoma-bearing mice via metabolomic analysis. Male ICR mice were randomly assigned to the control (CG), model (MG), positive (25 mg/kg/day cyclophosphamide; PG), low-level EPA (LG, 100 mg/kg/day), and high-level EPA (HG, 300 mg/kg/day) groups. Various biochemical indicators were assessed via enzyme-linked immunosorbent assay, TdT-mediated dUTP nick-end labeling assay, and hematoxylin and eosin staining. Western blot was utilized to assess tumor apoptosis-related caspase-3, cleaved caspase-3, Bcl-2, Bcl-2-associated X, and vascular endothelial growth factor. Ultra-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry and chemometric approaches were applied to determine serum metabolomics. EPA substantially impacted tumor growth in vivo without causing adverse reactions, indicating liver and kidney protection. EPA significantly increased the levels of glutamine, leucine, histidine, citrulline, creatine, prostaglandin A2, and prostaglandin D2 while decreasing levels of arachidonic acid, 20-hydroxyeicosatetraenoic acid, thromboxane B2, and pyruvate. These changes reflected a reduction in protein digestion and absorption, alterations in γ-aminobutyric acid metabolism, and shifts in amino acid metabolism, particularly affecting arachidonic acid, arginine, and proline. EPA exerted significant anticancer effects in mice mainly by reducing the compensatory energy supply from branched-chain amino acids, regulating amino acid metabolism, inhibiting negative nitrogen balance, enhancing immune responses, inhibiting inflammatory mediators, and promoting tumor cell apoptosis in the tumor microenvironment.

Keywords:   Pholiota adiposa ; Antitumor activity; Pharmacological mechanism; Serum metabonomic; UPLC-ESI-QTOF/MS

DOI:  https://doi.org/10.1007/s10863-025-10070-1