bims-glucam 2026-05-10 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–05–10
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Emerging roles and regulatory mechanisms involved in glutamine metabolism.
BCAT1 inhibits glutamine-dependent Akt/mTOR signaling and nucleotide synthesis by initiating BTRC-mediated degradation of SLC3A2 in pancreatic adenocarcinoma.
Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer.
PCK2 Promotes Non-Small Cell Lung Cancer Progression via SLC38A2- Mediated Glutamine Uptake and mTORC1 Activation.
A Novel Glutamine Riboswitch, LRN, Regulates the Expression of a Nucleoside Permease in Bacillus thuringiensis.
SLC7A7 Downregulation in Monocytes Drives Immunosuppression and Osteosarcoma Progression.
Multi-omics reveals CXCR4 drives immune escape in colorectal cancer via metabolic reprogramming and immune microenvironment remodeling.
GLS1 Orchestrates Exosome-Mediated Tumor-Endothelial Communication to Facilitate Angiogenesis.
Metabolic Profiling and Perturbations of Human CD34+ Hematopoietic Stem and Progenitors to Regulate HSPC Function.
The central role of macrophages in skeletal muscle regeneration: Phenotypic Polarization, metabolic reprogramming, and therapeutic prospects.
Clinico-Metabolic Profiling Unraveled Key Metabolic Alterations Underlying the Pathophysiology of Chronic Myeloid Leukemia.
Glyceraldehyde-induced metabolic defects in cortical astrocytes: implication for Alzheimer's disease pathogenesis and therapy.
Alpha-Ketoglutarate: A Metabolic Regulator of Cellular Homeostasis and Pathophysiology.
Amino Acid Dysregulation in the Mother-Fetus Unit: Multi-Compartment Metabolomic Signatures of Gestational Diabetes Mellitus and Fetal Macrosomia.
Chemoproteomic profiling reveals histone H4 dopaminylation inhibiting cell growth.
Development and validation of HILIC-MS/MS method for the analysis of glutathione metabolism in cell cultures.

Trends Biochem Sci. 2026 May 07. pii: S0968-0004(26)00108-8. [Epub ahead of print]

Emerging roles and regulatory mechanisms involved in glutamine metabolism.

Keun Woo Ryu, Tak Shun Fung, Craig B Thompson.

  Glutamine is the most abundant circulating amino acid and a central nutrient supporting carbon and nitrogen metabolism. It donates nitrogen for nucleotide and amino acid biosynthesis, protein glycosylation, and provides carbon for the tricarboxylic acid cycle anaplerosis. Glutamine catabolism maintains redox homeostasis via glutathione production, as well as the synthesis of polyamines, urea cycle precursors, and neurotransmitters. Glutamine residues in proteins serve as sites for post-translational modification, while de novo glutamine synthesis is essential for ammonia detoxification. Although glutamine metabolism is regulated by mass action and product inhibition, emerging evidence reveals additional post-translational mechanisms, including regulation through higher-order structural assemblies of enzymes. In this review, we highlight the multifaceted roles of glutamine and emphasize emerging regulatory mechanisms that govern glutamine metabolism.

Keywords:  carbon metabolism; enzyme filaments; glutamine; nitrogen metabolism; post-translational regulation

DOI:  https://doi.org/10.1016/j.tibs.2026.04.008
Cancer Metab. 2026 May 07.

BCAT1 inhibits glutamine-dependent Akt/mTOR signaling and nucleotide synthesis by initiating BTRC-mediated degradation of SLC3A2 in pancreatic adenocarcinoma.

Huimin Huang, Xinheng Liu, Xi Chen, Xinyi Tang, Hanxiang Qiu, Huajun Yu, Guihua Jin, Linhua Lan.

   PURPOSE: Pancreatic adenocarcinoma (PAAD) is characterized by profound metabolic reprogramming, including altered branched-chain amino acid (BCAA) metabolism. While the tumor-promoting role of branched-chain aminotransferase 2 (BCAT2) in PAAD has been well documented, the function of branched-chain aminotransferase 1 (BCAT1) remains unclear, particularly in PAAD cells with low endogenous BCAT1 expression. This study aimed to define the context-dependent role of BCAT1 in PAAD and to elucidate the underlying molecular mechanisms.
METHODS: The expression of BCAT1 and BCAA metabolism-related molecules was assessed by Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effects of BCAT1 and SLC3A2 on PAAD cell proliferation were evaluated using CCK-8 assays in vitro and xenograft nude mouse models in vivo. Astral DIA proteomics and LC-MS-based untargeted metabolomics were performed to characterize protein and metabolic alterations induced by BCAT1 overexpression or SLC3A2 depletion. Stable SLC3A2-knockdown PAAD cell lines were established by lentiviral transduction. Seahorse XFe96 analysis was used to assess cellular bioenergetics by measuring the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR).
RESULTS: BCAT1 expression was markedly reduced in multiple PAAD cell lines, and ectopic BCAT1 overexpression significantly inhibited PAAD cell proliferation both in vitro and in vivo. Mechanistically, BCAT1 overexpression suppressed Akt/mTOR signaling, impaired mitochondrial respiration and glycolytic activity, and disrupted glutamine metabolism, glutathione metabolism, and nucleotide biosynthesis. Notably, intracellular BCAA levels were not significantly altered, whereas glutamine was markedly reduced. Glutamine supplementation partially rescued the BCAT1-induced inhibition of Akt/mTOR signaling and cell growth. Proteomic analysis further revealed that BCAT1 overexpression reduced SLC3A2 expression, and SLC3A2 depletion phenocopied the effects of BCAT1 overexpression on glutamine metabolism, bioenergetics, Akt signaling, and tumor growth. Mechanistically, BCAT1 promoted SLC3A2 degradation through a BTRC-dependent proteasomal pathway, thereby restricting glutamine uptake and reducing intracellular nucleotide availability.
CONCLUSIONS: BCAT1 functions as a context-dependent tumor suppressor in PAAD. In BCAT1-low PAAD cells, BCAT1 overexpression inhibits tumor growth by promoting BTRC-dependent proteasomal degradation of SLC3A2, thereby limiting glutamine uptake and suppressing Akt/mTOR signaling, cellular bioenergetics, and nucleotide biosynthesis, despite minimal changes in intracellular BCAA levels. These findings identify the BCAT1-BTRC-SLC3A2 axis as a previously unrecognized metabolic regulatory pathway in PAAD and suggest a potential therapeutic strategy for targeting tumor metabolic vulnerabilities.

Keywords:  BCAT1; E3 ubiquitin ligase BTRC; Glutamine uptake; Pancreatic adenocarcinoma; SLC3A2

DOI:  https://doi.org/10.1186/s40170-026-00436-3
bioRxiv. 2026 Apr 21. pii: 2026.04.18.719329. [Epub ahead of print]

Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer.

Wen-Hsuan Chang, Alec J Vaughan, Addison G Stamey, Mariana Mancini, Makiko Hayashi, Runying Yang, Ryan Robb, Daniel Andrussier, Jeffrey A Klomp, Andrew M Waters, Antje Schaefer, Brian M Wolpin, Kirsten L Bryant, Adrienne D Cox, Fernando Moreira Simabuco, Kwok-Kin Wong, Andrew J Aguirre, Clint A Stalnecker, Thales Papagiannakopoulos, Channing J Der.

The recent approval of KRAS inhibitors supports the therapeutic value of targeting mutant KRAS cancers. However, clinical efficacy is hindered by both primary and treatment-associated acquired resistance. We applied a CRISPR-Cas9 loss-of-function screen and identified loss of KEAP1 as a resistance mechanism to the KRAS G12D -selective inhibitor MRTX1133 and the RAS(ON) multi-selective inhibitor RMC-7977 in pancreatic cancer models. RNA-sequencing analyses revealed a KEAP1 KO transcriptome that is distinct from the ERK-, MYC-, and YAP/TAZ-TEAD-dependent transcriptional programs that drive KRAS inhibitor resistance, demonstrating a distinct mechanism of resistance. We then established a PDAC KEAP1-deficient (PKD) gene signature that was enriched in patients and preclinical models insensitive to KRAS inhibitor treatment. Finally, we observed that KEAP1-deficient cells exhibited elevated glutamine metabolism, and combination treatment with the glutamine antagonist DRP-104 (sirpiglenastat) enhanced KRAS inhibitor suppression of pancreatic and lung tumors.
SIGNIFICANCE: KEAP1 loss is associated with reduced response to KRAS inhibitor therapy. We demonstrate that KEAP1 loss-associated resistance can be overcome by pharmacologic inhibition of the KEAP1 loss-induced glutamine dependency, establishing a combination to enhance RAS inhibitor clinical efficacy.

DOI: https://doi.org/10.64898/2026.04.18.719329
Curr Cancer Drug Targets. 2026 Apr 28.

PCK2 Promotes Non-Small Cell Lung Cancer Progression via SLC38A2- Mediated Glutamine Uptake and mTORC1 Activation.

Libo Ruan, Fan Zhang, Ling Xiao, Minjun Zhao, Kewang Xu, Wenjun Zeng, Haiyan Zhang.

   INTRODUCTION/OBJECTIVE: Phosphoenolpyruvate carboxykinase 2 (PCK2) contributes to cancer metabolic adaptation, yet its role in glutamine (Gln) transport and downstream signaling in non-small cell lung cancer (NSCLC) under glucose deprivation is unclear. This study aimed to investigate the PCK2-SLC38A2-mTORC1 axis in NSCLC under metabolic stress.
METHODS: A549 NSCLC cells were subjected to PCK2 knockdown using shRNA. Glutamine transporter expression was assessed via PRM proteomics and Western blot. Proliferation, migration, apoptosis, mTORC1 activity, and autophagy were analyzed under low-glucose conditions. Rescue assays were performed using Gln supplementation or SLC38A2 overexpression. Expression of PCK2 and SLC38A2 was evaluated in NSCLC tissues using immunohistochemistry.
RESULTS: PCK2 knockdown reduced Gln transporter levels, especially SLC38A2, and impaired cell proliferation and migration, while inducing apoptosis under low-glucose conditions. These effects were reversed by Gln supplementation or SLC38A2 overexpression. Mechanistically, PCK2 knockdown suppressed mTORC1 signaling and disrupted autophagy flux, both of which were restored by SLC38A2. Clinically, high expression of PCK2 and SLC38A2 was observed in NSCLC tissues and correlated with poor prognosis. Experimental results from both NSCLC patient-derived samples and tissue models demonstrated that downregulation of PCK2 effectively attenuated the progression of non-small cell lung cancer.
DISCUSSION: PCK2 promoted NSCLC cell survival and progression by maintaining Gln uptake through SLC38A2, thereby activating mTORC1 and modulating autophagy. These findings support a metabolic adaptation mechanism critical to tumor aggressiveness.
CONCLUSION: The PCK2-SLC38A2-mTORC1 signaling axis sustains NSCLC cell viability under glucose limitation and represents a potential metabolic vulnerability for therapeutic targeting.

Keywords:  Non-small cell lung cancer (NSCLC); PCK2; SLC38A2; glutamine transport; low glucose; mTORC1

DOI:  https://doi.org/10.2174/0115680096423756251125052704
Environ Microbiol. 2026 May;28(5): e70318

A Novel Glutamine Riboswitch, LRN, Regulates the Expression of a Nucleoside Permease in Bacillus thuringiensis.

Jiaxin Qin, Yizhuo Zhang, Cheng Qian, Xia Cai, Bing Yan, Jun Cai.

  Knowledge of the regulatory mechanism of riboswitches is vital for understanding how microorganisms cope with changes in both intracellular and extracellular environments and for developing and applying RNA biosensors. To date, two types of glutamine-based riboswitches, which are exclusively distributed in cyanobacteria, have been identified. Here, we found an RNA regulatory element in the 5'UTR of the nucleoside permease gene (nupC) in Bacillus thuringensis BMB171; it was identified as a novel glutamine riboswitch and named LRN (leader RNA of nupC). Unlike the two previously known types of glutamine riboswitches found in cyanobacteria, LRN is a single-domain RNA element representing a novel type III glutamine riboswitch. Binding glutamine leads to rearrangements the LRN RNA structure, which inhibits downstream gene expression at the transcriptional level. Biocomputational searches revealed that LRN is frequently found in the Bacillus cereus group and is located mainly upstream of the coding region of the nupC homologues. Thus, this RNA-based sensing mechanism establishes a regulatory feedback loop that couples intracellular glutamine levels to nucleoside transport, which is shared by the B. cereus group.

Keywords:   nupC ; glutamine; nucleoside transport; riboswitch

DOI:  https://doi.org/10.1111/1462-2920.70318
Int J Genomics. 2026 ;2026 8314828

SLC7A7 Downregulation in Monocytes Drives Immunosuppression and Osteosarcoma Progression.

Bingjie Jiang, Haoran Zhu, Zhenxing Zhang.

   Background: Metabolic reprogramming and the formation of an immunosuppressive tumor microenvironment(TME) are hallmarks of osteosarcoma (OS). However, the metabolic characteristics of OS and its associated immune microenvironment remain largely unknown.
Methods: The single-cell data were processed for dimensionality reduction and cell-type annotation by using the Seurat package. Pseudotime analysis and metabolic difference prediction were performed using the SCPA algorithm to predict the metabolic profiles of immune cells. Through integrative analyses using BeyondCell and scMetabolism, three distinct cancer cell subpopulations were identified. Metabolic flux potential and intercellular metabolic communication within each subpopulation were subsequently quantified using METAFlux and Mebocost. Spatial colocalization analysis and intercellular communication prediction were conducted using SpaCET and CellChat. Furthermore, qRT-PCR and survival analyses were performed on our cohort of OS patients.
Results: Monocytes emerged as the predominant immune cell population within OS tissues, displaying pronounced metabolic reprogramming marked by significant upregulation of glycolysis and tryptophan metabolism. Additionally, three cancer cell subpopulations with distinct chemosensitivity profiles were identified; Subpopulation 2, characterized by high expression of CCNA2, UBE2C, and CENPF, demonstrated significantly reduced sensitivity to methotrexate, doxorubicin, cisplatin, ifosfamide, and etoposide. Moreover, both cancer cells and monocytes function as key metabolic regulators, with glutamine serving as a critical metabolic mediator. Monocytes were predominantly localized in proximity to tumor cells and exhibited activation of signaling pathways such as SPP1 and ICAM. SLC7A7 expression was significantly downregulated in OS tissues, and its expression level was correlated with patient prognosis. Furthermore, monocytes exhibiting SLC7A7 downregulation may display aberrant recruitment patterns and functional deficits, potentially playing a pivotal role in supplying glutamine to OS cells and fostering an immunosuppressive TME.
Conclusions: This study provides a preliminary characterization of the metabolic landscape of OS and its associated immune microenvironment. Targeting SLC7A7-deficient monocytes may represent promising strategies for enhancing the efficacy of immunotherapy in OS.

Keywords:  SLC7A7; chemotherapy; metabolism; monocytes; osteosarcoma

DOI:  https://doi.org/10.1155/ijog/8314828
Cell Death Dis. 2026 May 04.

Multi-omics reveals CXCR4 drives immune escape in colorectal cancer via metabolic reprogramming and immune microenvironment remodeling.

Chengle Zhu, Yuting Liu, Shaopeng Xu, Ruonan Li, Jiwen Shi, Guohui Tang, Ruorong Ran, Bo Pang, Zixiang Chi, Yongxing Ding, Wenrui Wang, Qingling Yang, Changjie Chen.

Colorectal cancer (CRC) is one of the most common malignant tumors with the highest incidence and mortality rates worldwide. Immune checkpoint blockade (ICB) therapy has revolutionized the landscape of cancer treatment; however, most patients with CRC gain limited benefits from it. The immunosuppressive microenvironment of CRC is an important cause of tumor progression, metastasis, and immunotherapy resistance. This study aimed to reveal the key role of chemokine receptor 4 (CXCR4) in the immunosuppressive microenvironment and glutamine metabolism reprogramming using integrated single-cell transcriptomics and metabolomics analyses. The in vivo and in vitro experiments verified that CXCR4 mediated metabolic reprogramming in CRC cells by regulating the PI3K-Akt-SMAD4 pathway. Further co-culture experiments revealed that CXCR4 promoted the polarization of tumor-associated macrophages (TAMs) to M2 type through glutamine metabolic reprogramming and induced the exhaustion of CD8+ T cells, thereby intensifying immune escape. The knockdown of CXCR4 significantly increased the infiltration of CD8+ T cells and M1 TAMs, reduced the infiltration of M2 TAMs, effectively reshaped the immunosuppressive microenvironment of CRC-bearing mice, and significantly enhanced the immunotherapeutic effect against programmed cell death protein 1 (PD-1). This study discovered a novel mechanism by which CXCR4 drove CRC immune escape through the dual-axis regulation of the "glutamine metabolism-immune microenvironment." Targeting CXCR4 not only inhibits tumor metabolic adaptability but also reverses TAMs polarization and T cell exhaustion, thereby effectively sensitizing PD-1 inhibitors. This study provides an important theoretical basis and a highly promising new combined treatment strategy for overcoming ICB resistance in patients with CRC.

DOI: https://doi.org/10.1038/s41419-026-08795-x
Adv Sci (Weinh). 2026 May 03. e75510

GLS1 Orchestrates Exosome-Mediated Tumor-Endothelial Communication to Facilitate Angiogenesis.

Jianqiang Yang, Zhenzhen Fu, Fanghui Chen, Soumya Vijaya Kumar, Fan Yang, Yaochao Zheng, Yunqi Li, Yao Yao, Nabil F Saba, Yong Teng.

  Glutaminase 1 (GLS1) drives glutaminolysis to support tumor growth and survival, yet its role in the tumor microenvironment remains poorly understood. Here, we demonstrate that GLS1 promotes angiogenesis in head and neck squamous cell carcinoma (HNSCC) via an exosome-dependent mechanism. In HNSCC xenograft models, genetic silencing of GLS1 or treatment with CB-839 markedly reduces intratumoral angiogenesis. Exosomes from GLS1-deficient cells impair endothelial cell migration and tube formation compared with control exosomes. Proteomic analysis reveals a loss of the pro-angiogenic protein Tenascin C (TNC) in GLS1-deficient exosomes. Mechanistically, loss of GLS1 interferes with USP1-mediated deubiquitination of Caveolin-1 (CAV1), resulting in CAV1 degradation and impaired recruitment of TNC into exosomes. Exosomes deficient in CAV1-TNC complexes subsequently disrupt integrin-dependent FAK-SRC signaling in endothelial cells, inhibiting their angiogenic activity. Collectively, these findings uncover a non-metabolic role of GLS1 in promoting tumor angiogenesis through exosome-mediated CAV1-TNC signaling, suggesting that targeting GLS1 may simultaneously inhibit tumor metabolism and angiogenesis in HNSCC.

Keywords:  CAV1‐TNC signaling; GLS1; HNSC; angiogenesis; exosomes

DOI:  https://doi.org/10.1002/advs.75510
Blood Adv. 2026 May 06. pii: bloodadvances.2025018876. [Epub ahead of print]

Metabolic Profiling and Perturbations of Human CD34+ Hematopoietic Stem and Progenitors to Regulate HSPC Function.

Kai Yuan, Mingfang Xiong, Rong Yang, Keyu Sun, Zheng Zhang, Shiwei Zhang, Yanyu Xiu, Bo Cai, Jing Yang, Yan Ju, Hongyu Yin, Fei Liang, Yuying Sun, Guangyu Zhao, Yang Zeng.

Hematopoietic stem cells (HSCs) possess self-renewal and multilineage differentiation abilities to generate blood cells and sustain hematopoiesis. Recent studies indicate that HSC metabolism is crucial for regulating their function and cell fate determination in mammals. However, a comprehensive understanding of the metabolic landscape of human HSCs across distinct developmental stages remains lacking. In this study, we performed untargeted metabolomics of Lin-CD34+ hematopoietic stem and progenitor cells (HSPCs) from human fetal liver (FL), umbilical cord blood (UCB), and adult bone marrow (aBM), revealing different developmentally associated metabolic signatures that shape HSPC function across ontogeny. Metabolomic analysis identified D-glutamine and arachidonic acid (AA) as metabolites exhibiting distinct abundance during HSPC development, suggesting their potential roles in modulating HSPC function. Transcriptomic profiling after specific metabolic treatment further revealed distinct gene expression programs associated with lineage commitment, stemness maintenance, and metabolic regulation. Functional assays demonstrated that the inhibition of glutamine metabolism with 6-diazo-5-oxo-L-norleucine (DON) induced HSPCs into quiescent cell states, improving the engraftment of HSPCs and myeloid differentiation. Conversely, exogenous AA supplementation in HSPC culture promoted proliferation and significantly enhanced megakaryocytic differentiation both in vitro and in vivo. Collectively, our study profiled the metabolic landscape of human HSPCs from embryonic to adult period through the newborn stages, suggesting that metabolic modulation could regulate HSPC function. These findings provide novel mechanistic insights and potential strategies for metabolite-based interventions to promote and enhance human HSPC function, with broad implications for basic research and regenerative medicine.

DOI: https://doi.org/10.1182/bloodadvances.2025018876
Biochem Pharmacol. 2026 Apr 30. pii: S0006-2952(26)00358-8. [Epub ahead of print]250(Pt 2): 118025

The central role of macrophages in skeletal muscle regeneration: Phenotypic Polarization, metabolic reprogramming, and therapeutic prospects.

Ruiqi Liu, Yuntian Shen, Yutong Wei, Chuli Zhu, Xinlei Yao, Xiaosong Gu, Lei Qi, Hualin Sun.

  Macrophages are central regulators of skeletal muscle regeneration, dynamically transitioning from pro-inflammatory (M1-like) to reparative (M2-like) phenotypes to coordinate debris clearance, inflammation modulation, satellite cell activation, and tissue remodeling. This review details the underlying molecular mechanisms, focusing on metabolic reprogramming, such as the shift to oxidative phosphorylation and key roles of AMPK, lactate, and glutamine metabolism. It further examines the transcriptional networks (e.g., PPARγ, Nfix) and multicellular crosstalk that shape the regenerative niche. We analyze macrophage dysfunction in pathological contexts: aging-related impairments in dynamics and metabolism that hinder repair, and in Duchenne Muscular Dystrophy (DMD), where sustained inflammation and trained immunity drive fibrosis. Current challenges include deciphering macrophage heterogeneity beyond the M1-like/M2-like paradigm and bridging translational gaps between models and human disease. The review outlines therapeutic strategies to reprogram macrophage function, spanning pharmacological agents (AMPK/PPARγ agonists, cytokine/chemokine modulation), nanotechnology, cell therapies (e.g., exosomes), and physical interventions. A key feature is the integration of molecular docking analyses, revealing structural interactions between compounds (e.g., AICAR, Cenicriviroc) and targets like AMPK, PPARγ, CCR2, and CCR5. This provides a structural pharmacology foundation for developing targeted immunometabolic therapies to restore muscle regeneration in injury and degenerative diseases.

Keywords:  Aging; Duchenne Muscular Dystrophy; Macrophages; Metabolic Reprogramming; Phenotypic Polarization; Skeletal Muscle Regeneration

DOI:  https://doi.org/10.1016/j.bcp.2026.118025
ACS Omega. 2026 Apr 28. 11(16): 24225-24236

Clinico-Metabolic Profiling Unraveled Key Metabolic Alterations Underlying the Pathophysiology of Chronic Myeloid Leukemia.

Surbhi Gupta, Nitu Nigam, Shailendra Prasad Verma, Rimjhim Trivedi, Vimala Venkatesh, Dinesh Kumar.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm. Despite the success of tyrosine kinase inhibitors, therapeutic resistance and disease progression remain significant challenges. This highlights the need for novel biomarkers to facilitate early diagnosis, deepen our understanding of the disease, and pave the way for new therapeutic approaches. This study analyzed serum metabolic profiles of 30 newly diagnosed treatment-naive CML patients and 20 age- and sex-matched healthy controls using 1H nuclear magnetic resonance (NMR) spectroscopy, followed by multivariate and univariate statistical approaches. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analysis. Thirty-eight metabolites were identified, and multivariate analysis revealed significant metabolic disparity between CML and control subjects with substantial alterations in amino acid and energy metabolism. Key eight metabolites, including histidine, alanine, valine, glutamine, tyrosine, serine, glucose, and isoleucine, demonstrated consistent downregulation in CML, reflecting enhanced cellular uptake and metabolic rewiring characteristic of leukemic proliferation. Depletion of branched-chain amino acids and increased reliance on glutamine and glycolytic intermediates highlight vulnerabilities that may be exploited for therapeutic intervention. ROC analysis demonstrated promising discriminatory ability of these metabolites in this cohort, with several achieving an area under the ROC curve (AUROC) > 0.90, suggesting their potential as biomarkers in this cohort their utility . Serum metabolomics reveals a distinct CML signature marked by enhanced bioenergetic and biosynthetic demands, immune evasion, and drug resistance mechanisms. These findings underscore the potential of serum metabolic profiles as noninvasive biomarkers at the exploratory discovery stage, while also providing preliminary pathophysiological insights that may guide future studies on metabolism-targeted therapeutic strategies.

DOI: https://doi.org/10.1021/acsomega.5c13117
Biomed Pharmacother. 2026 May 01. pii: S0753-3322(26)00509-3. [Epub ahead of print]199 119473

Glyceraldehyde-induced metabolic defects in cortical astrocytes: implication for Alzheimer's disease pathogenesis and therapy.

Silvia Piccirillo, Alessandra Preziuso, Tiziano Serfilippi, Valentina Terenzi, Pasqualina Castaldo, Vincenzo Lariccia, Agnese Secondo, Simona Magi.

  A growing body of evidence suggests that reduced metabolic activity in astrocytes may compromise their normal supportive role for neurons and trigger pathophysiological pathways that contribute to the progression of Alzheimer's disease (AD). Due to the complexity of AD pathophysiology, it is crucial to study the disease not only within those contexts traditionally viewed from a neuron-centric perspective. In this study, we settled up a new model of AD by exposing primary rat cortical astrocytes to glyceraldehyde (GA), an inhibitor of glycolytic pathway able to induce a significant hypometabolism and recapitulate several AD pathomechanisms. Accordingly, GA-induced hypometabolism produced (a) astrocytosis, as revealed by the increase in GFAP and Glutamine Synthase (GS) immunosignals, (b) mitochondrial dysfunction, detected as reduced ATP level, mitochondrial ROS hyperproduction and Ca2 + dyshomeostasis at both cytosolic and mitochondrial level (c) inflammation, measured as NF-κB activation, TNFα release, AGEs hyperproduction/RAGE hyperexpression and increase in S100β immunosignal, and, finally (d) autophagy impairment, characterized by the p62 and LC3II protein accumulation. By virtue of glutamate ability to stimulate cell metabolism, we examined the effect of the neurotransmitter supplementation on cell damage and those correlated mechanisms in the proposed AD model. Of interest, metabolic, inflammatory and autophagy defects were mitigated when astrocytes were exposed to glutamate as metabolic boosting substrate. The protective effect of glutamate was counteracted by the pharmacological inhibition of astrocytic glutamate transporters, thus highlighting the relevance of glutamate intracellular action. Collectively, these results highlight the importance of considering astrocyte-targeted therapies as potential strategy in AD.

Keywords:  Alzheimer’s disease; Ca(2+) dysfunction; autophagy impairment; bioenergetics; cortical astrocytes; glutamate; inflammation

DOI:  https://doi.org/10.1016/j.biopha.2026.119473
Biomedicines. 2026 Apr 07. pii: 836. [Epub ahead of print]14(4):

Alpha-Ketoglutarate: A Metabolic Regulator of Cellular Homeostasis and Pathophysiology.

Vinay Devulapalli, Akash Sathiyamurthi, Surabhi Gautam, Pallavi Bhattaram.

  Alpha-Ketoglutarate (AKG), a central intermediate of the tricarboxylic acid cycle, is a crucial metabolic and signaling molecule that connects mitochondrial function with cellular homeostasis, immunological modulation, epigenetic remodeling, and lifespan. While mitochondrial AKG maintains energy metabolism, the nuclear AKG pool influences chromatin remodeling through DNA and histone modifications, which together control hypoxia responses and shape gene expression patterns. This dual role demonstrates AKG's significance in mediating metabolic state, gene expression, and long-term cellular adaptability. AKG modulates immunological responses, reduces reactive oxygen species (ROS), promotes the polarization of anti-inflammatory macrophages, and suppresses nuclear factor kappa B (NF-κB) activation, thereby reducing chronic inflammatory processes. AKG restricts pro-inflammatory cytokine production, increases extracellular matrix synthesis, and reduces cartilage degradation in arthritic models, suggesting potential therapeutic benefits in autoimmune diseases and joint degeneration. Additionally, AKG affects lifespan in several model organisms, where supplementation enhances metabolic resilience, lowers age-related inflammation, modifies mTOR signaling, and preserves youthful epigenetic profiles. Additionally, because endogenous AKG levels decrease with age, oral supplementation of AKG, especially with calcium and arginine, has drawn attention to its potential benefits in longevity and metabolic health. Thus, AKG is versatile and has encouraging therapeutic promise for cancer, aging, and inflammatory illnesses. However, a lack of human clinical evidence prompts further research to determine ideal dosage, tissue selectivity, and long-term safety. The goal of this review is to critically examine the current mechanistic knowledge related to AKG biosynthesis and breakdown and its future implications in maintaining cellular homeostasis and controlling chronic inflammation.

Keywords:  TCA cycle; alpha-ketoglutarate; epigenetics; inflammation; macrophage

DOI:  https://doi.org/10.3390/biomedicines14040836
Int J Mol Sci. 2026 Apr 08. pii: 3346. [Epub ahead of print]27(8):

Amino Acid Dysregulation in the Mother-Fetus Unit: Multi-Compartment Metabolomic Signatures of Gestational Diabetes Mellitus and Fetal Macrosomia.

Natalia A Frankevich, Alisa O Tokareva, Anna A Derenko, Vitaliy V Chagovets, Anastasia V Novoselova, Vladimir E Frankevich, Gennadiy T Sukhikh.

  The role of amino acid disturbances in the mother-fetus system remains poorly understood, despite their critical involvement in gestational diabetes mellitus (GDM), fetal macrosomia (FM) and offspring metabolic programming. This study included 62 mother-newborn dyads stratified by GDM and FM status. An analysis of the association of amino acids with clinical parameters was performed using the Spearman test. Amino acid markers of GDM were identified using the mutual information index and the Mann-Whitney test. A random forest method was used to identify amino acid markers, with the SHAP value used to estimate the contribution of each amino acid. In maternal serum, GDM was associated with significantly lower levels of glycine, 1-methylhistidine, γ-aminobutyric acid, lysine, and tryptophan. Umbilical cord serum from GDM pregnancies showed reduced concentrations of glutamine, glycine, asparagine, methionine, and proline. In amniotic fluid, GDM with FM was characterized by elevated lysine and 1-methylhistidine. Cord blood exhibited increased lysine, proline, leucine, and allo-isoleucine, while amniotic fluid showed low homocitrulline, asparagine, and lysine, together with high histidine. Fetal weight correlated directory with lysine and isoleucine and inversely with homocitrulline. Pathway analysis linked maternal serum markers to disturbances in biotin, glutamate, and carnitine metabolism, whereas cord blood markers involved broader alterations in amino acid, purine, and amino sugar metabolism. In amniotic fluid from GDM with FM, the methylhistidine pathway was specifically enriched, suggesting changes in neonatal muscle protein turnover. GDM induces distinct alterations in the amino acid profiles of all three compartments, and the combination with FM yields unique metabolic signatures. These findings identify candidate biomarkers for prediction of GDM and its complications and point to potential targets for metabolic intervention.

Keywords:  amino acid profiling; amniotic fluid; biomarkers; branched-chain amino acids; fetal macrosomia; gestational diabetes mellitus; maternal serum; metabolic pathways; metabolomics; umbilical cord blood

DOI:  https://doi.org/10.3390/ijms27083346
Nat Chem Biol. 2026 May 08.

Chemoproteomic profiling reveals histone H4 dopaminylation inhibiting cell growth.

Yinfeng Zhang, Yaqi Yang, Wenyan Wu, Min Zhang, Jianan Rao, Wenting Song, Yi Pan, Nan Shen, Linxue Li, Taishan Min, Kai Li, Xiaoqing Zhang, Xin-Yue Qiu, Shu-Yu Zhang, Wenjun Yang, Jianye Zang, Yu Liu, Xi Mo.

Dopaminylation, the covalent attachment of dopamine to the side chain of glutamine in proteins, represents a newly characterized class of posttranslational modifications. Because of the limited identification of substrates, the functions and molecular mechanisms associated with dopaminylation remain largely uncharacterized. Using an alkyne-functionalized dopamine probe, we developed a method for selectively enriching dopaminylated proteins in whole-cell systems. This approach provided a comprehensive resource of 4,133 dopamine-enriched protein candidates and peptide-level analysis with acid-cleavable tags identified 1,181 putative dopaminylated proteins, including histone H4 dopaminylation at Q27 (H4Q27dop), which we further validated. Functionally, H4Q27dop acts as a transcriptional repressor in a neuroblastoma model, where it blocks CEBPD binding at the CCND1 promoter, leading to transcriptional downregulation of CCND1 and subsequent suppression of cell proliferation. Our findings provide both a valuable resource of dopaminylated substrate proteins and a distinct mechanistic insight into how dopamine regulates neuroblastoma cell growth.

DOI: https://doi.org/10.1038/s41589-026-02225-x
Anal Bioanal Chem. 2026 May 07.

Development and validation of HILIC-MS/MS method for the analysis of glutathione metabolism in cell cultures.

Miroslav Kubát, Erika Roušarová, Tomáš Roušar, Petr Česla.

  Glutathione is a critical intracellular antioxidant that neutralizes reactive oxygen species and participates in detoxification. The ratio of its two forms, the reduced and disulfide, serves as an indicator of cellular oxidative stress associated with both acute and chronic disorders. Monitoring intracellular levels of glutathione and thiols involved in its metabolism is important for the proper characterization of cellular injury. However, current analytical methods often require tedious chemical derivatization, lack adequate retention and selectivity for highly polar analytes, or suffer from severe matrix effects when profiling the broader metabolic pathway. In this study, a robust hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method was developed and optimized for the comprehensive analysis of glutathione metabolism in cell samples without chemical derivatization. The method focused on the label-free quantitation of 21 key metabolites, encompassing intact glutathione and other thiols, their oxidized forms, precursor amino acids, and related sulfur-containing compounds. Chromatographic performance was systematically investigated in HILIC mode using sulfobetaine zwitterionic stationary phase. The final method employed 0.05% difluoroacetic acid in the mobile phase and 5% 5-sulfosalicylic acid for sample preparation, ensuring efficient protein precipitation, stabilization of thiols, and compatibility with electrospray ionization. The method demonstrated high analytical performance, with intra- and inter-day precision (≤5%) and accuracy (≤15%) for all target analytes. Application to A549 lung cancer cells incubated with CdCl₂ and cisplatin for 24 and 48 h revealed significant glutathione depletion and multiple metabolic alterations, including elevated γ-glutamylcysteine levels.

Keywords:  Glutathione; High-performance liquid chromatography; Hydrophilic interaction liquid chromatography; Oxidative stress; Tandem mass spectrometry; Thiols

DOI:  https://doi.org/10.1007/s00216-026-06530-1