bims-glucam 2025-08-24 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–08–24
eleven papers selected by
Sreeparna Banerjee, Middle East Technical University

Recent advances in ASCT2 inhibitors: ligand design and therapeutic applications.
The ATF4-glutamine axis: a central node in cancer metabolism, stress adaptation, and therapeutic targeting.
Calcium Signaling and Metabolic Reprogramming in Cancer: Mechanisms and Therapeutic Implications.
Exploring the metabolic signaling network of GFPT in cancer.
Cholestasis associated microtrabecular and pseudoacinar morphologies in hepatocellular carcinoma: Predicting immunophenotypes, clinical, and radiological outcome.
Dehydration promotes intracellular lipid synthesis and accumulation.
Integrative Omics Reveals Glutamine Catabolism-Driven Apoptotic Suppression in Monocytes upon Mechanical Unloading.
Monocarboxylate Transporter 4 Inhibition Reduces Synovial Hyperproliferation and Metabolic Reprogramming Under Hypoxia in Rheumatoid Arthritis.
Automated, aseptic sampling with small-volume capacity from microbioreactors for cell therapy process analysis.
Disrupting NtrC function reveals unexpected robustness in a central cell cycle regulatory network.
Enhanced detection of crowded NMR peaks using longitudinal multi-spin order for chemical analysis.

Future Med Chem. 2025 Aug 17. 1-14

Recent advances in ASCT2 inhibitors: ligand design and therapeutic applications.

Li'ao Zhang, Guangyue Gong, Yao Xu, Qijian Zhang, Zhiyu Li, Jinlei Bian.

  "Glutamine addiction" is a hallmark metabolic feature of many cancer cells. Driven by the "Warburg effect," tumor cells exhibit an increased reliance on glutamine uptake and metabolism to sustain rapid proliferation and survival. As such, precise modulation of glutamine metabolic pathways has emerged as a promising strategy for cancer therapy. Alanine - serine - cysteine transporter 2 (ASCT2), a key glutamine transporter, is frequently overexpressed in a variety of cancer cells, facilitating elevated glutamine influx to meet the metabolic demands of malignant cells. Accordingly, pharmacological inhibition of ASCT2 represents an attractive approach to reduce intracellular glutamine availability and suppress tumor cell growth. This review provides a comprehensive overview of ASCT2, including its structural and functional characteristics, recent progress in small-molecule inhibitor development, and the potential for future therapeutic applications.

Keywords:  ASCT2; Glutamine metabolism; drug discovery; future perspectives; small-molecule inhibitors

DOI:  https://doi.org/10.1080/17568919.2025.2546777
Cell Death Discov. 2025 Aug 19. 11(1): 390

The ATF4-glutamine axis: a central node in cancer metabolism, stress adaptation, and therapeutic targeting.

Xing Yan, Changhong Liu.

At the center of tumor(neoplasm) metabolic adaptation lies activating transcription factor 4 (ATF4), a key regulator that orchestrates Glutamine (Gln) uptake, utilization, and redox balance under conditions of nutrient deprivation and oxidative stress. This review explores how ATF4 integrates environmental and cellular stress signals to drive Gln metabolic processes, enabling tumor survival, metabolic reprogramming, and immune evasion. The ATF4-Gln axis emerges as a pivotal vulnerability in cancer metabolic processes. Preclinical studies of small-molecule inhibitors and synthetic derivatives disrupting this pathway show promising results. Understanding the intricate interplay between ATF4, Gln metabolic processes, and cancer progression provides valuable insights for novel therapeutic strategies. Future research must address tumor heterogeneity and metabolic flexibility to fully harness the potential of ATF4-centered therapies. However, challenges such as off-target effects of ATF4 inhibitors and metabolic plasticity in tumors remain critical barriers. Future studies integrating multi-omics approaches and AI-driven drug discovery are warranted to overcome these hurdles.

DOI: https://doi.org/10.1038/s41420-025-02683-7
Cold Spring Harb Perspect Biol. 2025 Aug 18. pii: a041764. [Epub ahead of print]

Calcium Signaling and Metabolic Reprogramming in Cancer: Mechanisms and Therapeutic Implications.

Evan Courmont, Anna Rita Cantelmo.

Calcium is essential for cellular homeostasis, orchestrating a vast array of physiological processes through tightly regulated storage, flux, and signaling pathways. Dysregulation of calcium homeostasis disrupts these finely tuned processes, leading to aberrant signaling that contributes to cancer progression. Beyond its role in cellular dysfunction, calcium also regulates the metabolic reprogramming in cancer cells, enabling them to adapt their metabolism to support tumor growth, survival, and resistance. Despite its fundamental role, direct therapeutic targeting of calcium signaling in cancer remains elusive. This review explores the intricate cross talk between calcium signaling and cancer metabolism, dissecting how distinct calcium dynamics drive adaptive oncogenic adaptations. Deciphering this interplay may reveal therapeutic opportunities that leverage calcium-dependent metabolic vulnerabilities in cancer. Given its broad influence, calcium signaling regulation could serve as a multitargeting strategy for anticancer therapy, broadening the range of potential therapeutic interventions.

DOI: https://doi.org/10.1101/cshperspect.a041764
Cell Death Discov. 2025 Aug 19. 11(1): 388

Exploring the metabolic signaling network of GFPT in cancer.

Chibuzo Sampson, Pengfei Li, Yiqian Wang, Jing Liu, Jing Lv, Tian Xia, Hai-Long Piao, Yegang Ma.

Metabolic homeostasis is essential for cellular function in living organisms. In cancer cells, metabolic processes are reprogrammed to meet the energy demands and biosynthetic needs for rapid growth. This reprogramming enhances nutrient flux through the glycolytic pathway, supporting ATP production and branching into pathways that synthesize macromolecules required for cell proliferation. One critical branching pathway is the hexosamine biosynthesis pathway (HBP), which, driven by metabolic reprogramming, facilitates the synthesis of uridine-5'-diphospho-N-acetylglucosamine (UDP-GlcNAc), a glycosylation substrate. This pathway is regulated by the rate-limiting enzyme glutamine-fructose-6-phosphate transaminase (GFPT), a key controller of cellular UDP-GlcNAc levels and protein glycosylation. Dysregulation of GFPT is linked to metabolic disorders, like in diabetes, and it is also frequently upregulated in cancers. Given that GFPT plays a pivotal role in cancer metabolism, elucidating its regulatory interactions with other metabolic signaling pathways under metabolic stress is crucial to identifying therapeutic vulnerabilities in cancer. This review discusses the interaction network of GFPT with other metabolic pathways, its role in nutrient sensing, and the implications of GFPT deregulation in cancer.

DOI: https://doi.org/10.1038/s41420-025-02687-3
Indian J Pathol Microbiol. 2025 Aug 14.

Cholestasis associated microtrabecular and pseudoacinar morphologies in hepatocellular carcinoma: Predicting immunophenotypes, clinical, and radiological outcome.

Ajit Sahu, Susama Patra, Chinmayee Panigrahi, Mukund Namdev Sable, Sudipta Mohakud, Subash Chandra Samal, Manas Kumar Panigrahi, Shalini Chaudhary.

   INTRODUCTION: Over the last two decades, there has been gradual shift in the approach to management of hepatocellular carcinoma (HCC). More emphasis on obtaining pretreatment biopsies for morphomolecular characterization and developing targeted therapies is becoming increasingly crucial. Gain-of-function mutations of CTNNB1, which encodes beta-catenin, occur in 27% of HCC patients. Although molecular analysis for beta-catenin mutation is considered gold standard, immunohistochemical (IHC) analysis is a routinely practiced method. In this study, we aim to address different histomorphological patterns of HCC and their correlation with immunohistochemical expression patterns of beta-catenin, glutamine synthetase expression, clinicoradiological and serological parameters.
MATERIALS AND METHODS: A retrospective, single-center study was conducted on 18 selected HCC cases from 73 diagnosed in core needle biopsies at our institute between 2020 and 2023. Four histological groups were identified: microtrabecular, pseudoacinar, mixed pattern, and any of the aforementioned groups with cholestasis. Beta-catenin expression was classified into membranocytoplasmic, nucleocytoplasmic, and pure membranous patterns. A semiquantitative scoring system for glutamine synthetase (GS) expression was used (nil, low, medium, and high). Clinicopathological and radiological data were analyzed statistically and radiological data were correlated with appropriate statistical analysis.
RESULTS: The morphological group with cholestasis was found to have a statistically significant correlation with nucleocytoplasmic beta-catenin (P = 0.009), high GS expression (P = 0.003), nil portal vein involvement (P = 0.018) and better survival (P = 0.017).
CONCLUSION: We propose that HCCs showing strong GS expression and cholestasis irrespective of microtrabecular, pseudoacinar, or mixed pattern should be subjected to further beta-catenin analysis by IHC and molecular testing to categorize them as CTNNB1-mutated tumors as they have prognostic and predictive values.

Keywords:  ; Beta-catenin; IHC; cholestasis; glutamine synthetase; hepatocellular carcinoma; microtrabecular; portal vein; pseudoacinar; serology; survival

DOI:  https://doi.org/10.4103/ijpm.ijpm_954_24
bioRxiv. 2025 Aug 11. pii: 2025.08.07.669190. [Epub ahead of print]

Dehydration promotes intracellular lipid synthesis and accumulation.

Joshua S Carty, Jazlyn Selvasingh, Yvonne Zuchowski, Hyuck-Jin Nam, Clothilde Pénalva, Gayani Nanayakkara, Erin Q Jennings, Kelsey Voss, Edith T Adame, John T Tossberg, Wei Sheng Yap, Meiling Melzer, Olga Viquez, A Scott McCall, Elizabeth R Piotrowski, Ryoichi Bessho, Shirong Cao, Katrina L Leaptrot, Alexandra C Schrimpe-Rutledge, Simona G Codreanu, Stacy D Sherrod, John A McLean, Jonathan B Trapani, Matthew A Cottam, Ma Wan, Deepti Shrivastava, Don Delker, Matthew H Wilson, Clinton M Hasenour, Louise Lantier, Irene Chernova, Jamey D Young, Volker H Haase, Jose Pablo Vazquez-Medina, Dylan K Kosma, Peter Kim, Jean-Philippe Cartailler, Mingzhi Zhang, Roy Zent, Raymond C Harris, Jason A Watts, Andrew S Terker, Fabian Bock, Jeffrey C Rathmell, Aylin R Rodan, Juan P Arroyo.

Lipids can be considered a water reservoir used to offset dehydration stress as their oxidation by the mitochondria generates water. However, whether dehydration directly regulates lipid synthesis is unknown, which is the focus of this study. We found that dehydration stress decreases cellular oxygen consumption, increases intracellular lipid synthesis, and favors glutamine oxidation as a carbon precursor for lipid synthesis via remodeling mitochondrial metabolism. These findings provide a mechanism whereby cellular dehydration leads to intracellular lipid accumulation, functionally linking water availability to lipid storage.

DOI: https://doi.org/10.1101/2025.08.07.669190
Adv Sci (Weinh). 2025 Aug 18. e00585

Integrative Omics Reveals Glutamine Catabolism-Driven Apoptotic Suppression in Monocytes upon Mechanical Unloading.

Yi Ding, Fan Tong, Mingqiu Liu, Pin Yang, Jing Zeng, Yinghua Wei, Chunlin Li, Dong Li, Cheng Chang, Yangjun Zhang, Shaoqiong Yi, Fan Hu, Wenjie Shu, Lingqiang Zhang, Chun-Ping Cui.

  Osteoclasts derived bone marrow monocytes have been documented to modulate bone quality by directly sensing mechanical forces. However, the mechanisms by which osteoclasts perceive and respond to mechanical disturbances remain unclear. Through integrating multi-omics data of bone tissues from hindlimb unloading (HLU) and control mice, it is revealed that glutamine (Gln) catabolism-induced suppression of apoptosis is critical for monocytes sensing and responding to mechanical unloading. Gln uptake is essential for the survival of monocytes under mechanical unloading. Deprivation of Gln or blockade of Gln transporter solute carrier family 1 member 5 (SLC1A5) inhibits bone resorption by enhancing apoptosis of monocytes. Unloading exposure-induced cell survival is mediated by X-linked inhibitor of apoptosis protein (XIAP)/direct IAP binding protein with low pI (Diablo) axis. Upon mechanical unloading XIAP is upregulated, then interacts with Diablo in mitochondrial and promotes the K63-linkage ubiquitylation of Diablo at the K212 site. This sequesters Diablo within the mitochondrial and inhibits its release into the cytosol, ultimately inhibiting cell apoptosis of osteoclasts and the precursors. Clinically, the serum Gln levels are positively correlated with cross linked C-telopeptide of type I collagen (CTX) levels, indicating that serum Gln levels might serve as a potential biomarker for predicting the risk of osteoporosis. Gln-deficient diet, as well as SLC1A5 inhibitor L-γ-Glutamyl-p-nitroanilide (GPNA), effectively preserves bone mass in HLU mice, implicating attractive approaches for combating bone loss induced by weightlessness or disuse.

Keywords:  K63‐linkage ubiquitylation; bone resorption; glutamine; intrinsic apoptosis pathway; mechanical unloading

DOI:  https://doi.org/10.1002/advs.202500585
Arch Med Res. 2025 Aug 18. pii: S0188-4409(25)00103-1. [Epub ahead of print]57(1): 103283

Monocarboxylate Transporter 4 Inhibition Reduces Synovial Hyperproliferation and Metabolic Reprogramming Under Hypoxia in Rheumatoid Arthritis.

Meican Ma, Ting Liu, Haifeng Chen, Zhao Wang, Jie Zhou, Yu Zhou, Fenghong Yuan.

   OBJECTIVES: In hypoxic conditions, the acidic environment characteristic of rheumatoid arthritis (RA) induces metabolic changes in fibroblast-like synoviocytes (FLS), markedly promoting the synovial proliferation. Monocarboxylate transporter 4 (MCT4) plays a crucial role in cellular pH regulation and synovial fibroblast activation by regulating lactate export. This study investigates the impact of MCT4 inhibition on RA and elucidates its underlying mechanisms.
METHOD: RA-FLS cells were treated with siMCT4 and VB124 (a selective MCT4 inhibitor), significantly affecting glucose and glutamine uptake and altering lactate efflux. Metabolite analysis using liquid chromatography-mass spectrometry (LC-MS) revealed the mechanisms of carbon metabolism reprogramming. ChIP-qPCR analysis demonstrated changes in hypoxia-inducible factor-1α (HIF1-α) binding to the MCT4 promoter. The therapeutic effects of siMCT4 and VB124 were validated in a collagen-induced arthritis (CIA) model, and their efficacy was assessed through arthritis scores and histological examination.
RESULTS: In patients with RA, MCT4 levels are significantly elevated. Inhibition of MCT4 effectively reduces synovial hyperproliferation and impacts metabolic reprogramming. Specifically, blocking MCT4 in RA-FLS reduces glucose consumption and lactate production while remodeling the metabolic landscape by increasing fumarate, citrate, and malate levels, and decreasing glucose-6-phosphate and aspartate levels. This metabolic shift is accompanied by improvements in mitochondrial structure and function, reduced mitochondrial swelling, and decreased oxidative stress, underscoring the relationship between MCT4 inhibition and cellular energetics. Furthermore, our investigations reveal that HIF1-α directly regulates MCT4 activation, providing a molecular mechanism by which hypoxia promotes MCT4-mediated metabolic reprogramming.
CONCLUSION: These findings highlight MCT4 as a central regulator of RA proliferation and a promising therapeutic target.

Keywords:  Carbon metabolism; Fibroblast-like synoviocyte; Hypoxia; Monocarboxylate transporter 4; Rheumatoid arthritis

DOI:  https://doi.org/10.1016/j.arcmed.2025.103283
Front Bioeng Biotechnol. 2025 ;13 1612648

Automated, aseptic sampling with small-volume capacity from microbioreactors for cell therapy process analysis.

Zhi Xian Chan, Shruthi Pandi Chelvam, Wei-Xiang Sin, Denise Bei Lin Teo, Ahmad Amirul Bin Abdul Rahim, Ying Ying Wu, Dan Liu, Michael E Birnbaum, Derrick Yong, Rajeev J Ram.

  Current workflows in autologous cell therapy manufacturing are reliant on manual processes that are difficult to scale out to meet patient demands. High throughput bioreactor systems that enable multiple cultures to occur in parallel can address this need, but require good bioprocess monitoring workflows to produce good quality cell therapy products. Commercial sampling systems have thus been developed for better feedback control and monitoring capabilities. However, they are targeted towards large scale processes and often bioreactor specific, making them less robust for integration across different bioreactor scales and types, such as perfusion-capable microbioreactors which allows for greater process intensification. Here, an automated cell culture sampling system (Auto-CeSS) was developed to eliminate laborious manual sampling while minimizing sterility risks for cell therapy manufacturing processes. The system is aseptically integrated with a variety of bioreactors of different working volumes. This system can accurately and aseptically sample a minimum volume of 30 μL and can consistently perform periodic sampling of supernatant over a minimum interval of 15 min. We integrated Auto-CeSS with a 2 mL perfusion microbioreactor and a 8 mL gas-permeable well-plate for T cell culture, collecting 200 μL of supernatant samples daily for metabolite analysis. Comparison of the metabolic profiles of the samples collected via Auto-CeSS versus manual sampling revealed insignificant differences in metabolite levels, including glucose, lactate, glutamine, and glutamate. This report demonstrates the potential of Auto-CeSS as an at-line sampling platform in a real-time T cell production run to facilitate in-process culture monitoring.

Keywords:  aseptic; autosampler; bioreactor; car-t; microbioreactor; sampling; small-volume

DOI:  https://doi.org/10.3389/fbioe.2025.1612648
mBio. 2025 Aug 18. e0196225

Disrupting NtrC function reveals unexpected robustness in a central cell cycle regulatory network.

Hunter North, Molly Hydorn, Jonathan Dworkin, Aretha Fiebig, Sean Crosson.

  Cell cycle progression relies on coordinated signaling systems that integrate diverse cellular and environmental cues. In Caulobacter and related Alphaproteobacteria, the essential sensor histidine kinase CckA initiates a phosphorelay signaling cascade that controls both the transcriptional activity and proteolytic stability of the master cell cycle regulator, CtrA. To uncover regulatory connections between this essential Caulobacter signaling pathway and other cellular processes, we selected for mutations that bypassed the loss of CckA function. Among the identified mutations were structurally distinct loss-of-function alleles of the conserved nitrogen assimilation regulator ntrC, which differentially suppressed the viability defect of a temperature-sensitive (ts) cckA mutant. Complete loss of NtrC function reduces intracellular glutamine, elevates levels of the alarmone ppGpp, and sustains CtrA protein levels, partially rescuing cckA(ts) viability. In contrast, loss-of-function NtrC mutants that retain intact AAA+ ATPase and phosphoreceiver domains but lack a DNA-binding domain fully rescue cckA(ts) viability and display unexpected transcriptional properties. Specifically, strains expressing these NtrC alleles activate a subset of σ54-dependent flagellar genes, even though Caulobacter NtrC does not contain the conserved GAFTGA motif required for NtrC-related enhancer-binding proteins to interact with σ54-RNA polymerase. We propose that bypass of CckA function by NtrC DNA-binding mutants involves a combination of metabolic changes induced by glutamine limitation and an emergent NtrC activity that modulates transcription from non-native sites on the chromosome. This study reveals unexpected genetic routes to bypass an essential signaling process, highlighting the mutational robustness of a conserved cell cycle control system.IMPORTANCEThe study of essential genes offers insight into the core biological processes required for life. Yet, gene essentiality is often conditional, shaped by both environmental factors and genomic context. Here, we show that mutations in Caulobacter ntrC, a conserved regulator of nitrogen assimilation, enable bypass of an essential signaling process catalyzed by the CckA cell cycle kinase. These mutations coordinately alter metabolism, protein levels, and gene expression in ways that sustain cell growth and division even when the essential regulatory activity of CckA is severely impaired. Our results highlight the capacity of bacterial cells to maintain essential functions through evolutionary reconfiguration of metabolic and regulatory networks.

Keywords:  Caulobacter; RNA polymerase; bacterial enhancer binding protein; evolution; sigma factor; signal transduction

DOI:  https://doi.org/10.1128/mbio.01962-25
Anal Chim Acta. 2025 Oct 15. pii: S0003-2670(25)00823-2. [Epub ahead of print]1371 344429

Enhanced detection of crowded NMR peaks using longitudinal multi-spin order for chemical analysis.

Yulan Lin, Wei Liang, Longxiang Chen, Chaoxing Liu, Mengqi Cui, Hongrong Chen, Zhong Chen.

   BACKGROUND: High-resolution one-dimensional (1D) nuclear magnetic resonance (NMR) spectroscopy plays a critical role in enabling the detail analysis of complex samples, precise determination of molecular structures, and investigation of molecular interactions. However, challenges arise when two spins exhibit very similar chemical shifts, potentially interfering with signal separation. Identifying low-concentration components in complex mixtures with overlapping spectral features becomes even more difficult. Therefore, addressing the challenge of extracting low-intensity peaks from crowded or overlapping NMR spectra is of urgent importance.
RESULTS: We introduce double-quantum-filtered longitudinal multiple-spin orders (DQF-LMO) method to extract low-intensity peaks from crowded or overlapping NMR spectra. This approach enables the acquisition of sparse 1D spectra that isolate a single spin coupled to an excited spin, enhancing sensitivity and resolution. Building on this approach, we further develop the DQF-LMO-TOCSY method, incorporating isotropic mixing from the TOCSY technique to detect all spins within a particular spin system. We demonstrate the practical utility of these techniques by applying them to real-world samples, including orange juice and functional beverages, where key compounds such as sucrose, glucose, citric acid, and ethanol were successfully isolated and identified. Additionally, the accurate quantification of glutamine in mixtures with glutamate highlights the capability of these methods to resolve closely overlapping spectra features.
SIGNIFICANCE: These innovations offer a more efficient and precise approach to molecular characterization, enabling better chemical analysis in complex environments. Our work paves the way for enhanced NMR-based chemical analysis and component identification, positioning NMR as a crucial tool for modern analytical chemistry.

Keywords:  Accurate quantification; Complex mixture; NMR; Sparse 1D spectra

DOI:  https://doi.org/10.1016/j.aca.2025.344429