bims-glucam 2025-12-14 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–12–14
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Jianpi Jiedu formula modulates glutamine metabolism to inhibit colorectal cancer liver metastasis.
Glutamine Promotes Myogenesis in Myoblasts Through Glutaminolysis-Mediated Histone H3 Acetylation That Enhances Myogenin Transcription.
ACSL5 Regulates Glucose Metabolism and Chemotherapy Sensitivity in Colorectal Cancer Cells under Glutamine Deficiency.
Glutamine synthetase regulates the changes of vascular permeability in glioma induced by radiotherapy.
The sour regulation of metabolism: acidity challenges tumor cells while fueling their metabolic survival.
Integrating biochemical and computational approaches to identify targeted therapeutic strategies for liver fibrosis: Effects of Telaglenastat (CB-839) on the glutaminase pathway.
High matrix stiffness triggers the YAP-OPA1-TET1/3 loop to drive chemoresistance via enhanced nuclear-mitochondrial communication.
Single-cell analysis of lung cancer metabolism and its clinical implications.
Three mammalian VDAC isoforms distinctly regulate mitochondrial function and proteome to maintain cell metabolism.
Multiomics analysis of neutrophils in SLE: insights from adult and pediatric disease.
A Remote-Controlled Nanopump Delivers Oxygen to Boost Energy Production in Osteoarthritis.
Promoter demethylation and protein O-GlcNAcylation-mediated enhancement of fatty acid synthase contributes to hepatic steatosis and inflammation in MASLD.
Macropinocytosis and Vascularization Determine Response to mTOR Inhibitors in Lung Squamous Cell Carcinoma.
Elucidating time-resolved intracellular metabolic dynamics via label-free Raman microspectroscopy and 2D correlation spectroscopy.
Accessing Altered Metabolic Profile in Acute Deep Vein Thrombosis Through Nuclear Magnetic Resonance Spectroscopy.
Dual-functional copper nanoplatform potentiates cuproptosis through p53 reactivation and metabolic reprogramming.

Phytomedicine. 2025 Dec 07. pii: S0944-7113(25)01315-7. [Epub ahead of print]150 157680

Jianpi Jiedu formula modulates glutamine metabolism to inhibit colorectal cancer liver metastasis.

Yicun Han, Yiran Ouyang, Yunzhou Pu, Peishan Zhou, Liu Yang, Wanli Deng, Qing Song, Qing Ji.

   BACKGROUND: Liver metastasis is a primary cause of mortality in colorectal cancer (CRC) patients and significantly impacts patient prognosis. Jianpi Jiedu formula (JPJDF), a traditional Chinese medicine composed of six herbal ingredients, demonstrates clinically proven anti-metastatic efficacy against CRC.
PURPOSE: This study investigates the therapeutic potential of JPJDF for CRC metastasis and elucidates its regulatory mechanisms targeting glutamine metabolism.
METHODS: Mass spectrometry identified blood-absorbed anticancer bioactive compounds in JPJDF and evaluated their pharmacokinetics. Energy metabolomics compared metabolic profiles between healthy liver and CRC liver metastatic tissues. A murine CRC liver metastasis model was established. Anti-metastatic effects were assessed via small-animal in vivo imaging and tumor volumetry. Glutamine/glutamate assays, immunofluorescence, flow cytometry, and molecular biology techniques explored JPJDF's mechanistic role in glutamine metabolism regulation and immune modulation across in vivo and in vitro systems.
RESULTS: Following administration, bioactive compounds derived from JPJDF with anticancer activity were detected in the systemic circulation. JPJDF dose-dependently suppressed primary tumor growth and distant metastasis. Liver metastasis exhibited pronounced glutamine metabolic reprogramming. JPJDF inhibited metastasis by modulating glutamine metabolism in metastatic niches through the YTHDF1/GID8 axis. Mechanistically, this axis mediates SLC1A3/GLS pathway suppression, reducing glutamine utilization by CRC cells. Furthermore, comprehensive immunophenotyping of metastatic liver lesions revealed that JPJDF effectively reversed the immunosuppressive TME, characterized by reduced macrophage infiltration and increased abundance of T lymphocytes and mature dendritic cells.
CONCLUSION: JPJDF suppresses CRC metastasis by targeting glutamine metabolism via the YTHDF1/GID8 axis and by remodeling the immunosuppressive tumor microenvironment, highlighting its potential as an adjunct therapeutic strategy for metastatic CRC.

Keywords:  Colorectal cancer; Glutamine metabolism; Jianpi Jiedu formula; Liver metastasis; SLC1A3/GLS; YTHDF1/GID8

DOI:  https://doi.org/10.1016/j.phymed.2025.157680
Nutrients. 2025 Nov 24. pii: 3673. [Epub ahead of print]17(23):

Glutamine Promotes Myogenesis in Myoblasts Through Glutaminolysis-Mediated Histone H3 Acetylation That Enhances Myogenin Transcription.

Masaru Takatoya, Tomoya Kasugai, Daichi Arai, Urara Kasuga, Chisato Miyaura, Michiko Hirata, Yoshifumi Itoh, Tsukasa Tominari, Yoshitsugu Aoki, Masaki Inada.

  Background/Objectives: Plasma glutamine levels in skeletal muscle change in response to exercise intensity and duration, both in physiological and pathological states. Glutamine contributes to muscle differentiation and regeneration; however, the mechanisms underlying this process remain unclear. This study investigated the role of glutamine glutaminolysis in myogenic differentiation, with a focus on epigenetic regulation of myogenin gene expression. Methods: C2C12 myoblasts were differentiated into myotubes using media containing various concentrations of glutamine, glutamate, or dimethyl 2-oxoglutarate (DM-α-KG), a cell-permeable analog of α-ketoglutarate. Results: Glutamine, glutamate, and DM-α-KG promoted C2C12 myoblast differentiation in a concentration-dependent manner, whereas the glutaminase inhibitor CB-839 suppressed differentiation. 4 mM glutamine increased myogenin mRNA expression by about 5-fold. CB-839 also inhibited glutamine-induced expression of myogenin but did not influence the effects of glutamate or DM-α-KG. Furthermore, glutamine increased histone H3 lysine 27 acetylation (H3K27ac) by about two-fold, whereas CB-839 (200 nM) and A-485 (10 µM), a CBP/p300 histone acetyltransferase inhibitor, reduced H3K27ac levels by about half. These results indicate that glutamine not only serves as a structural amino acid for muscle formation but also enhances myogenin transcription through epigenetic mechanisms. Conclusions: This report demonstrates glutaminolysis-dependent histone H3 acetylation, which induces myogenin transcription in myoblasts. These results, connecting glutamine supplementation during resistance training, may make it an effective strategy to accelerate muscle regeneration.

Keywords:  C2C12 myoblast; epigenetic regulation; glutamine; glutaminolysis; histone H3 acetylation

DOI:  https://doi.org/10.3390/nu17233673
Adv Sci (Weinh). 2025 Dec 08. e10801

ACSL5 Regulates Glucose Metabolism and Chemotherapy Sensitivity in Colorectal Cancer Cells under Glutamine Deficiency.

Shuai Tian, Qiaoxia Zhang, Xuedan Sun, Rick Francis Thorne, Zeyuan Shi, Qiang Ji, Zhangran Sun, Yuanxiang Lu, Qun Zhao, Xianjun Yu, Wanglai Hu, Mian Wu.

  Glutamine metabolism is crucial for sustaining tumor cell viability and growth, broadly promoting prospects for the therapeutic targeting of glutamine dependence. However, further research is needed to address key translational issues, particularly to better understand the adaptive survival responses employed by cancer cells in overcoming nutrient deficiency. Long-chain acyl-CoA synthetase 5 (ACSL5) is found to be upregulated under glutamine deprivation, acting to sustain tumor cell viability by enhancing both glycolytic flux and oxidative phosphorylation. ACSL5 operates within a p53 regulatory loop: p53 transcriptionally upregulates ACSL5, while ACSL5 competes with MIB1 to stabilize MDM2, suppressing p53 expression. Mechanistically, ACSL5 relieves p53-mediated inhibition of PGAM1 to drive glycolysis, while its mitochondrial localization promotes IDH2 activation to accelerate the TCA cycle. Nonetheless, these metabolic increases also generate reactive oxygen species (ROS), inducing DNA damage and significantly enhancing colorectal cancer cell sensitivity to oxaliplatin. The latter provides an explanation as to why colorectal tumors with high ACSL5 expression display preferentially improved patient outcomes from chemotherapy. Collectively, the findings reveal a new pathway for non-genetic chemotherapy resistance mechanisms, deepen the understanding of metabolic reprogramming in tumor cells, and offer potential therapeutic targets for future treatment strategies.

Keywords:  ACSL5; DNA damage; chemotherapy sensitivity; glucose metabolism; glutamine deficiency; p53

DOI:  https://doi.org/10.1002/advs.202510801
Med Oncol. 2025 Dec 12. 43(1): 51

Glutamine synthetase regulates the changes of vascular permeability in glioma induced by radiotherapy.

Dandan Wang, Xinyu Liu, Zimeng Wang, Guangyu Ju, Genxia He, Junchao Qian.

  Glioma, as a common malignant tumor of the central nervous system, is characterized by high invasiveness and a strong tendency for recurrence. Although radiotherapy is one of the main treatment strategies, it may also increase vascular permeability, thereby affecting the tumor microenvironment and facilitating tumor metastasis and recurrence. Previous studies have shown that glutamine plays an important role in maintaining the structure and function of vascular endothelium. However, the involvement of glutamine synthetase (GS) in regulating radiotherapy-induced changes in vascular permeability has not yet been systematically investigated. This study evaluated the role of glutamine synthetase (GS) in radiotherapy-induced vascular permeability using C166 mouse endothelial cells, subcutaneous xenografts in nude mice, and an orthotopic rat model. Following treatment with the GS inhibitor L-methionine sulfoximine (MSO) combined with 10 Gy irradiation, we assessed vascular permeability, glutamate levels, and the expression/activity of N-methyl-D-aspartate receptors (NMDAR), nitric oxide synthase (NOS), and nitric oxide (NO). Our results demonstrate that GS inhibition significantly augmented radiation-induced endothelial hyperpermeability. This process was mediated by increased glutamate levels, which activated NMDAR signaling, thereby promoting NOS expression and NO production. These mechanistic findings were consistently validated in both the subcutaneous and orthotopic glioma models. Our findings indicate that GS plays a critical role in regulating glioma vascular permeability following radiotherapy, providing a novel perspective for understanding radiation-induced vascular dysfunction and tumor recurrence.

Keywords:  Glioma; Glutamine synthetase; Nitric oxide; Radiotherapy; Vascular permeability

DOI:  https://doi.org/10.1007/s12032-025-03190-6
Cancer Res. 2025 Dec 11.

The sour regulation of metabolism: acidity challenges tumor cells while fueling their metabolic survival.

Bruna Martins Garcia, Patricia Altea-Manzano.

The tumor microenvironment imposes diverse metabolic challenges to cancer cells. Overcoming these challenges is essential for survival, proliferation, and dissemination. However, how cancer cells cope with the harsh environment and how the different coexisting stresses affect the tumor in vivo is unknown. Recently, Groessl, Kalis and colleagues published their findings in Science showing that acidosis outweighs all other stresses and plays a major role in the adaptation to them. Mechanistically, acidosis inhibits the ERK-DRP1 pathway, resulting in mitochondria elongation, which triggers a metabolic shift from glycolysis to oxidative phosphorylation. These findings highlight the plasticity of cancer cell mitochondria and refute the previous belief that cancer mitochondria are inherently dysfunctional. Indeed, inhibition of mitochondrial fusion or oxidative phosphorylation in acidic tumors is sufficient to promote cell death. Thus, enhancing respiration under acidosis comes to light as an essential metabolic adaptation to cancer survival and proliferation and targeting how cancer cells adapt to acidosis emerges as a new avenue for therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5633
Biochem Biophys Res Commun. 2025 Dec 05. pii: S0006-291X(25)01817-0. [Epub ahead of print]795 153101

Integrating biochemical and computational approaches to identify targeted therapeutic strategies for liver fibrosis: Effects of Telaglenastat (CB-839) on the glutaminase pathway.

Hoda E Fakher, Eman T Mehanna, Abdel-Aziz A Zidan, Noha M Mesbah, Dina M Abo-Elmatty, Sherin R El-Afify, Ghada M Al-Ashmawy.

   PURPOSE: Liver fibrosis, which can progress to liver cirrhosis and hepatocellular carcinoma, presents a significant health challenge. This study evaluates the effects of two l-glutaminase (GLS) inhibitors, Telaglenastat (CB-839) and compound 968, on carbon tetrachloride (CCl4)-induced liver fibrosis in rats.
METHODS: Sixty rats were divided into six groups: control, CB-839, 968, CCl4, CCl4+CB-839, and CCl4+968. Liver tissues were analyzed for fibrosis biomarkers, including l-hydroxyproline, GLS levels, and gene expression of transforming growth factor beta-1 (TGF-β1), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), peroxisome proliferator-activated receptor gamma (PPAR-γ), GLS-1, GLS-2, and sodium-dependent neutral amino acid transporter-2 (SNAT-2).
RESULTS: CCl4 treatment caused significant liver damage, indicated by elevated liver enzymes and hydroxyproline levels. CB-839 significantly reduced these markers, suggesting a protective effect against fibrosis. In contrast, 968 had minimal effects on liver enzymes and hydroxyproline. Gene expression analysis revealed that CCl4 increased fibrotic markers while decreasing PPAR-γ expression. CB-839 downregulated SNAT-2 and TGF-β1, likely by inhibiting glutamine metabolism. Histopathological assessments confirmed reduced collagen deposition with CB-839 treatment. Network pharmacology identified 115 potential targets for CB-839, with notable overlap in liver fibrosis pathways, suggesting its potential as an antifibrotic agent and a foundation for future therapies.
CONCLUSION: These findings demonstrate that CB-839 exhibits significant antifibrotic effects in a rat model of liver fibrosis, primarily by modulating glutamine metabolism and key fibrotic biomarkers. CB-839 has the potential to be a promising therapeutic approach for liver fibrosis.

Keywords:  968-Compound; CB-839; Liver fibrosis; MMP-2; PPAR-γ; SNAT-2; TGF-β1; l-glutaminase enzyme

DOI:  https://doi.org/10.1016/j.bbrc.2025.153101
iScience. 2025 Dec 19. 28(12): 113996

High matrix stiffness triggers the YAP-OPA1-TET1/3 loop to drive chemoresistance via enhanced nuclear-mitochondrial communication.

Peng Wu, Sicheng Wang, Zanmin Hu, Haoyan Zhang, Yuqing Lin, Zizhao Li, Jiahong Wu, Yani Chen, Yujie Chen, Yuandong Xu, Jun Li, Yupeng Guan.

  Chemoresistance remains a major obstacle in prostate cancer therapy. This study demonstrates that high extracellular matrix stiffness promotes chemoresistance by disrupting mitochondrial-nuclear communication. Culturing prostate cancer cells on polyacrylamide hydrogels of varying stiffness revealed that a high-stiffness environment promotes mitochondrial fusion and enhances function. Mechanistic investigations revealed that high matrix stiffness activates YAP, leading to dysregulation of the Hippo signaling pathway, which subsequently upregulates the expression of OPA1 and induces mitochondrial fusion. This fusion triggers a reprogramming of glutamine metabolism. The resulting metabolite, α-ketoglutarate, activated DNA demethylases TET1 and TET3, causing epigenetic modifications of YAP target genes and further exacerbating Hippo pathway dysregulation. Together, this establishes a YAP-OPA1-TET1/3-mediated positive feedback loop between the nucleus and mitochondria that drives drug resistance. Crucially, targeting OPA1 disrupted this loop and reversed stiffness-induced chemoresistance. These findings reveal a novel mitochondrial-nuclear communication, offering new insights for overcoming chemoresistance in prostate cancer.

Keywords:  bioinformatics; biological sciences; cell biology; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.113996
Cancer Treat Res Commun. 2025 Dec 02. pii: S2468-2942(25)00191-1. [Epub ahead of print]46 101055

Single-cell analysis of lung cancer metabolism and its clinical implications.

Xinglong Li, Guangsong Tang, Wenyue Wang, Chen Zhang, Yu Xue, Ning Xu, Qing Fa Wu, Wei Qiang Yu.

   BACKGROUND: Lung cancer is a highly prevalent and invasive malignancy, characterized by profound metabolic reprogramming as one of its key features. The advent of single-cell RNA sequencing (scRNA-seq) has allowed us to study cellular metabolism in greater detail. In this study, we systematically explore the metabolic pathways of distinct cell types within the lung cancer tumor microenvironment using scRNA-seq data. Moreover, we identify potential biomarkers with diagnostic and prognostic significance.
METHODS: We leveraged scRNA-seq data from lung cancer to map the metabolic landscape of different cell types in the tumor microenvironment. Malignant cells were classified into three distinct subgroups based on their metabolic activity: high-metabolism, intermediate-metabolism, and low-metabolism.
RESULTS: Malignant cells exhibit significantly higher metabolic activity compared to non-malignant cell types. The low-metabolism state was strongly associated with immune signaling pathways, with FSCN1 identified as a key marker. This state revealed a distinct population of cells enriched for cancer stem cell (CSC)-like characteristics.
CONCLUSION: This study provides a comprehensive exploration of the metabolic characteristics of malignant cells in lung cancer at single-cell resolution. Our findings provide insights that could improve prognosis and support more targeted treatments for lung cancer patients.

Keywords:  Lung cancer; Metabolic characteristics; Metabolic pathways; ScRNA-seq

DOI:  https://doi.org/10.1016/j.ctarc.2025.101055
J Biol Chem. 2025 Dec 05. pii: S0021-9258(25)02861-3. [Epub ahead of print] 111009

Three mammalian VDAC isoforms distinctly regulate mitochondrial function and proteome to maintain cell metabolism.

Megha Rajendran, William M Rosencrans, Nina A Bautista, Wendy Fitzgerald, Diana Huynh, Bethel G Beyene, Baiyi Quan, Jennifer D Petersen, Julie Hwang, Tsui-Fen Chou, Sergey M Bezrukov, Tatiana K Rostovtseva.

  The Voltage Dependent Anion Channel (VDAC) is the most ubiquitous protein in the mitochondrial outer membrane. This channel facilitates the flux of water-soluble metabolites and ions like calcium across the mitochondrial outer membrane. Beyond this canonical role, VDAC has been implicated, through interactions with protein partners, in several cellular processes such as apoptosis, calcium signaling, and lipid metabolism. There are three VDAC isoforms in mammalian cells, VDAC1, VDAC2, and VDAC3, with varying tissue-specific expression profiles. From a biophysical standpoint, all three isoforms conduct metabolites and ions with similar efficiency. However, isoform knockouts (KOs) in mice lead to distinct phenotypes, which may be due to differences in VDAC isoform interactions with partner proteins. To understand the functional role of each VDAC isoform within a single cell type, we created functional KOs of each isoform in HeLa cells and performed a comparative study of their metabolic activity and proteomics. We found that each isoform KO alters the proteome differently, with VDAC3 KO dramatically downregulating key members of the electron transport chain (ETC) while shifting the mitochondria into a glutamine-dependent state. Importantly, this unexpected dependence of mitochondrial function on the VDAC3 isoform is not compensated for by the more ubiquitously expressed VDAC1 and VDAC2 isoforms. In contrast, VDAC2 KO did not affect respiration but upregulated ETC components and decreased key enzymes in the glutamine metabolic pathway. VDAC1 KO specifically reduced glycolytic activity linked to decreased hexokinase localization to mitochondria. These results reveal non-redundant roles of VDAC isoforms in cancer cell metabolic adaptability.

Keywords:  CRISPR/Cas9 gene knockout; metabolic regulation; mitochondrial respiratory chain complex; proteomics; voltage-dependent anion channel

DOI:  https://doi.org/10.1016/j.jbc.2025.111009
Clin Exp Immunol. 2025 Dec 09. pii: uxaf077. [Epub ahead of print]

Multiomics analysis of neutrophils in SLE: insights from adult and pediatric disease.

Grace Filbertine, Isobel Kynoch, Genna A Abdullah, Lucy Gill, Rudi Grosman, Marie M Phelan, Zoe McLaren, Tawatchai Deekajorndech, Direkrit Chiewchengchol, Nattiya Hirankarn, Helen L Wright.

Neutrophils contribute to systemic lupus erythematosus (SLE) pathogenesis through ROS and NET production, and increased apoptotic debris which causes autoantibody production and immune complex formation. These processes drive inflammation and tissue damage. The aim of this study was to perform integrated transcriptomic and metabolomic analyses comparing paediatric and adult SLE neutrophils. Adult (aSLE) and pediatric (jSLE) patient and healthy adult (HA) and juvenile (HJ) control neutrophils were subjected to RNAseq and 1H-NMR metabolomics. Univariate, multivariate and multiomics enrichment analyses were conducted in R and with Ingenuity Pathway Analysis (IPA). Transcriptomic analysis revealed distinct gene expression profiles. Adult and juvenile SLE neutrophils were enriched for genes regulating IFN-α/β signalling, neutrophil degranulation and NET signalling pathways (IPA, adj.p-value<0.01). Gene Ontology analysis revealed enrichment in cell cycle and interferon signalling in aSLE, and angiogenesis and tissue-specific development in jSLE. Metabolomic profiling identified distinct metabolic alterations in aSLE, with a greater complexity of metabolic changes in jSLE. Multivariate PLS-DA demonstrated group discrimination, particularly in aSLE (balanced accuracy 80%, sensitivity 80%). VIP>1 metabolites were enriched in taurine/hypotaurine and amino acid metabolism in aSLE. Integrating transcriptomic and metabolomic data strengthened IFN-α/β signalling, neutrophil degranulation and NET signalling (adj. p <0.001). Additional metabolic pathways uniquely down-regulated in aSLE included glutamate and glutamine metabolism, nucleotide biosynthesis and tryptophan catabolism (adj.p<0.01). In summary, neutrophils from SLE patients, especially in jSLE, displayed complex transcriptomic and metabolic profiles, with aberrant IFN responses and neutrophil activation.

DOI: https://doi.org/10.1093/cei/uxaf077
ACS Nano. 2025 Dec 09.

A Remote-Controlled Nanopump Delivers Oxygen to Boost Energy Production in Osteoarthritis.

Xiaowei Xia, Wu Xu, Zhiyuan He, Yingjie Lu, Yong Zhang, Huilin Yang, Lixin Huang, Dinghua Jiang, Lisong Li, Yijian Zhang, Xuesong Zhu.

  The pro-energy synthesis strategy has been considered a promising approach for addressing degenerative disorders, including osteoarthritis (OA). However, the physiologically low oxygen tension in articular cartilage limits aerobic respiration and energy production. In this study, a hemoglobin (Hb)-loaded zeolitic imidazolate framework-8 (ZIF-8) nanopump was developed for efficient oxygen delivery. This nanopump was further functionalized with cartilage-targeting peptides (CZIF@Hb) and specifically guided to aggregate on chondrocytes. In response to active (ultrasonic driving) and passive stimuli (acidic microenvironment), CZIF@Hb underwent responsive disassembly. ZIF-8 drove CO2 adsorption, while Hb facilitated O2 release. These processes synergistically enhanced the tricarboxylic acid (TCA) cycle and subsequent oxidative phosphorylation (OXPHOS), thereby promoting adenosine triphosphate (ATP) generation. Mechanistically, in addition to direct oxygen supply, CZIF@Hb nanopump indirectly facilitated the incorporation of α-KG into the TCA cycle by activating the solute carrier family 1 member 5 (SLC1A5)/solute carrier family 38 member 2 (SLC38A2)-glutamate dehydrogenase 1 (GLUD1)-glutaminase (GLS) axis. The enhanced energy metabolism mitigated free radical-induced damage and concurrently promoted the formation of hyaline cartilage instead of fibrocartilage. Administration of CZIF@Hb nanopump exerted therapeutic effects on cartilage degeneration, subchondral bone sclerosis, and synovial inflammation. Overall, the oxygen-carrying nanoplatform offers a feasible strategy for overcoming energy deficits in hypometabolic organs.

Keywords:  energy metabolism; fibrocartilage hyalinization; glutamine metabolism; oxygen delivery; ultrasound response

DOI:  https://doi.org/10.1021/acsnano.5c15534
J Nutr Biochem. 2025 Dec 06. pii: S0955-2863(25)00389-4. [Epub ahead of print] 110227

Promoter demethylation and protein O-GlcNAcylation-mediated enhancement of fatty acid synthase contributes to hepatic steatosis and inflammation in MASLD.

Zou-Han Lin, Pin-I Chou, Jia-Wei Chang, Zong-Chen Lin, Yuan-Ting Sun, Ming-Hui Chang, Shih-En Huang, Yu-Min Yeh, Chien-Chin Chen, I-Chen Peng.

  Dysregulated lipid metabolism in hepatocytes heightens the risk of metabolic dysfunction-associated steatotic liver disease (MASLD). Fatty acid synthase (FAS), one of the key enzymes regulating lipid production in the liver, is upregulated in MASLD patients, making it a prime target for treatment. However, the regulatory mechanisms governing FAS expression and its post-translational modification in MASLD, as well as their potential contribution to hepatic inflammation, remain incompletely understood. In this study, we find that ten-eleven translocation 2 (TET2), thymine DNA glycosylase (TDG), FAS, and glutamine synthetase (GS) are upregulated in lipid mixture- or high-fat diet-induced hepatic steatosis, both in vitro and in vivo. The lipid mixture increases FAS and GS expression through TDG-mediated promoter demethylation. It also promotes hepatic lipid droplet accumulation and inflammation through TDG, FAS, and GS. Additionally, GS is essential for lipid mixture-induced O-linked N-acetylglucosaminylation (O-GlcNAcylation) of FAS, which enhances its stability in hepatocytes. These findings demonstrate that upregulation of FAS through TDG-mediated promoter demethylation and GS-mediated O-GlcNAcylation accelerates hepatic steatosis and inflammation in MASLD, providing mechanistic insights and highlighting these regulatory pathways as potential targets for therapeutic intervention.

Keywords:  DNA demethylation; O-GlcNAcylation; fatty acid synthase; glutamine synthetase; lipid droplet; metabolic dysfunction-associated steatotic liver disease; thymine DNA glycosylase

DOI:  https://doi.org/10.1016/j.jnutbio.2025.110227
Cancer Res. 2025 Dec 09.

Macropinocytosis and Vascularization Determine Response to mTOR Inhibitors in Lung Squamous Cell Carcinoma.

Morgan R Brady, Nedas Matulionis, Heather R Christofk, Edward B Garon, Aaron Lisberg, David B Shackelford, Milica Momcilovic.

The capacity of cancer cells to rewire their cellular metabolism in response to therapeutic pressure confers resistance to treatments targeting key metabolic pathways, which represents a significant challenge in personalized cancer therapy for lung tumors. In this study, we investigated the mechanisms of resistance to the small molecule mTOR inhibitor TAK228 across lung squamous cell carcinoma (LUSC) models, including cell lines, xenografts, and patient-derived xenografts (PDXs). LUSC cells adapted to mTOR inhibition by engaging macropinocytosis, a form of endocytosis that facilitates enhanced uptake of extracellular nutrients, thereby increasing amino acid availability. Co-inhibition of both mTOR and macropinocytosis using small molecule inhibitors effectively reduced tumor growth. Additionally, angiogenesis limited the efficacy of inhibition of mTOR and macropinocytosis by ensuring a sufficient nutrient supply. Notably, inhibiting angiogenesis in combination with inhibitors of mTOR and macropinocytosis reduced tumor growth in xenografts and PDXs. Moreover, prolonged treatment of LUSC PDXs with TAK228 and the glutaminase inhibitor CB-839 led to upregulation of vascularization, which coincided with a rebound in tumor growth despite continued therapeutic administration. These findings highlight adaptive resistance mechanisms to small molecule inhibitors that target key metabolic pathways, lending insight into potential future clinical strategies for the treatment of LUSC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0921
Analyst. 2025 Dec 11.

Elucidating time-resolved intracellular metabolic dynamics via label-free Raman microspectroscopy and 2D correlation spectroscopy.

Zohreh Mirveis, Nitin Patil, Hugh J Byrne.

Understanding dynamic metabolic processes is central to elucidating cellular function and disease mechanisms. Glycolysis and glutaminolysis are particularly important, as they support bioenergetic and biosynthetic pathways, and their dysregulation is strongly linked to disorders. Raman spectroscopy provides a powerful, non-invasive approach for probing cellular dynamics, and recent advances in instrumentation and computational analysis have enhanced its sensitivity, enabling detection of subtle metabolic variations in complex environments. In this study, Raman spectroscopy combined with two-dimensional correlation spectroscopy (2D-COS) was applied to investigate metabolic responses of cells exposed either to glucose alone or glucose supplemented with glutamine, with emphasis on glutamine's effect on overall metabolic dynamics. Cells were starved for 2 h and then exposed to nutrients, after which they were fixed at 15 minute intervals for up to 2 h and spectroscopically monitored to evaluate the kinetic evolution of the metabolic response. To validate the approach, simulated datasets were initially used to model simplified metabolic pathway dynamics, which confirmed that 2D-COS could reliably track the kinetic evolution of simulated variables, even in the presence of high background interference. Analysis of cellular spectra revealed systematic temporal changes across biomolecular bands, suggesting partial synchronisation of metabolic responses, with oscillatory patterns observed under glucose-only conditions. In contrast, glucose-glutamine samples showed accelerated and amplified metabolic variability, with stronger correlations and additional variable bands, particularly linked to nucleic acid vibrations. Overall, these findings demonstrate the utility of Raman 2D-COS for resolving intracellular metabolic dynamics from complex datasets, offering new opportunities for advancing diagnostics and therapeutic interventions.

DOI: https://doi.org/10.1039/d5an01114k
Int J Mol Sci. 2025 Nov 24. pii: 11345. [Epub ahead of print]26(23):

Accessing Altered Metabolic Profile in Acute Deep Vein Thrombosis Through Nuclear Magnetic Resonance Spectroscopy.

Letícia Queiroz da Silva, Thyerre Santana da Costa, Lucas Gelain Martins, Silmara Aparecida de Lima Montalvão, Stephany Cares Huber, Sandra Martins Silva Soares, Ljubica Tasic, Joyce Maria Annichino-Bizzacchi.

  Deep venous thrombosis (DVT) is characterized by the formation of a thrombus within deep veins. The unmet need to identify new biomarkers and causal risk factors in DVT patients has led to the use of novel techniques, such as metabolite analyses. This study aimed to characterize metabolic alterations in acute DVT patients using 1H-NMR spectroscopy and determine the persistence of these changes over a six-month follow-up. Metabolomics, particularly 1H-NMR spectroscopy, was performed on serum samples from acute DVT patients (first 30 days from diagnosis) and healthy controls (HC). Additionally, 10 plasma markers were evaluated using a Luminex kit. A total of 30 patients, with a mean age of 44 ± 12.5 years, primarily women (9 males:21 females), were included. Acute DVT patients showed elevated inflammatory markers, such as IL-6, IL-8, PDGF-AB/BB, and P-selectin, which later decreased in the follow-up group. However, adhesion molecules like sVCAM-1 and sICAM-1 have increased after six months. Metabolomics analysis revealed significantly decreased levels of glutamine, glucose, and branched-chain amino acids (BCAAs), alongside increased lactate levels in acute DVT samples. Metabolomic profiles showed only partial normalization at follow-up, indicating persistent metabolic dysregulation. Overall, the reduced glucose metabolism and increased lactate levels indicate anaerobic metabolism, likely caused by tissue hypoxia due to impaired blood flow. Glutamine, essential for DNA, ATP, and protein synthesis, was notably reduced, potentially impairing endothelial cell proliferation and vascular repair. The presence of adhesion molecules in the follow-up group confirms persistent endothelial dysfunction. These findings suggest that metabolic and endothelial alterations may persist long after acute inflammation resolves in DVT patients. In conclusion, the persistence of metabolic dysregulation suggests chronic metabolic stress in these patients, potentially resulting from ongoing endothelial damage, low-grade inflammation, or altered mitochondrial function due to past tissue hypoxia.

Keywords:  deep vein thrombosis; metabolites; metabolomics; profiling; venous thromboembolism

DOI:  https://doi.org/10.3390/ijms262311345
J Colloid Interface Sci. 2025 Dec 03. pii: S0021-9797(25)03017-6. [Epub ahead of print]706 139625

Dual-functional copper nanoplatform potentiates cuproptosis through p53 reactivation and metabolic reprogramming.

Lele Ma, Huiying Zheng, Wanlin Xie, Weidi Sun, Qunying Yuan, Kun Song, Peiyu Xi, Fengli Qu, Hui Zhang.

  Cuproptosis, a copper-dependent form of regulated cell death driven by mitochondrial metabolism, holds promise as a therapeutic strategy for cancer. However, its efficacy is hampered by tumor metabolic heterogeneity and mutant p53 (mut-p53)-driven metabolic rewiring that blunts cuproptosis sensitivity. Here, we report the rational design of CuF16@246, an acid-responsive, dual-functional copper-based nanocoordination polymer that integrates Cu2+ and the p53 reactivator eprenetapopt (APR-246) within a single perfluorosebacic acid (PFSEA)-coordinated framework to synergistically induce cuproptosis and reverse tumor metabolic reprogramming. CuF16@246 comprises a PFSEA-coordinated copper framework with good colloidal stability and pH-dependent co-release of Cu2+ and APR-246, enabling controlled Cu2+ release and in situ APR-246 loading. Mechanistically, CuF16@246 triggers hallmarks of cuproptosis, including dihydrolipoamide S-acetyltransferase (DLAT) oligomerization and the depletion of the iron‑sulfur (Fe-S) cluster proteins ferredoxin 1 (FDX1) and lipoic acid synthase (LIAS), while APR-246 converts mut-p53 toward a wild-type-like, DNA-binding-competent state, upregulates metabolic targets such as TP53-induced glycolysis and apoptosis regulator (TIGAR) and glutaminase 2 (GLS2), suppresses glycolysis, and enhances tricarboxylic acid (TCA) cycle flux, thereby sensitizing tumor cells to cuproptosis. In vitro and in vivo studies demonstrate that CuF16@246 exhibits more efficient cellular uptake, more potent cytotoxicity, and more significant tumor growth inhibition than individual treatments, without inducing hemolysis or major organ toxicity. This work establishes a dual-functional strategy that combines metabolic reprogramming with sensitized cuproptosis, providing a promising framework for developing advanced copper-based nanomedicines for the treatment of mut-p53-positive cancers.

Keywords:  APR-246; Cancer therapy; Copper-based nanomedicine; Cuproptosis; Metabolic reprogramming; p53 reactivation

DOI:  https://doi.org/10.1016/j.jcis.2025.139625