bims-glucam 2026-05-03 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–05–03
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Critical Role for Malic Enzymes in MYC-Mediated Cellular Adaptation to Glutamine Depletion.
Inhibitory Activity of Conferone on FAK Activity and Glutamine Metabolism in Human Colorectal Cancer.
GLUL drives metabolic reprogramming and confers docetaxel resistance in prostate cancer.
Glutamine metabolic enzymes: to filament or not to filament?
Structure and enzymology of glutaminase S482C and H461L variants associated with excess brain glutamate and neurological disease.
[Glutamine-induced autophagy exacerbates muscle atrophy in cachectic nude mice: a multi-omics analysis].
TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.
KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer.
Discovery of the protective effect of glutamine on acute alcoholic liver injury.
Glutamine Potentiates Cefoperazone-Sulbactam against Klebsiella pneumoniae by Enhancing Cellular Uptake and ROS Production.
1H NMR-Based Plasma Metabolomics and Machine Learning Reveal Distinct Metabolic Signatures of Breast Cancer in Nigerian Women.
BCAT1-dependent HIF-1α stabilization is a targetable metabolic vulnerability in hepatocellular carcinoma.
Multi-Dimensional Data Integration Reveals the Molecular Mechanism of Metabolic Reprogramming Associated With Low Asparaginase Expression in Hepatocellular Carcinoma.
Pelargonium graveolens Essential Oil Suppresses Proliferation and Migration and Modulates Mesenchymal-Associated Cellular Functions in Human Endometriotic Cells.
6H2L, a novel derivative of bifendate, dually suppresses glycolysis and glutaminolysis in hepatocellular carcinoma via inhibiting YAP stability.
Metabolomic Insights into Head and Neck Cancer: Recent Advances and Future Directions.
LIPT1 loss confers replication stress and PARP inhibitor sensitivity through PrimPol-mediated ssDNA gaps.

Metabolites. 2026 Apr 20. pii: 282. [Epub ahead of print]16(4):

Critical Role for Malic Enzymes in MYC-Mediated Cellular Adaptation to Glutamine Depletion.

Yufan Si, Wei Li, Yang Chen, Jiayang Yuan, Chenrui Hu, Yanan Liu, Li Li.

  Background/Objectives: MYC-driven tumors exhibit significant glutamine addiction, but the metabolic adaptation mechanisms enabling their survival under glutamine deprivation remain incompletely understood. Malic enzymes catalyze the oxidative decarboxylation of malate to pyruvate while generating NADPH, linking central carbon metabolism to redox homeostasis. This study investigates whether and how ME1 and ME2 mediate cell adaptation to glutamine starvation and explores their functional division in relation to p53 status. Methods: Using MYC-amplified, p53-mutant (G266E) SF188 glioblastoma cells, we performed siRNA-mediated knockdown, overexpression, and rescue experiments. Cell survival was assessed by trypan blue exclusion and Annexin V/PI staining. ROS levels and NADP+/NADPH ratios were measured by DCFH-DA fluorescence and enzymatic assays. Metabolite tracing was conducted using [U-13C5] glutamine followed by LC-MS. Key findings were validated in additional cell lines including HCT116, U2OS and MDA-MB-231. Results: ME1 and ME2 promote SF188 cell survival under glutamine deprivation, an effect that depends on their catalytic activity but is independent of TCA cycle anaplerosis. ME1 maintains redox balance by generating NADPH, and antioxidant treatment rescues the survival defect caused by ME1 knockdown. In contrast, ME2 does not contribute to redox regulation but stabilizes mutant p53 (G266E) via proteasome inhibition. Both of these pro-survival functions are attenuated upon MYC knockdown, suggesting a dependency on MYC expression. Across all cell lines tested, ME1 and ME2 also promote survival through redox maintenance, although the isoform responsible for antioxidant function differs. Conclusions: ME1 and ME2 support metabolic adaptation to glutamine starvation through distinct, isoform-specific mechanisms that depend on MYC expression and p53 mutation status. These findings suggest malic enzymes as potential therapeutic targets in MYC-driven, p53-mutant tumors.

Keywords:  MYC; glutamine starvation; malic enzyme; metabolic adaptation

DOI:  https://doi.org/10.3390/metabo16040282
J Cell Mol Med. 2026 May;30(9): e71165

Inhibitory Activity of Conferone on FAK Activity and Glutamine Metabolism in Human Colorectal Cancer.

Hien Thi My Ong, Eda Ates, Jaeyong Jung, Jeong Soo Sung, Jae-Chul Pyun, Min-Jung Kang.

  Colorectal cancer (CRC) is a major global cause of death, with metastases and chemotherapy resistance contributing to poor outcomes. To identify natural compounds with anticancer potential against CRC and elucidate their action mechanisms, the cytotoxicity of 37 natural compounds was evaluated against the HCT116, leading to the identification of conferone as the lead candidate. Its anti-migratory and anti-invasive effects were evaluated in HCT116, Colo205, and SW480 cells. The interactions between conferone and focal adhesion kinase (FAK) were assessed through protein expression analysis and molecular docking. Glutaminolysis regulation was determined by LC-MS/MS, and related enzyme levels were detected by western blotting. Conferone inhibited migration and invasion in all three CRC cell lines, though it showed limited anti-proliferative activity. At 10 μM, conferone reduced FAK and p-FAK (Tyr397) protein levels, reversing the epithelial-mesenchymal transition. Docking analysis confirmed direct FAK binding and predicted inhibition of its phosphorylation, with greater affinity than the FAK inhibitor 1,2,4,5-benzene tetramine tetrahydrochloride. Conferone also downregulated glutaminase and glutamate-ammonia ligase, increasing glutamine and decreasing glutamic acid. Additionally, it suppressed c-raf phosphorylation and reduced c-Myc expression, blocking glutaminolysis-driven metabolism. These findings highlight conferone as a potential therapeutic agent that targets FAK, alters metabolic reprogramming, and impedes CRC progression.

Keywords:  FAK inhibition; colorectal cancer; conferone; glutamine metabolism suppression; molecular docking analysis

DOI:  https://doi.org/10.1111/jcmm.71165
Biochem Pharmacol. 2026 Apr 25. pii: S0006-2952(26)00341-2. [Epub ahead of print]250(Pt 2): 118008

GLUL drives metabolic reprogramming and confers docetaxel resistance in prostate cancer.

Zihang Wu, Yuqi Wu, Qiuxia Ding, Wei Huang, Yuanfei Huang, Ying Zhang, Ran Xu, Xiangwei Wang.

  Docetaxel is a first-line chemotherapeutic agent for advanced and castration-resistant prostate cancer (CRPC), yet acquired resistance limits its long-term efficacy. Metabolic reprogramming has emerged as a central mechanism of therapeutic resistance; however, the metabolic determinants of docetaxel resistance remain incompletely defined. Here, we identify glutamate-ammonia ligase (GLUL), the key enzyme mediating de novo glutamine synthesis, as a critical regulator of docetaxel resistance. Integrated transcriptomic, metabolomic, and single-cell RNA sequencing analyses of clinical specimens revealed significant enrichment of amino acid metabolic pathways, with glutamine metabolism as a dominant alteration. GLUL was consistently upregulated in resistant tumors and validated across independent cohorts. High GLUL expression was associated with activation of PI3K-AKT-mTOR signaling, glycolysis, and oxidative phosphorylation. Functionally, GLUL overexpression enhanced glutamine metabolic flux, promoted cell cycle progression, suppressed docetaxel-induced apoptosis, and increased cell viability under treatment. Conversely, GLUL knockdown restored chemosensitivity in resistant cells and significantly suppressed tumor growth in xenograft models. Mechanistically, GLUL-driven metabolic reprogramming reshaped bioenergetic and redox homeostasis and was tightly coupled to pro-survival signaling activation, forming a coordinated metabolism-signaling network that supports chemoresistance. Collectively, these findings establish GLUL as a key metabolic driver of docetaxel resistance and highlight glutamine synthesis as a pharmacologically actionable vulnerability in CRPC.

Keywords:  Chemoresistance; Docetaxel; GLUL; Glutamine; Prostate cancer

DOI:  https://doi.org/10.1016/j.bcp.2026.118008
Biochem Soc Trans. 2026 Apr 29. 54(4): 375-392

Glutamine metabolic enzymes: to filament or not to filament?

Raquel A C Machado, Ivan Rosa E Silva, Thaís Fontes-Milz, Yuan Chang-Halabi, Jhon A Vargas, Andre L B Ambrosio, Sandra M G Dias.

  The self-assembly of metabolic enzymes into filaments and other supramolecular structures is well-documented in bacteria and yeast but remains largely unexplored in mammalian cells. Enzyme filamentation is thought to play a crucial role in regulating metabolic networks by modulating enzymatic activity in response to cellular demands. Studies in yeast suggest that filament-forming enzymes are often positioned at key junctions of metabolic pathways, enabling dynamic activation or inactivation during growth or stress and directing metabolic flux accordingly. While this mechanism appears to be broadly conserved across species, the structural and functional characterization of human homologs of filamentous enzymes remains limited. In the present review, we focus on the glutamine metabolic pathway, highlighting enzymes known to form large self-assemblies in cells and examining the few cases where structural insights are available. Finally, we discuss the broader implications of metabolic enzyme filamentation in mammalian cells, underscoring its potential as an emerging area of research.

Keywords:  glutamine pathway; metabolic enzyme filamentation; supramolecular structure

DOI:  https://doi.org/10.1042/BST20253136
J Biol Chem. 2026 Apr 27. pii: S0021-9258(26)01963-0. [Epub ahead of print] 113091

Structure and enzymology of glutaminase S482C and H461L variants associated with excess brain glutamate and neurological disease.

Cléa S Crane, Thora K McIssac, Shawn K Milano, Richard A Cerione, Scott M Ulrich.

Glutaminase (GLS) catalyzes the hydrolysis of glutamine to produce glutamate, the brain's principal excitatory neurotransmitter. Two de novo gain-of-function mutations in GLS, S482C and H461L, were recently identified in patients with developmental delay, epilepsy, and infantile cataract. These patients exhibited high glutamate and low glutamine concentrations in the brain, suggesting that the GLS variants have abnormal enzymology. Here, we examined the enzymatic properties of the mutant enzymes and found that they no longer require the anionic activator phosphate to stimulate enzymatic activity or induce filament formation. The mutant enzymes also exhibit a total (S482C) or partial (H461L) loss of glutamate product inhibition, lifting this restriction on glutamate accumulation. Structural analysis of the S482C variant shows the mutation shifts the key catalytic residue Y466 into its catalytically active configuration and disrupts a key hydrogen bond between Y466 and the glutamate product, explaining how the S482C variant has enzymatic activity in the absence of phosphate and is insensitive to glutamate product inhibition. These results shed new light on the mechanism of phosphate activation and glutamate product inhibition of GLS and show that loss of these enzymatic properties disrupts glutamate homeostasis in the brain and causes neurological disease.

DOI: https://doi.org/10.1016/j.jbc.2026.113091
Nan Fang Yi Ke Da Xue Xue Bao. 2026 Apr 20. pii: 1673-4254(2026)04-0816-09. [Epub ahead of print]46(4): 816-824

[Glutamine-induced autophagy exacerbates muscle atrophy in cachectic nude mice: a multi-omics analysis].

Ziyuan Li, Xiaoyu Su, Zhihan Tian, Xingliang Chao, Yong Wang, Dufang Ma.

   OBJECTIVES: To clarify whether glutamine induces autophagy to promote skeletal muscle atrophy in cancer cachexia through integrated transcriptomic and metabolomic analyses.
METHODS: Twenty male BALB/c nude mice were randomized into control and model groups (n=10), and in the latter group cachexia was induced by subcutaneous implantation of CT-26 colon carcinoma cells. Tumor-free body mass and grip strength/body mass ratio of the mice were measured, myofiber transverse diameter was observed using HE staining, and muscle atrophy-related proteins (MuRF1 and atrogin-1) were detected. Transcriptomic and metabolomic analyses were used to identify the differentially expressed genes (DEGs) and differentially expressed metabolites (DEMs), respectively, and the metabolic pathways were mapped. Autophagosomes and gastrocnemius morphology were observed with transmission electron microscopy (TEM), and the autophagic markers (ULK1, LC3, and P62) and signaling pathway proteins (AMPK, FOXO3a, and mTOR) were assayed using Western blotting. The key findings were validated in C2C12 myoblasts treated with glutamine (Gln) and an AMPK inhibitor.
RESULTS: Compared with the control mice, the mice in the model group had significantly decreased tumor-free body mass, grip strength/body mass ratio and myofiber area with elevated atrogin-1 and MuRF1 expressions. The DEGs were mainly enriched in arginine/proline metabolism, AMPK, mTOR, autophagy and FOXO signaling pathways. Metabolomic analysis showed significantly increased glutamine and glutamate in the cachectic muscle. In the tumor-bearing mice, the number of autophagosomes increased significantly with blurred and fragmented myofibrils, upregulated AMPK/FOXO3a pathway proteins and ULK1, and downregulated mTOR pathway proteins and P62. In C2C12 myoblasts, treatment with glutamine obviously promoted autophagy, activated AMPK/FOXO3a signaling and inhibited the mTOR pathway, and these effects were strongly blocked by the AMPK inhibitor.
CONCLUSIONS: Glutamine promotes autophagy through activation of the AMPK/FOXO3a signaling axis and suppression of the mTOR pathway, leading to skeletal muscle atrophy in cancer cachexia.

Keywords:  AMPK/mTOR; autophagy; cancer cachexia; glutamine; muscle depletion

DOI:  https://doi.org/10.12122/j.issn.1673-4254.2026.04.10
Cell Stem Cell. 2026 Apr 24. pii: S1934-5909(26)00144-X. [Epub ahead of print]

TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.

Eleni Kafkia, David Pladevall-Morera, Lidia Argemi-Muntadas, Gangqi Wang, Roberta Noberini, Arnau Casòliba-Melich, Sandra Bagés-Arnal, Matthias Anagho-Mattanovich, Rita Silvério-Alves, Johanna Gassler, Tiziana Bonaldi, Ton J Rabelink, Thomas Moritz, Jan Jakub Żylicz.

  Metabolism shapes stem cell differentiation and epigenome regulation, especially during the exit from naive pluripotency in vitro. Yet how metabolic networks reorganize at implantation remains unclear. Here, we map metabolite routing in pre- and post-implantation mouse embryos and across dynamic pluripotency transitions in stem cells, revealing that the tricarboxylic acid (TCA) cycle undergoes spatio-temporal rewiring rather than a simple shutdown. Pyruvate emerges as a central metabolic nexus, where pyruvate carboxylase and malic enzyme activities create a cyclical carbon flow essential for balanced metabolic and transcriptional states, timely exit from naive pluripotency, and differentiation. As cells leave naive pluripotency, glutamine increasingly fuels the TCA cycle; unexpectedly, it is also the dominant carbon source for histone acetylation. The necessary acetyl-CoA is generated via IDH1-mediated reductive glutamine carboxylation and is coupled to pyruvate cycling, sustaining histone acetylation. These findings uncover a metabolically rewired, route-specific nutrient utilization program that links metabolism to epigenomic regulation and pluripotency transitions at implantation.

Keywords:  13C isotope tracing; development; differentiation; embryo; epigenetics; histone acetylation; metabolism; pluripotency; spatial metabolomics; stem cells

DOI:  https://doi.org/10.1016/j.stem.2026.04.004
Cancer Res. 2026 Apr 29.

KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer.

Ravi Thakur, Dezhen Wang, Tuo Hu, Chunbo He, Junzhang Zhao, Voddu Suresh, Girish H Rajacharya, Anjan K Pradhan, Vira Chumak, Carlos A Valenzuela, Asha D Kushwaha, Drew A Labreck, Tae Gyu Oh, Kar-Ming Fung, Daniel Zhao, Naoko Takebe, Susanna V Ulahannan, Surendra K Shukla, Kirsten L Bryant, Channing J Der, Kamiya Mehla, Pankaj K Singh.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent KRAS mutations, which activate the MAPK pathway to promote PDAC progression. Here, we explored metabolic vulnerabilities of PDAC by assessing initial metabolic reprogramming upon ERK inhibition using metabolomics, lipidomics, and isotope-tracing experiments. ERK inhibition enhanced lipid turnover and fatty acid oxidation while inhibiting glycolysis, glucose oxidation, and glutamine metabolism in PDAC cells. Moreover, lipophagy, but not cytosolic lipolysis, was responsible for the increased lipid turnover and fatty acid oxidation upon ERK inhibition. Lipophagy and lipophagy-fueled fatty acid oxidation were induced by increased nuclear translocation and activity of the transcription factor TFEB. Pharmacological inhibition of fatty acid oxidation in combination with KRASG12D/MEK/ERK inhibitors synergistically decreased the growth of PDAC cell lines and organoids. The combination decreased tumor burden and improved survival in orthotopic cell line and patient-derived xenograft PDAC models. Overall, this study provides mechanistic insights into the development of metabolic resistance to KRAS signaling inhibition and demonstrates that fatty acid oxidation is a metabolic vulnerability following KRAS signaling inhibition that can be utilized as an effective therapeutic target to treat PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1984
Indian J Pharmacol. 2026 May 01. 58(3): 215-223

Discovery of the protective effect of glutamine on acute alcoholic liver injury.

Huan Yang, Wei Guo, San-Qiang Li, Bing-Bing Zhang, Dan Wang, Wei-Gang Cheng, Shuning Chen.

   OBJECTIVE: Our research aims to evaluate the important role of glutamine (Gln) in alcohol (ethanol)-induced liver damage.
MATERIALS AND METHODS: In our study, the mice were simultaneously divided into normal group, alcohol group, and Gln+alcohol group. After different treatments, we detected alanine aminotransferase (ALT), aspartate aminotransferase (AST), and liver index. Then, some histopathological examination was used to observe the damage of liver tissue, glycogen, and liver cell apoptosis in mice. In addition, the expression of apoptosis-related proteins Bcl-2, Bax, Caspase3, heat stress protein 70 (HSP70), cytochrome cytochrome P450-2E1, NFκB pathway-related proteins IkB-a, NFκB-p65, and tumor necrosis factor-α were detected in different groups by western blotting. The experiment in vitro, we used normal hepatocytes L02, after treatment with alcohol and Gln for 24 h, carried out CCK-8 cell proliferation detection and western blotting to detect the expression of related proteins.
RESULTS: Our results showed that, in serological testing, Gln can significantly reduce the levels of ALT, AST, and liver index in Gln+alcohol group; and in the histopathological examination, Gln can increase the glycogen content and decrease the apoptosis rate in Gln+alcohol group. In addition, the differential expression of IκBα, NFκB-p65, and other factors in Western blotting shows that the NFκB signaling pathway plays important role in acute alcoholic liver injury.
CONCLUSIONS: Our results showed that Gln played an important protective role in alcohol-induced liver injury in mice by regulating glycogen stores, apoptosis, anti-oxidative stress and inhibiting NF-κB signaling pathways in liver cells.

Keywords:  Acute liver injury; alcohol; glutamine; mechanism; protective effect

DOI:  https://doi.org/10.4103/ijp.ijp_26_24
ACS Infect Dis. 2026 Apr 29.

Glutamine Potentiates Cefoperazone-Sulbactam against Klebsiella pneumoniae by Enhancing Cellular Uptake and ROS Production.

Shao-Hua Li, Yu-Yan Chen, Huan-Zhe Fu, Hui-Yin Lin, Yuan Tao, Xian-Liang Zhao, Yue-Tao Chen, Jiao Xiang, Ying-Yue Zeng, Shi-Wen Wang, Kui-Hai Wu, Zheng-Qi Shi, Jin Tang, Xiao-Xia Huang, Xin Wang, Hui Li, Li-Rong Lin, Xuan-Xian Peng.

  Antibiotic-resistant Klebsiella pneumoniae poses a serious global challenge to clinical practice and public health, highlighting an urgent need for effective therapeutic strategies. This study systematically evaluated the preclinical pharmacodynamics of cefoperazone-sulbactam (SCF) in combination with glutamine against K. pneumoniae. Clinically isolated strains were classified into three groups: 56 sensitive (S-KP), 62 multidrug-resistant but carbapenem-sensitive (MDR-KP), and 195 multidrug-resistant and carbapenem-resistant (CR-KP) isolates. Compared with SCF alone, the combination with glutamine enhanced bacterial killing in 95.85% of the tested isolates. This potentiation was further confirmed by time-kill kinetic assays and a murine infection model, with results showing consistent efficacy independent of pH and calcium levels but dependent on bacterial inoculum. Moreover, glutamine delayed the increase in the minimum inhibitory concentration of SCF, extended its postantibiotic effect, and reduced the mutation frequency. Mechanistically, glutamine overcomes antibiotic resistance by reprogramming bacterial metabolism to promote cefoperazone uptake and elevate reactive oxygen species (ROS) production. Increased intracellular drug levels counteract efflux- and hydrolysis-mediated defenses, while elevated ROS acts synergistically with the antibiotic, together resulting in enhanced bactericidal activity. This study demonstrates that glutamine enhances the activity of SCF against a broad range of K. pneumoniae pathogens, supporting its potential development as an adjuvant therapy for resistant infections.

Keywords:  Klebsiella pneumonia; carbapenem resistance; cefoperazone and sulbactam; glutamine; multidrug resistance; preclinical pharmacodynamics

DOI:  https://doi.org/10.1021/acsinfecdis.6c00129
J Proteome Res. 2026 Apr 27.

1H NMR-Based Plasma Metabolomics and Machine Learning Reveal Distinct Metabolic Signatures of Breast Cancer in Nigerian Women.

Abimbola F Onyia, Olutola E Olasehinde, Uchechukwu Shagaya, Emmanuella Nwachukwu, Ademola Oyekan, Omolara Fatiregun, Temitope Olatunji, AbdulRazzaq Lawal, Adewumi Alabi, Eben A Aje, Anthonia Sowunmi, Oluwabusayo B Ogunniyi, Chidiebere Ndukwe Ogo, Ebenezer S Nkom, Opeyemi Christianah De Campos, Oluwakemi A Rotimi, Jelili Oyelade, Toluwanimi O P Ajibola, Timothy A Anake, Nnenna Elebo, Ekene Emmanuel Nweke, Luiz F Zerbini, Stefano Cacciatore, Solomon O Rotimi.

  Untargeted 1H NMR metabolomics offers a noninvasive means to identify biomarkers in breast cancer (BC) patients; however, metabolic signatures specific to Nigerian women remain poorly understood. This study aimed to identify plasma metabolomic and lipidomic biomarkers associated with BC in Nigerian patients, evaluate their diagnostic performance using machine learning (ML), and identify dysregulated metabolic pathways. This case-control study recruited 100 BC patients and 100 healthy controls from 4 Nigerian teaching hospitals. Plasma metabolites and lipids were profiled using 1H NMR spectroscopy and the Liposcale test. Multivariate and ML analyses revealed a clear distinction between BC and controls (PLS-DA accuracy: 92.4-94.4%). Twenty-four metabolites were significantly altered (FDR < 0.05), with decreased glycine and glutamine, and increased GlycA, GlycB, glucose, and ketone bodies. Lipoprotein profiling showed reduced small HDL, LDL, and large VLDL particles, alongside with increased HDL diameter. The random forest model achieved the best classification performance (AUC = 0.985) and identified 23 key biomarkers. Pathway analysis revealed 29 enriched metabolic pathways, including glyoxylate and dicarboxylate metabolism. Overall, these findings highlight distinct metabolic alterations in Nigerian BC patients and demonstrate the potential of combining NMR-based metabolomics with ML for population-specific, noninvasive BC diagnostics.

Keywords:  NMR metabolomics; Nigeria; breast cancer; lipidomics; machine learning

DOI:  https://doi.org/10.1021/acs.jproteome.5c00965
Cell Rep Med. 2026 Apr 29. pii: S2666-3791(26)00201-6. [Epub ahead of print] 102784

BCAT1-dependent HIF-1α stabilization is a targetable metabolic vulnerability in hepatocellular carcinoma.

Misty Shuo Zhang, Kenneth Kin-Leung Kwan, Aki Pui-Wah Tse, Gengchao Wang, Larry Lai Wei, Kejie Sun, Noreen Nog-Qin Chui, Derek Lee, Macus Hao-Ran Bao, Xiaoxuan Pang, Zhenqi Wu, Yanyan Chen, Yangyang Wang, Zifan Yang, Xue Jiang, Qidong Li, Yan Zhang, Yajie Zhong, Jacinth Wing-Sum Cheu, Yiling Chen, Weixing Li, Chun-Ming Wong, Jianing Wang, Zongwei Cai, Qi Zhang, Tingbo Liang, Irene Oi-Lin Ng, Adonia E Papathanassiu, Carmen Chak-Lui Wong.

  Hypoxia is a common characteristic of solid tumors, especially in hepatocellular carcinoma (HCC). Hypoxia-inducible factors (HIFs), particularly HIF-1α, mediate metabolic adaptation, which is crucial for survival of hypoxic cells. Branched-chain amino transferase 1 (BCAT1) catalyzes the reversible transamination reaction between branched-chain amino acids (BCAAs) and branched-chain keto acids (BCKAs), involving the inter-conversion of α-ketoglutarate (α-KG) and glutamate. We investigate and delineate the mechanisms by which BCAT1 consumes α-KG and stabilizes HIF-1α, suppressing α-KG-dependent oxygen dehydrogenase, prolyl hydroxylase-domain protein (PHD), inducing HIF-1α-mediated metabolic reprogramming and promoting hypoxic survival of HCC. We evaluate the potency of a BCAT1 inhibitor, ERG245, as a single or combination treatment with tyrosine kinase inhibitor (TKI) in vivo. We further validate the over-expression and correlation of BCAT1 and HIF-1α downstream metabolic genes in HCC clinical samples. Our results indicate that BCAT1 benefits HCC growth through HIF-1α-induced metabolic reprogramming. Targeting BCAT1 will provide an effective therapeutic strategy for HCC patients.

Keywords:  EGR245; branched-chain amino transferase 1; hepatocellular carcinoma; hypoxia; hypoxia-inducible factor; metabolic reprogramming; prolyl hydroxylase-domain protein; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.xcrm.2026.102784
Front Biosci (Landmark Ed). 2026 Apr 21. 31(4): 49215

Multi-Dimensional Data Integration Reveals the Molecular Mechanism of Metabolic Reprogramming Associated With Low Asparaginase Expression in Hepatocellular Carcinoma.

Yiwu Dang, Yulong Deng, Yuxing Tang, Ruiling Su, Kesong Nong, Wei Qin, Zhendong Chen, Li Xiao, Dandan Xiong, Zhenbo Feng.

   BACKGROUND: To investigate the impact of low expression of asparaginase (ASPG) in hepatocellular carcinoma (HCC) on tumor metabolic reprogramming, tumor microenvironment interactions, and drug sensitivity, and to assess the potential of ASPG as a tumor suppressor gene through multi-dimensional functional mechanisms.
METHODS: Thus, ASPG expression in HCC was systemically evaluated by integrating global multi-center mRNA datasets, including RNA-seq and microarray data from 3967 HCCs and 2645 non-HCC samples, single-cell RNA sequencing (scRNA-seq) data from 10 HCCs and 8 adjacent normal tissues, spatial transcriptomics (STs), and internal immunohistochemistry data from 301 HCCs and matched adjacent liver tissues. A CRISPR-mediated gene knockout model was employed to examine the effects of ASPG deletion on HCC cell proliferation. ASPG-associated regulatory pathways were analyzed using Gene Set Enrichment Analysis (GSEA), GeneMANIA, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Changes in ligand-receptor interactions between low-expression ASPG (ASPG-low) and the tumor microenvironment were examined using CellChat, based on scRNA-seq data. Single-cell metabolism (scmetabolism) and single-cell flux estimation analysis (scFEA) were applied to infer metabolic activity and metabolite conversion pathways under ASPG-low conditions. Finally, correlations between ASPG expression and the IC50 values of anticancer drugs were assessed using OncoPredict.
RESULTS: Multi-dimensional analyses consistently showed that both ASPG mRNA and protein levels were significantly downregulated in HCC. CRISPR-mediated ASPG knockout was associated with significantly increased cell proliferation. Mechanistically, HCC cells with low ASPG expression were enriched in pathways related to alanine, aspartate, and glutamate metabolism, as well as amino acid biosynthesis, gluconeogenesis, and lipid metabolism. Cell-cell communication analysis revealed strong interactions between ASPG-low malignant hepatocytes and myeloid cells, with significant activation of the MIF-(CD74+CXCR4) and MIF-(CD74+CD44) signaling axes. Metabolic analysis demonstrated that the ASPG-low state was associated with alanine, aspartate, and glutamate metabolism, as well as the citric acid (TCA) cycle, thereby regulating the conversion of the aspartate-asparagine and glutamate-2OG metabolites. ASPG-low HCC was associated with resistance to drugs such as cisplatin, oxaliplatin, and gemcitabine, but increased sensitivity to lapatinib and paclitaxel.
CONCLUSION: Low ASPG expression in HCC may drive aspartate metabolism and reprogramming of the TCA cycle, thereby influencing sensitivity to drug treatment.

Keywords:  asparaginase; hepatocellular carcinoma; immunohistochemistry; metabolic reprogramming; single-cell analysis; spatial transcriptomics

DOI:  https://doi.org/10.31083/FBL49215
Cells. 2026 Apr 15. pii: 702. [Epub ahead of print]15(8):

Pelargonium graveolens Essential Oil Suppresses Proliferation and Migration and Modulates Mesenchymal-Associated Cellular Functions in Human Endometriotic Cells.

Elif Karakoç, Sezai Berkand Koçak, Kevser Kişifli Köş, Hülya Kayhan, Eda Erdem Şahinkesen, Cemil Can Eylem, Ferda Topal Çelikkan, Emirhan Nemutlu, Pergin Atilla.

  Endometriosis is characterized by enhanced cellular proliferation, migration, and resistance to apoptosis, contributing to lesion persistence and progression. Targeting cellular plasticity and mesenchymal-associated functions may therefore represent a promising therapeutic strategy. Here, we investigated the effects of Pelargonium graveolens essential oil (PGEO) on proliferation, apoptosis, migration, cytoskeletal organization, transcriptional regulation, and metabolic alterations in human endometriotic 12Z cells. PGEO treatment suppressed proliferative capacity in a concentration-dependent manner and significantly impaired cell migration, accompanied by reduced β-tubulin expression and decreased levels of mesenchymal-associated markers CD73 and CD105. Increased GRP78 expression together with ultrastructural alterations, including cytoplasmic vacuolization and mitochondrial and endoplasmic reticulum changes, indicated activation of cellular stress responses. Although transcriptional analysis revealed increased CCND1 and PIK3CA mRNA levels, these changes did not parallel the observed suppression of proliferation, suggesting compensatory regulatory responses. Untargeted metabolomic profiling revealed alterations in energy metabolism characterized by increased levels of glycolysis-related metabolites, reduced levels of several amino acids including glutamine and histidine, and changes in lipid-associated metabolites. Collectively, these findings demonstrate that PGEO suppresses proliferative and migratory behavior in endometriotic cells while modulating cytoskeletal, transcriptional, and metabolic pathways, highlighting its potential as a candidate for further investigation in endometriosis-targeted therapeutic strategies.

Keywords:  Pelargonium graveolens; apoptosis; electron microscopy; endometriosis; mesenchymal; metabolomics; migration; organelle; proliferation; xCELLigence

DOI:  https://doi.org/10.3390/cells15080702
Chem Biol Interact. 2026 Apr 29. pii: S0009-2797(26)00224-3. [Epub ahead of print] 112116

6H2L, a novel derivative of bifendate, dually suppresses glycolysis and glutaminolysis in hepatocellular carcinoma via inhibiting YAP stability.

Beibei Zhang, Kaixuan Sheng, Yue Yan, Xinlei Wang, Xinning Cheng, Rong Liao, Zhiyi Yang, Mengyi Li, Fan Wang, Qi Qi, Yu Wang, Chenglin Li.

  Hepatocellular carcinoma (HCC) has poor clinical outcomes due to limited chemotherapy response and low targeted therapy efficacy. Metabolic reprogramming, a key hallmark of HCC tumorigenesis, represents a promising therapeutic target. This study elucidated the regulatory effects and underlying mechanism of 6H2L, a novel bifendate derivative, on metabolic reprogramming in HCC. CCK-8, EdU, and colony formation assays were employed to evaluate cell proliferation. The expression of key enzymes involved in glycolysis and glutaminolysis was analyzed by western blot and qPCR. Cycloheximide/MG-132 treatment, co-immunoprecipitation, and luciferase reporter assay were performed to investigate the effects of 6H2L on Yes associated protein (YAP) stability, localization, and transcriptional activity. The anti-tumor activity of 6H2L were verified by a subcutaneous xenograft model. 6H2L inhibited HCC cell proliferation by dually suppressing glycolysis and glutaminolysis. YAP was found to promote HCC growth in vivo by facilitating both glycolysis and glutaminolysis. Mechanistically, 6H2L directly bond to nuclear Dbf2-related kinase 1 (NDR1) and activated NDR signaling, thereby increasing phosphorylation of YAP at Ser127, which enhanced the binding of YAP to 14-3-3 protein and facilitated subsequent ubiquitin-mediated YAP degradation. This process inhibited YAP activity and reduced glycolysis and glutaminolysis. NDR1 knockdown attenuated the inhibitory effects of 6H2L on YAP stability, metabolic reprogramming, and cell proliferation. In vivo studies confirmed that 6H2L inhibited HCC growth via NDR/YAP axis with a favorable safety profile. Collectively, these findings identify the NDR/YAP axis as a novel target for disrupting glycolysis and glutaminolysis in HCC, and further highlight 6H2L as a promising therapeutic candidate.

Keywords:  Bifendate derivative; Glutaminolysis; Glycolysis; Hepatocellular carcinoma; NDR; YAP

DOI:  https://doi.org/10.1016/j.cbi.2026.112116
Curr Oncol. 2026 Mar 31. pii: 201. [Epub ahead of print]33(4):

Metabolomic Insights into Head and Neck Cancer: Recent Advances and Future Directions.

Srikanth Ponneganti, Kousalya Lavudi, Maharshi Thalla, Gayatri Narkhede, Reva Dwivedi, Rekha Kokkanti, Prashant Pandey.

  Head and neck squamous cell carcinoma (HNSCC) continues to pose a major global health challenge, with over 600,000 new cases diagnosed annually and persistently poor survival outcomes despite advances in surgery, radiotherapy, and immunotherapy. Growing evidence implicates metabolic reprogramming, including enhanced glycolysis, glutaminolysis, lipid synthesis, and one-carbon/redox flux as a central driver of HNC initiation, progression, and therapy resistance. In contrast, metabolic crosstalk within the hypoxic, acidic tumor microenvironment (TME) further shapes immune evasion and stromal support. Recent innovations in mass spectrometry platforms (LC-MS, GC-MS, NMR) have attracted attention in clinical therapeutics, and spatial metabolomics imaging techniques now enable high-resolution in situ mapping of metabolites, revealing intratumoral heterogeneity and offering new insights into tumor-immune-stromal interactions and potential biomarkers for precision oncology. In this review, we integrate critical methodological considerations from sample collection and data-analysis workflows to analytical pitfalls with a balanced, pathway-focused analysis of HNSCC dysmetabolism, examine tumor immune stromal metabolic interactions, and highlight translational opportunities through emerging biomarkers, targeted inhibitors, and cutting-edge approaches such as single-cell and AI-driven metabolomics to chart a roadmap toward precision oncology for HNSCC.

Keywords:  cancer-associated fibroblasts; metabolomics; squamous cell carcinoma; tumor microenvironment

DOI:  https://doi.org/10.3390/curroncol33040201
Sci Adv. 2026 May;12(18): eaed8013

LIPT1 loss confers replication stress and PARP inhibitor sensitivity through PrimPol-mediated ssDNA gaps.

Zengfu Shang, Jui-Chung Chiang, Ching-Cheng Hsu, Ciara Newman, Anthony J Davis, Yuanyuan Zhang.

Replication stress (RS) and altered metabolism are two hallmarks of cancer, yet how metabolic perturbations contribute to RS remains poorly understood. Lipotransferase 1 (LIPT1) catalyzes the covalent attachment of lipoic acid to mitochondrial 2-ketoacid dehydrogenases, sustaining flux through the tricarboxylic acid (TCA) cycle. Loss of LIPT1 causes accumulation of 2-hydroxyglutarate (2-HG), which is known to inhibit α-ketoglutarate (α-KG)-dependent histone demethylases and promotes heterochromatin formation. Here, we show that 2-HG-driven heterochromatin impedes replication fork progression, causing fork stalling and RS in LIPT1-deficient cancer cells. To bypass stalled forks, PrimPol-mediated repriming resumes DNA synthesis but leaves behind single-stranded DNA (ssDNA), which requires poly(adenosine 5'-diphosphate-ribose) polymerase 1 (PARP1) for repair. Furthermore, nascent DNA at reprimed forks undergoes MRE11-dependent degradation, further destabilizing replication fork integrity. Consequently, LIPT1 deficiency promotes replication and genome instability, and therapeutic vulnerability to PARP inhibitor. Together, these findings reveal a mechanistic link between mitochondrial lipoylation and replication fork stability, uncovering a metabolic basis for genome instability in cancer.

DOI: https://doi.org/10.1126/sciadv.aed8013