bims-glucam 2025-02-16 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–02–16
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Results of the phase I/II study and preliminary B cell gene signature of combined inhibition of glutamine metabolism and EGFR in colorectal cancer.
Role of amino acid metabolism in tumor immune microenvironment of colorectal cancer.
Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutaminase and glutamate export.
A hybrid machine learning framework for functional annotation of mitochondrial glutathione transport and metabolism proteins in cancers.
Glutamine transporter inhibitor enhances the sensitivity of NSCLC to trametinib through GSDME-dependent pyroptosis.
Metabolic Heterogeneity in Diffuse Large B-Cell Lymphoma Cells Reveals an Innovative Antimetabolic Combination Strategy.
Metabolic reprogramming of macrophages by a nano-sized opsonization strategy to restore M1/M2 balance for osteoarthritis therapy.
Longevity Humans Have Youthful Erythrocyte Function and Metabolic Signatures.
Tumor-Targeted Glutamine Metabolism Blocker Synergizes with TiO2-Au Janus Nanoparticles for Enhanced Sono-Metabolic Antitumor Therapy.
Glutathione and transglutaminase responsive janus gold nanorods for photoacoustic imaging-guided radiotherapy and chemodynamic therapy of tumors.
ACAT1-Mediated ME2 Acetylation Drives Chemoresistance in Ovarian Cancer by Linking Glutaminolysis to Lactate Production.
Metabolic landscape and rewiring in normal hematopoiesis, leukemia and aging.
α-Ketoglutarate inhibits the pluripotent-to-totipotent state transition in stem cells.
CircMFN2/miR-361-3p/ELK1 feedback loop promotes glutaminolysis and the progression of hepatocellular carcinoma.

Clin Cancer Res. 2025 Feb 10.

Results of the phase I/II study and preliminary B cell gene signature of combined inhibition of glutamine metabolism and EGFR in colorectal cancer.

Kristen K Ciombor, Seong-Woo Bae, Jennifer G Whisenant, Gregory D Ayers, Quanhu Sheng, Todd E Peterson, Gary T Smith, Kangyu Lin, Saikat Chowdhury, Preeti Kanikarla Marie, Alexey Sorokin, Allison S Cohen, Laura W Goff, Dana B Cardin, John Paul Shen, Scott Kopetz, Cathy Eng, Yu Shyr, Jordan Berlin, H Charles Manning.

PURPOSE: EGFR-targeting monoclonal antibodies are essential for managing RAS WT metastatic colorectal cancer (mCRC), but their limited efficacy necessitates exploring immunological and metabolic factors influencing response. This study evaluated glutamine metabolism targeting with EGFR inhibition to identify response biomarkers in patients with prior anti-EGFR treatment progression.
EXPERIMENTAL DESIGN: We conducted a phase I/II trial in KRAS WT mCRC patients, combining panitumumab and CB-839, hypothesizing that dual inhibition of glutamine metabolism and MAPK signaling would enhance outcomes. As study correlatives, we investigated the B cell activation signature 'Bscore' and glutamine PET as potential treatment response biomarkers.
RESULTS: The combination of panitumumab and CB-839 was tolerable with manageable side effects, including Grade 4 hypomagnesemia in four patients, a known panitumumab-related event. Two patients achieved partial response (PR), and five had stable disease (SD), with a 41% disease control rate (DCR). Median progression-free survival (PFS) and overall survival (OS) were 1.84 and 8.87 months, respectively. A positive correlation between 'Bscore' and lesion size reduction suggested its association with clinical benefit (PR and SD). Lower 'Bscore' correlated with greater tumor avidity for glutamine by PET, indicating B cell activation sensitivity to glutamine depletion.
CONCLUSIONS: The combination of CB-839 and panitumumab showed safety and promising preliminary responses, but the study closed early due to CB-839 development termination. The B cell activation signature 'Bscore' emerged as a potential biomarker for EGFR and glutaminase inhibition in mCRC, warranting further studies. These findings suggest opportunities to improve immune response and therapies in glutaminolysis-dependent tumors.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-3133
Am J Cancer Res. 2025 ;15(1): 233-247

Role of amino acid metabolism in tumor immune microenvironment of colorectal cancer.

Minjing Zhu, Yanyan Hu, Yangjia Gu, Xuedan Lin, Xiang Jiang, Chaoju Gong, Zejun Fang.

  This review investigates the role of amino acid metabolism in the tumor microenvironment of colorectal cancer (CRC) and explores potential targeted therapeutic strategies. The paper synthesized current research on amino acid metabolism in the colorectal cancer tumor microenvironment, focusing on amino acids such as tryptophan, methionine, glutamine, and arginine. It examined their impact on tumor growth, immune evasion, and patient prognosis, as well as the metabolic reprogramming of tumor cells and complex tumor microenvironment interactions. Aberrant amino acid metabolism was a hallmark of colorectal cancer, influencing tumor proliferation, survival, and invasiveness. Key findings included: Tryptophan metabolism via the kynurenine and serotonin pathways significantly affected immune response and tumor progression in CRC. Methionine influenced T cell function and DNA methylation, playing a critical role in tumor development. Glutamine was extensively used by tumor cells for energy metabolism and supported immune cell function. Arginine metabolism impacted CD8+ T cell functionality and tumor growth. The review also discussed the dual roles of immune cells in the tumor microenvironment and the potential of targeting amino acid metabolic pathways for CRC treatment. In conclusion, amino acid metabolism significantly impacts the colorectal cancer tumor microenvironment and immunity. Understanding these metabolic pathways provides valuable insights into CRC pathogenesis and identifies potential therapeutic targets. Future research should focus on developing treatments that disrupt these metabolic processes to improve patient outcomes in CRC.

Keywords:  Colorectal cancer; amino acid metabolism; immune evasion; therapeutic targets; tumor microenvironment

DOI:  https://doi.org/10.62347/ZSOO2247
Neoplasia. 2025 Feb 11. pii: S1476-5586(25)00015-6. [Epub ahead of print]61 101136

Disruption of redox balance in glutaminolytic triple negative breast cancer by inhibition of glutaminase and glutamate export.

Hoon Choi, Mamta Gupta, Arjun Sengupta, Emma E Furth, Christopher Hensley, Aalim M Weljie, Hsiaoju Lee, Yu-Ting Lu, Austin Pantel, David Mankoff, Rong Zhou.

  Resistance to chemotherapy is an important challenge in the clinical management of triple-negative breast cancer (TNBC). Utilization of the amino acid glutamine as a key nutrient is a metabolic signature of TNBC featuring high glutaminase (GLS) activity and a large pool of cellular glutamate, which mediates intracellular enrichment of cystine via xCT (SLC7A11) antiporter activity. To overcome chemo-resistant TNBC, we identified a strategy of dual metabolic inhibition of GLS and xCT to sensitize resistant TNBC cells to chemotherapy. We successfully tested this strategy in a human TNBC line and its chemoresistant variant in vitro and their xenograft models in vivo. Key findings of our study include: 1. Dual metabolic inhibition induced pronounced reductions of cellular glutathione accompanying significant increases of cellular superoxide level in both parent and resistant TNBC cells. While GLS and xCT inhibition did not directly kill cells via apoptosis, they potentiated doxorubicin (DOX) and cisplatin (CIS) to induce remarkably higher levels of apoptosis than DOX or CIS alone. 2. Although the resistant TNBC cells exhibited higher capacity to mitigate oxidative stress than the parent cells, their resistance was overcome by dual metabolic inhibition combined with DOX or CIS. 3. In vivo efficacy and safety of the triple combination (GLS and xCT inhibition plus DOX or CIS) were demonstrated in both chemo sensitive and resistant TNBC tumors in mice. In conclusion, GLS and xCT inhibition resulted in unmitigated oxidative stress due to depletion of glutathione, representing a promising strategy to overcome chemoresistance in glutamine-dependent TNBC.

Keywords:  Chemo-resistance; Glutaminase; Glutathione; Redox; Triple-negative breast cancer; cystine transporter

DOI:  https://doi.org/10.1016/j.neo.2025.101136
BMC Bioinformatics. 2025 Feb 11. 26(1): 48

A hybrid machine learning framework for functional annotation of mitochondrial glutathione transport and metabolism proteins in cancers.

Luke Kennedy, Jagdeep K Sandhu, Mary-Ellen Harper, Miroslava Cuperlovic-Culf.

   BACKGROUND: Alterations of metabolism, including changes in mitochondrial metabolism as well as glutathione (GSH) metabolism are a well appreciated hallmark of many cancers. Mitochondrial GSH (mGSH) transport is a poorly characterized aspect of GSH metabolism, which we investigate in the context of cancer. Existing functional annotation approaches from machine (ML) or deep learning (DL) models based only on protein sequences, were unable to annotate functions in biological contexts.
RESULTS: We develop a flexible ML framework for functional annotation from diverse feature data. This hybrid ML framework leverages cancer cell line multi-omics data and other biological knowledge data as features, to uncover potential genes involved in mGSH metabolism and membrane transport in cancers. This framework achieves strong performance across functional annotation tasks and several cell line and primary tumor cancer samples. For our application, classification models predict the known mGSH transporter SLC25A39 but not SLC25A40 as being highly probably related to mGSH metabolism in cancers. SLC25A10, SLC25A50, and orphan SLC25A24, SLC25A43 are predicted to be associated with mGSH metabolism in multiple biological contexts and structural analysis of these proteins reveal similarities in potential substrate binding regions to the binding residues of SLC25A39.
CONCLUSION: These findings have implications for a better understanding of cancer cell metabolism and novel therapeutic targets with respect to GSH metabolism through potential novel functional annotations of genes. The hybrid ML framework proposed here can be applied to other biological function classifications or multi-omics datasets to generate hypotheses in various biological contexts. Code and a tutorial for generating models and predictions in this framework are available at: https://github.com/lkenn012/mGSH_cancerClassifiers .

Keywords:  Cancer; Gene ontology; Glutathione; Knowledge-based; Machine learning; Mitochondria; Multi-omics; Protein function annotation; SLC25; Transmembrane transport

DOI:  https://doi.org/10.1186/s12859-025-06051-1
Biochem Pharmacol. 2025 Feb 07. pii: S0006-2952(25)00058-9. [Epub ahead of print] 116796

Glutamine transporter inhibitor enhances the sensitivity of NSCLC to trametinib through GSDME-dependent pyroptosis.

Qingxia Liu, Jinxia Hu, Xinzhen Li, Haiwang Gao, Dexin Kong, Meihua Jin.

  Trametinib, an inhibitor of mitogen-activated extracellular signal-regulated kinases 1/2 (MEK1/2), is used to treat BRAFV600E/K melanoma and non-small-cell lung cancer (NSCLC). Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) promotes glutamine utilization, therefore, in the present study we investigated the anti-cancer effects of trametinib in combination with V-9302, a glutamine transporter inhibitor, in NSCLC with KRAS mutations. Trametinib in combination with V-9302 exhibited a potent synergistic antitumor effect, inducing cell cycle arrest and pyroptosis. Mechanistically, combination treatment triggered caspase-3 activation and gasdermin E (GSDME) cleavage, as well as elevated lactate dehydrogenase (LDH) and IL-1β levels. Meanwhile, combination treatment reduced cyclin D1 and p-Rb levels and increased p27 expression. Moreover, this combination increased forkhead box class O3a (FOXO3a) levels and decreased forkhead box M1 (FOXM1) expression by regulating the phosphorylation of ERK, Akt, AMPK, and c-Jun N-terminal kinase (JNK). Trametinib in combination with V-9302 increased reactive oxygen species (ROS) generation and reduced glutathione (GSH) synthesis and ATP levels. Furthermore, V-9302 in combination with trametinib inhibited the trametinib-induced autophagy, thereby enhancing pyroptosis in cancer cells. In vivo, the co-administration of trametinib and V-9302 remarkably inhibited tumor growth in a xenograft mouse model compared to each drug alone. Taken together, the combination of trametinib and V-9302 resulted in increased pyroptosis and cell cycle arrest compared to each single agent through regulation of the FOXO3a/FOXM1 axis and autophagy and significantly enhanced antitumor efficacy in vivo. Our results suggest a potential new therapeutic strategy for KRAS-mutant NSCLC using trametinib in combination with glutamine restriction.

Keywords:  Autophagy; Glutamine; NSCLC; Pyroptosis; Trametinib

DOI:  https://doi.org/10.1016/j.bcp.2025.116796
Cancers (Basel). 2025 Jan 24. pii: 394. [Epub ahead of print]17(3):

Metabolic Heterogeneity in Diffuse Large B-Cell Lymphoma Cells Reveals an Innovative Antimetabolic Combination Strategy.

Leonardo Lordello, Stéphanie Nuan-Aliman, Karoline Kielbassa-Elkadi, Aurélie Montagne, Konstantina Kotta, Isabelle Martins, Eva Pinto Jurado, Cédric Caradeuc, Jacqueline Lehmann-Che, José Ángel Martínez-Climent, Véronique Meignin, Nicolas Giraud, Guido Kroemer, Gildas Bertho, Catherine Thieblemont, Véronique Baud.

  Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, characterized by aggressive and heterogeneous tumors originating from B-cells. Especially in patients with relapsed or refractory (R/R) disease, DLBCL remains a challenging cancer to treat. Metabolic reprogramming is a hallmark of malignant cells. Our research focuses on developing strategies to enhance clinical outcomes for R/R DLBCL patients by targeting metabolic vulnerabilities. Methods: We investigated the effects of combining metformin and L-asparaginase, two FDA-approved antimetabolic drugs, on DLBCL cell metabolism and survival. Nuclear magnetic resonance (NMR) spectroscopy was employed to assess metabolic disturbances induced by the drug combination. The impact on lipid metabolism, glycolysis, glutaminolysis, the tricarboxylic acid (TCA) cycle, and antioxidant responses was examined. Induction of apoptosis was evaluated by FACS analysis. Results: The combination of metformin and L-asparaginase strongly sensitized DLBCL cells to apoptosis, independently of their oxidative phosphorylation (OxPhos) or BCR/glycolytic status. NMR spectroscopy revealed that this combination induces broader metabolic disturbances than either drug alone. It disrupts lipid metabolism by altering levels of phospholipids, cholesterol, and fatty acids. Additionally, it counteracts the pro-glycolytic effect of metformin, decreases glycolysis, and reduces glutaminolysis. It also affects the TCA cycle and antioxidant responses, critical for cellular energy production and redox balance. Furthermore, this combination interferes with two key cancer survival pathways, mTORC1 and MAPK signaling. Importantly, proof of principle for its beneficial effect was demonstrated in DLBCL patients. Conclusions: Combining metformin and L-asparaginase affects DLBCL cell survival by targeting multiple metabolic pathways and may represent a novel therapeutic approach for R/R DLBCL patients.

Keywords:  B-cell lymphoma; apoptosis; cell death; combination of antimetabolic drugs; diffuse large B-cell lymphoma (DLBCL); metabolism; oncogenic pathways

DOI:  https://doi.org/10.3390/cancers17030394
J Control Release. 2025 Feb 11. pii: S0168-3659(25)00111-7. [Epub ahead of print]380 469-489

Metabolic reprogramming of macrophages by a nano-sized opsonization strategy to restore M1/M2 balance for osteoarthritis therapy.

Ruijie Chen, Shimin Zheng, Xinyu Zhao, Huirong Huang, Yitianhe Xu, Chenyu Qiu, Shengjie Li, Xindan Liang, Pengfei Mao, Yuqi Yan, Yinhao Lin, Shengnan Song, Wenjing Cai, Haoxiong Guan, Yinsha Yao, Wanling Zhu, Xianbao Shi, Vadivel Ganapathy, Longfa Kou.

  Osteoarthritis is a chronic and progressive joint disease accompanied by cartilage degeneration and synovial inflammation. It is associated with an imbalance of synovial macrophage M1/M2 ratio tilting more towards the pro-inflammatory M1 than the anti-inflammatory M2. The M1-macrophages rely on aerobic glycolysis for energy whereas the M2-macrophages derive energy from oxidative phosphorylation. Therefore, inhibiting aerobic glycolysis to induce metabolic reprogramming of macrophages and consequently promote the shift from M1 type to M2 type is a therapeutic strategy for osteoarthritis. Here we developed a macrophage-targeting strategy based on opsonization, using nanoparticles self-assembled to incorporate Chrysin (an anti-inflammatory flavonoid) and V-9302 (an inhibitor of glutamine uptake), and the outer layer modified by immunoglobulin IgG by electrostatic adsorption into IgG/Fe-CV NPs. In vitro studies showed that IgG/Fe-CV NPs effectively target M1 macrophages and inhibit HIF-1α and GLUT-1 essential for aerobic glycolysis and promote polarization from M1 to M2-type macrophages. In vivo, IgG/Fe-CV NPs inhibit inflammation and protect against cartilage damage. The metabolic reprogramming strategy with IgG/Fe-CV NPs to shift macrophage polarization from inflammatory to anti-inflammatory phenotype by inhibiting aerobic glycolysis and glutamine delivery may open up new avenues to treat osteoarthritis.

Keywords:  Aerobic glycolysis; HIF-1α; Macrophage reprogramming; Opsonization; Osteoarthritis

DOI:  https://doi.org/10.1016/j.jconrel.2025.02.005
Aging Cell. 2025 Feb 09. e14482

Longevity Humans Have Youthful Erythrocyte Function and Metabolic Signatures.

Fang Yu, Changhan Chen, Wuping Liu, Zhixiang Zhao, Yuhua Fan, Zhenjiang Li, Weilun Huang, Tingting Xie, Cheng Luo, Zhouzhou Yao, Qi Guo, Zhiyu Yang, Juan Liu, Yujin Zhang, Rodney E Kellems, Jian Xia, Ji Li, Yang Xia.

  Longevity individuals have lower susceptibility to chronic hypoxia, inflammation, oxidative stress, and aging-related diseases. It has long been speculated that "rejuvenation molecules" exist in their blood to promote extended lifespan. We unexpectedly discovered that longevity individuals exhibit erythrocyte oxygen release function similar to young individuals, whereas most elderly show reduced oxygen release capacity. Untargeted erythrocyte metabolomics profiling revealed that longevity individuals are characterized by youth-like metabolic reprogramming and these metabolites effectively differentiate the longevity from the elderly. Quantification analyses led us to identify multiple novel longevity-related metabolites within erythrocytes including adenosine, sphingosine-1-phosphate (S1P), and glutathione (GSH) related amino acids. Mechanistically, we revealed that increased bisphosphoglycerate mutase (BPGM) and reduced MFSD2B protein levels in the erythrocytes of longevity individuals collaboratively work together to induce elevation of intracellular S1P, promote the release of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from membrane to the cytosol, and thereby orchestrate glucose metabolic reprogramming toward Rapoport-Luebering Shunt to induce the 2,3-BPG production and trigger oxygen delivery. Furthermore, increased glutamine and glutamate transporter expression coupled with the enhanced intracellular metabolism underlie the elevated GSH production and the higher anti-oxidative stress capacity in the erythrocytes of longevity individuals. As such, longevity individuals displayed less systemic hypoxia-related metabolites and more antioxidative and anti-inflammatory metabolites in the plasma, thereby healthier clinical outcomes including lower inflammation parameters as well as better glucose-lipid metabolism, and liver and kidney function. Overall, we identified that youthful erythrocyte function and metabolism enable longevity individuals to better counteract peripheral tissue hypoxia, inflammation, and oxidative stress, thus maintaining healthspan.

Keywords:  erythrocyte; longevity; metabolomic; oxidative stress; oxygen release

DOI:  https://doi.org/10.1111/acel.14482
Adv Mater. 2025 Feb 14. e2418800

Tumor-Targeted Glutamine Metabolism Blocker Synergizes with TiO2-Au Janus Nanoparticles for Enhanced Sono-Metabolic Antitumor Therapy.

Jinling Zheng, Fenghuan Zhao, Eugenie Pariente, Xiaoyu Xu, Xu Zhang, Shayibai Shabiti, Yingying Ke, Junjie Hao, Jean-Pierre Delville, Marie Helene Delville, Wenjun Li.

  Sonodynamic therapy (SDT) is a promising therapeutic modality known for its non-invasiveness, temporal-spatial controllability, and deeper tissue penetration. However, the SDT treatment efficacy is still hampered by the scarcity of ideal sonosensitizers and complex tumor microenvironment (TME). To address these challenges, a sono-metabolic nano-composite (TiO2-Au@DON) using the metabolic reprogramming prodrugs of 6-Diazo-5-oxo-l-norleucine (DON) grafted on TiO2-Au Janus nanoparticles (NPs) is fabricated. The coupling of TiO2 and gold in the TiO2-Au@DON effectively prevents the fast recombination of excited electrons and holes under ultrasound irradiation. The result is the generation of higher levels of both type I and II reactive oxygen species (ROS) compared to pure TiO2, which helps overcome the limitations of SDT in the hypoxic TME. Furthermore, the TiO2-Au Janus NPs act as nano-carriers, delivering DON prodrugs to the tumor site. The released DON can disrupt nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and tumor redox homeostasis by reprogramming the metabolic pathways while it intensifies the activities of immune cells. This metabolic disruption amplifies SDT-mediated oxidative stress, resulting in the increase of tumor sensitivity to ROS through TiO2-Au@DON-integrated synergistic effects of SDT and glutamine reprogramming strategies. This increased sensitivity ultimately induces robust immunogenic cell death (ICD), enhancing antitumor therapeutic efficacy and remodeling the tumor's immunosuppressive microenvironment.

Keywords:  TiO2‐Au@DON Janus nanoparticles; metabolic reprogramming; sonodynamic therapy; sonosensitizers; sono‐metabolic

DOI:  https://doi.org/10.1002/adma.202418800
J Control Release. 2025 Feb 11. pii: S0168-3659(25)00139-7. [Epub ahead of print]

Glutathione and transglutaminase responsive janus gold nanorods for photoacoustic imaging-guided radiotherapy and chemodynamic therapy of tumors.

Youjia Zhang, Xiaoguang Ge, Shi Gao, Jibin Song.

  Gold nanorods (AuNRs) have become promising as radiosensitizers and photoacoustic (PA) imaging agents due to their strong X-ray attenuation ability and adjustable near-infrared (NIR) absorption. However, there remains room to further improve AuNRs for the imaging and treatment of tumors. We developed a biomarker responsive AuNR-based Janus nanoprobe by integrating MnO2 on one end of the AuNRs and specific ligands on the other end. In the tumor microenvironment, highly expressed transglutaminase (TGase), which facilitates the formation of isopeptide linkages between glutamine (Gln) and lysine (Lys), induces the aggregation of AuNRs. This in-situ aggregation amplifies the PA signal, extends the time window for PA imaging and enhances the radiosensitization effect. Meanwhile, the highly expressed glutathione (GSH) in tumors degrades MnO2 which triggers a chemodynamic treatment.

Keywords:  Janus nanoprobe; NIR II; Photoacoustic imaging; Radiosensitization; Stimuli-responsive

DOI:  https://doi.org/10.1016/j.jconrel.2025.02.026
Adv Sci (Weinh). 2025 Feb 14. e2416467

ACAT1-Mediated ME2 Acetylation Drives Chemoresistance in Ovarian Cancer by Linking Glutaminolysis to Lactate Production.

Cuimiao Zheng, Hao Tan, Gang Niu, Xi Huang, Jingyi Lu, Siqi Chen, Haoyuan Li, Jiayu Zhu, Zhou Zhou, Manman Xu, Chaoyun Pan, Junxiu Liu, Jie Li.

  Lactate derived from aerobic glycolysis is crucial for DNA damage repair and chemoresistance. Nevertheless, it is frequently noted that cancer cells depend on glutaminolysis to replenish essential metabolites. Whether and how glutaminolysis might enhance lactate production and facilitate DNA repair in cancer cells remains unknown. Here, it is shown that malate enzyme 2 (ME2), which metabolizes glutamine-derived malate to pyruvate, contributes to lactate production and chemotherapy resistance in ovarian cancer. Mechanistically, chemotherapy reduces the expression of glucose transporters and impairs glucose uptake in cancer cells. The resultant decrease in intracellular glucose levels triggers the acetylation of ME2 at lysine 156 by ACAT1, which in turn potentiates ME2 enzyme activity and facilitates lactate production from glutamine. ME2-derived lactate contributes to the development of acquired chemoresistance in cancer cells subjected to prolonged chemotherapy, primarily by facilitating the lactylation of proteins involved in homologous recombination repair. Targeting ACAT1 to inhibit ME2 acetylation effectively reduced chemoresistance in both in vitro and in vivo models. These findings underscore the significance of acetylated ME2-mediated lactate production from glutamine in chemoresistance, particularly under conditions of reduced intracellular glucose within cancer cell, thereby complementing the Warburg effect and offering new perspectives on the metabolic links to chemotherapy resistance.

Keywords:  ME2; acetylation; lactylation; platinum resistance

DOI:  https://doi.org/10.1002/advs.202416467
Semin Cancer Biol. 2025 Feb 09. pii: S1044-579X(25)00018-5. [Epub ahead of print]

Metabolic landscape and rewiring in normal hematopoiesis, leukemia and aging.

Hui Fang, Enze Yu, Chang Liu, Christy Eapen, Chunming Cheng, Tianxiang Hu.

  Recent advancements in metabolism research have demonstrated its critical roles in a lot of critical biological processes, including stemness maintenance, cell differentiation, proliferation, and function. Hematopoiesis is the fundamental cell differentiation process with the production of millions of red blood cells per second in carrying oxygen and white blood cells in fighting infection and cancers. The differentiation processes of hematopoietic stem and progenitor cells (HSPCs) are accompanied by significant metabolic reprogramming. In hematological malignancy, metabolic reprogramming is also essential to the malignant hematopoiesis processes. The metabolic rewiring is driven by distinct molecular mechanisms that meet the specific demands of different target cells. Leukemic cells, for instance, adopt unique metabolic profiles to support their heightened energy needs for survival and proliferation. Moreover, aging HSPCs exhibit altered energy consumption compared to their younger counterparts, often triggering protective mechanisms at the cellular level. In this review, we provide a comprehensive analysis of the metabolic processes involved in hematopoiesis and the metabolic rewiring that occurs under adverse conditions. In addition, we highlight current research directions and discuss the potential of targeting metabolic pathways for the management of hematological malignancies and aging.

Keywords:  aging; hematopoiesis; hematopoietic stem and progenitor cells; malignant hematopoiesis; metabolic rewiring; metabolism

DOI:  https://doi.org/10.1016/j.semcancer.2025.02.003
FEBS J. 2025 Feb 10.

α-Ketoglutarate inhibits the pluripotent-to-totipotent state transition in stem cells.

Mengran Yin, Yan Li, Zhenzhu Sun, Xinyu Wu, Liang Ding, Qiang Zhang, Hai Zhou, Man Zhang, Dajiang Qin, Baoming Qin, Lulu Wang.

  In early mouse embryogenesis, the distinct enrichment of α-ketoglutarate (αKG) in blastocysts and L-2-hydroxyglutarate (L-2HG) in 2-cell (2C) embryos serves as a key metabolic signature. While elevated L-2HG levels inhibit the resolution of totipotency during the transition from the 2C stage to the blastocyst, the role of αKG remains elusive. Mouse embryonic stem cells (mESCs) cultured in vitro naturally harbor a subpopulation that transitions dynamically into a 2C-like totipotent state, providing a convenient model to investigate the role of αKG in totipotency reprogramming. This study demonstrates that αKG significantly inhibits the pluripotency to totipotency transition through upregulating ten-eleven translocation (TET) DNA hydroxylases. We further show that reducing endogenous αKG levels via glutamine withdrawal or inhibiting αKG-dependent dioxygenases by blocking succinate dehydrogenase (SDH) markedly enhances the induction of 2C-like cells (2CLCs). Finally, leveraging the potent SDH inhibitor dimethyl malonate (DMM), we have developed a highly efficient protocol for 2CLC induction, producing cells that transcriptionally resemble mid-to-late 2C embryos. Our findings deepen the understanding of the metabolic regulation of totipotency and provide a previously undescribed approach for capturing totipotent-like stem cells in vitro.

Keywords:  DMM; TET; succinate; totipotency; α‐ketoglutarate

DOI:  https://doi.org/10.1111/febs.70008
Cancer Lett. 2025 Feb 09. pii: S0304-3835(25)00037-0. [Epub ahead of print] 217473

CircMFN2/miR-361-3p/ELK1 feedback loop promotes glutaminolysis and the progression of hepatocellular carcinoma.

Xiaopei Hao, Xiangjun Qian, Chenxi Xie, Zhengzheng Wang, Xiaoqian Wang, Yang Ji, Xiaokai Zhang, Qingjun Li, Baishun Wan, Hong Cui, Li Wang, Nanmu Yang, Liang Qiao, Haibo Yu, Feng Han, Hao Zhuang, Jinxue Zhou.

  Current evidence indicates that circRNAs are involved in the development of multiple malignancies including hepatocellular carcinoma (HCC). However, the specific functions of circRNAs in HCC metabolism and progression and their underlying regulatory mechanisms remain unclear. We have identified a novel circRNA circMFN2, by bioinformatics analysis of circRNA microarray data from the GEO database. The levels of circMFN2 were assessed in HCC cell lines and tissues, and its clinical relevance was assessed. The effect of circMFN2 on HCC cells was evaluated in vitro and in vivo. The effect of ELK1 on glutaminolysis and HCC progression was also explored. Patients with HCC and high circMFN2 expression exhibited worse survival outcomes. Functionally, downregulation of circMFN2 repressed the proliferation, invasion, and migration of HCC cells in vitro, whereas ectopic expression of circMFN2 had the opposite effects. The effects of tumor enhancement by circMFN2 on HCC were confirmed by in vivo experiments. Mechanistically, circMFN2 acted as a sponge for miR-361-3p, leading to the upregulation of its target ELK1, whereas ELK1 was enriched in the MFN2 promoter to enhance the transcription and expression of MFN2, indirectly leading to the upregulation of circMFN2. Additionally, we found that circMFN2 promotes glutaminolysis in HCC by increasing ELK1 phosphorylation. We concluded that circMFN2 facilitates HCC progression via a circMFN2/miR-361-3p/ELK1 feedback loop, which promotes glutaminolysis mediated by the upregulation of phosphorylated ELK1. Therefore, circMFN2 not only serves as a potential prognostic indicator, but it could also serve as a therapeutic target for HCC. Further studies are warranted.

Keywords:  ELK1; Hepatocellular carcinoma; circMFN2; glutaminolysis

DOI:  https://doi.org/10.1016/j.canlet.2025.217473