bims-medica 2025-05-18 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–05–18
27 papers selected by
Brett Chrest, Wake Forest University

Mitochondrial HSP90 paralog TRAP1 deletion drives glutamine addiction in tumor cells via destablization of the Cys/Glu antiporter SLC7A11/xCT.
Metabolic pathway analysis of tumors using stable isotopes.
Approaches to stable isotope tracing and in vivo metabolomics in the cancer clinic.
Reduced Liver Mitochondrial Energy Metabolism Impairs Food Intake Regulation Following Gastric Preloads and Fasting.
ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression.
Inhibition Of One-Carbon Metabolism In Ewing Sarcoma Results In Profound And Prolonged Growth Suppression Associated With Purine Depletion.
Triggering tumorigenic signaling: Succinate dehydrogenase inhibitor (SDHi) fungicides induce oncometabolite accumulation and metabolic shift in human colon cells.
Real-Time Measurement of Mitochondrial Function and Glycolysis in Lymphoblastoid Cell Lines.
Glucose, glutamine, lactic acid and α‑ketoglutarate restore metabolic disturbances and atrophic changes in energy‑deprived muscle cells.
Targeted Redox Regulation α-Ketoglutarate Dehydrogenase Complex for the Treatment of Human Diseases.
BCR::ABL1 expression in chronic myeloid leukemia cells in low oxygen is regulated by glutamine via CD36-mediated fatty acid uptake.
Inhibition of ENT1 relieves intracellular adenosine-mediated T cell suppression in cancer.
Discovery of Cu(II)-Dipyridophenazine Complex for Synergistic Cuproptosis/Chemodynamic Therapy via Disrupting the Tricarboxylic Acid (TCA) Cycle in Metastatic TNBC.
Mutant IDH1 cooperates with NPM1c or FLT3ITD to drive distinct myeloid diseases and molecular outcomes.
A phase I/II study of the safety and efficacy of telaglenastat (CB-839) in combination with nivolumab in patients with metastatic melanoma, renal cell carcinoma, and non-small-cell lung cancer.
Structural Optimization and MD Simulation Study of Benzimidazole Derivatives as Potent Mutant FLT3 Kinase Inhibitors Targeting AML.
Altered free fatty acids levels and the onset of metabolic syndrome in childhood cancer survivors.
Unraveling Venetoclax Resistance: Navigating the Future of HMA/Venetoclax-Refractory AML in the Molecular Era.
Taurine from tumour niche drives glycolysis to promote leukaemogenesis.
Improved MALDI-MS Imaging of Polar and 2H-Labeled Metabolites in Mouse Organ Tissues.
Augmenting the Anti-Leukemic Activity of the BCL-2 Inhibitor Venetoclax Through Its Transformation Into Polypharmacologic Dual BCL-2/HDAC1 and Dual BCL-2/HDAC6 Inhibitors.
Gastric cancer cells shuttle lactate to induce inflammatory CAF-like phenotype and function in bone marrow-derived mesenchymal stem cells.
Efficacy and Safety of Surgical Treatment Among Older Adult Patients (80 Years) With Pancreatic Cancer: A Systematic Review and Meta-Analysis.
Hypoxia-Activated CBS/H2S Signaling Drives Drug Resistance in AML through CD36-Mediated Fatty Acid metabolism.
Database Analysis of Application Areas and Global Trends in Ketogenic Diets from 2019 to 2024.
Off-target depletion of plasma tryptophan by allosteric inhibitors of BCKDK.
Using novel oxidative phosphorylation inhibitors to attenuate drug resistance in human gliomas.

Mol Cancer Res. 2025 May 16.

Mitochondrial HSP90 paralog TRAP1 deletion drives glutamine addiction in tumor cells via destablization of the Cys/Glu antiporter SLC7A11/xCT.

Abhinav Joshi, Li Dai, Marisa Maisiak, Sunmin Lee, Elizabeth Lopez, Takeshi Ito, Len Neckers.

TRAP1, the mitochondrial isoform of HSP90, has emerged as a key regulator of cancer cell metabolism, yet the mechanisms by which it rewires nutrient utilization remain poorly understood. We previously reported that TRAP1 loss increases glutamine dependency of mitochondrial respiration following glucose withdrawal. Here, we investigate how TRAP1 deletion impacts glucose metabolism and the mechanisms enabling glutamine retention to support mitochondrial respiration via reductive carboxylation and the oxidative TCA cycle. TRAP1 knockout (KO) in bladder and prostate cancer cells recapitulates the carbon source-specific metabolic rewiring previously observed. Stable isotope tracing reveals that although glucose oxidation remains functional, TRAP1 KO reduces overall glucose uptake and its contribution to glycolysis and the pentose phosphate pathway. This effect is consistent across multiple cell lines. Concurrently, TRAP1-deficient cells exhibit increased glutamine retention and reliance, potentially due to downregulation of the cystine/glutamate antiporter SLC7A11/xCT. Supporting this, xCT overexpression reduces glutamine-dependent respiration in TRAP1 KO cells. qPCR and proteasome inhibition assays suggest xCT is regulated post-translationally via protein stability. Notably, xCT suppression does not trigger ferroptosis, indicating a selective adaptation rather than induction of cell death. Together, our findings suggest that TRAP1 loss decreases glucose uptake while preserving its metabolic fate, promoting glutamine conservation through xCT downregulation to maintain mitochondrial respiration without inducing ferroptosis. Implications: These results reveal a TRAP1-dependent mechanism of metabolic rewiring in cancer cells and identify xCT-mediated glutamine conservation as a key adaptive response, underscoring TRAP1 as a potential metabolic vulnerability and therapeutic target in tumors with altered nutrient utilization.

DOI: https://doi.org/10.1158/1541-7786.MCR-24-0194
Semin Cancer Biol. 2025 May 08. pii: S1044-579X(25)00063-X. [Epub ahead of print]113 9-24

Metabolic pathway analysis of tumors using stable isotopes.

Qiufen Bi, Junzhang Zhao, Jun Nie, Fang Huang.

  Metabolic reprogramming is pivotal in malignant transformation and cancer progression. Tumor metabolism is shaped by a complex interplay of both intrinsic and extrinsic factors that are not yet fully elucidated. It is of great value to unravel the complex metabolic activity of tumors in patients. Metabolic flux analysis (MFA) is a versatile technique for investigating tumor metabolism in vivo, it has increasingly been applied to the assessment of metabolic activity in cancer in the past decade. Stable-isotope tracing have shown that human tumors use diverse nutrients to fuel central metabolic pathways, such as the tricarboxylic acid cycle and macromolecule synthesis. Precisely how tumors use different fuels, and the contribution of alternative metabolic pathways in tumor progression, remain areas of intensive investigation. In this review, we systematically summarize the evidence from in vivo stable- isotope tracing in tumors and describe the catabolic and anabolic processes involved in altered tumor metabolism. We also discuss current challenges and future perspectives for MFA of human cancers, which may provide new approaches in diagnosis and treatment of cancer.

Keywords:  Cancer metabolism; Metabolic flux analysis; Stable-isotope tracing

DOI:  https://doi.org/10.1016/j.semcancer.2025.05.002
EMBO J. 2025 May 12.

Approaches to stable isotope tracing and in vivo metabolomics in the cancer clinic.

Brandon Faubert, Alpaslan Tasdogan.



Keywords:  Cancer Metabolism; Intraoperative Patient Infusions; Stable Isotope Tracing

DOI:  https://doi.org/10.1038/s44318-025-00450-z
Mol Metab. 2025 May 12. pii: S2212-8778(25)00074-2. [Epub ahead of print] 102167

Reduced Liver Mitochondrial Energy Metabolism Impairs Food Intake Regulation Following Gastric Preloads and Fasting.

Michael E Ponte, John C Prom, Mallory A Newcomb, Annabelle B Jordan, Lucas L Comfort, Jiayin Hu, Patrycja Puchalska, Devin C Koestler, Caroline E Geisler, Matthew R Hayes, E Matthew Morris.

   OBJECTIVE: The capacity of the liver to serve as a peripheral sensor in the regulation of food intake has been debated for over half a century. The anatomical position and physiological roles of the liver suggest it is a prime candidate to serve as an interoceptive sensor of peripheral tissue and systemic energy state. Importantly, maintenance of liver ATP levels and within-meal food intake inhibition is impaired in human subjects with obesity and obese pre-clinical models. Previously, we have shown decreased hepatic mitochondrial energy metabolism (i.e., oxidative metabolism & ADP-dependent respiration) in male liver-specific, heterozygous PGC1a mice results in increased short-term diet-induced weight gain with increased within meal food intake. Herein, we tested the hypothesis that decreased liver mitochondrial energy metabolism impairs meal termination following nutrient oral pre-loads.
METHODS: Liver mitochondrial respiratory response to changes in ΔGATP and adenine nucleotide concentration following fasting were examined in male liver-specific, heterozygous PGC1a mice. Further, food intake and feeding behavior during basal conditions, following nutrient oral pre-loads, and following fasting were investigated.
RESULTS: We observed male liver-specific, heterozygous PGC1a mice have reduced mitochondrial response to changes in ΔGATP and tissue ATP following fasting. These impairments in liver energy state are associated with larger and longer meals during chow feeding, impaired dose-dependent food intake inhibition in response to mixed and individual nutrient oral pre-loads, and greater acute fasting-induced food intake.
CONCLUSION: These data support previous work proposing liver-mediated food intake regulation through modulation of peripheral satiation signals.

Keywords:  ATP; Liver; fasting; food intake; mitochondria; satiation

DOI:  https://doi.org/10.1016/j.molmet.2025.102167
Nat Cell Biol. 2025 May;27(5): 847-862

ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression.

Che-Chia Hsu, Chi-Yun Wang, Rajesh Kumar Manne, Zhen Cai, Vasudevarao Penugurti, Rajni Kant, Ling Bai, Bo-Syong Pan, Tingjin Chen, Yuan-Ru Chen, Hsin-En Wu, Yan Jin, Haiwei Gu, Chia-Yang Li, Hui-Kuan Lin.

MPC1 and MPC2 are two well-known components of the mitochondrial pyruvate carrier (MPC) complex maintaining MPC activity to transport pyruvate into mitochondria for tricarboxylic acid (TCA) cycle entry in mammalian cells. It is currently unknown whether there is an additional MPC component crucially maintaining MPC complex activity for pyruvate mitochondrial import. Here we show that ALDH4A1, a proline-metabolizing enzyme localized in mitochondria, serves as a previously unrecognized MPC component maintaining pyruvate mitochondrial import and the TCA cycle independently of its enzymatic activity. Loss of ALDH4A1 in mammalian cells impairs pyruvate entry to mitochondria, resulting in defective TCA cycle entry. ALDH4A1 forms an active trimeric complex with MPC1-MPC2 to maintain the integrity and oligomerization of MPC1-MPC2 and facilitates pyruvate transport in an in vitro system. ALDH4A1 displays tumour suppression by maintaining MPC complex activity. Our study identifies ALDH4A1 as an essential component of MPC for pyruvate mitochondrial import, TCA cycle entry and tumour suppression.

DOI: https://doi.org/10.1038/s41556-025-01651-8
bioRxiv. 2025 Apr 29. pii: 2025.04.13.647987. [Epub ahead of print]

Inhibition Of One-Carbon Metabolism In Ewing Sarcoma Results In Profound And Prolonged Growth Suppression Associated With Purine Depletion.

Sara Zirpoli, Noah Copperman, Shrey Patel, Alexander Forrest, Zhanjun Hou, Larry H Matherly, David M Loeb, Antonio Di Cristofano.

Ewing sarcoma (EWS) is the second most common primary bone malignancy in adolescents and young adults. Patients who present with localized disease have experienced a steadily improving survival rate over the years, whereas those who present with metastatic disease have the same dismal prognosis as 30 years ago, with long term survival rates less than 20%, despite maximal intensification of chemotherapy. Thus, novel treatment approaches are a significant unmet clinical need. Targeting metabolic differences between EWS and normal cells offers a promising approach to improve outcomes for these patients. One-carbon metabolism utilizes serine and folate to generate glycine and tetrahydrofolate (THF)-bound one-carbon units required for de novo nucleotide biosynthesis. Elevated expression of several one-carbon metabolism genes is significantly associated with reduced survival in EWS patients. We show that both genetic and pharmacological inhibition of a key enzyme of the mitochondrial arm of the one-carbon metabolic pathway, serine hydroxymethyltransferase 2 (SHMT2), leads to substantial inhibition of EWS cell proliferation and colony-forming ability, and that this effect is primarily caused by depletion of glycine and one-carbon units required for synthesis of purine nucleotides. Inhibition of one-carbon metabolism at a different node, using the clinically relevant dihydrofolate reductase inhibitor Pralatrexate, similarly yields a profound growth inhibition, with depletion of thymidylate and purine nucleotides. Genetic depletion of SHMT2 dramatically impairs tumor growth in a xenograft model of EWS. Together, these data establish the upregulation of the one-carbon metabolism as a novel and targetable vulnerability of EWS cells, which can be exploited for therapy.
Statement of Significance: Using both genetic and pharmacologic approaches, this study identifies Ewing sarcoma's dependence on the mitochondrial arm, but not the cytoplasmic arm, of one-carbon metabolism as a targetable vulnerability that can be effectively harnessed for therapy.

DOI: https://doi.org/10.1101/2025.04.13.647987
Environ Int. 2025 May 02. pii: S0160-4120(25)00254-5. [Epub ahead of print]199 109503

Triggering tumorigenic signaling: Succinate dehydrogenase inhibitor (SDHi) fungicides induce oncometabolite accumulation and metabolic shift in human colon cells.

Carolina Duarte Hospital, Arnaud Tête, Kloé Debizet, Clémence Rives, Jules Imler, Sofiane Safi-Stibler, Lara Gales, Floriant Bellvert, Julien Dairou, Auriane Hagimont, Agnès Burel, Dominique Lagadic-Gossmann, Robert Barouki, Jerry W Shay, Jean Bastin, Sophie Mouillet-Richard, Anthony Lemarié, Fatima Djouadi, Sandrine Ellero-Simatos, Xavier Coumoul, Judith Favier, Sylvie Bortoli.

  Succinate dehydrogenase inhibitors (SDHi) are fungicides used worldwide to control the proliferation of fungi in crops. They act by blocking the activity of succinate dehydrogenase (SDH), a universal enzyme involved in mitochondrial functions and metabolism. While SDH-encoding genes are tumour suppressors, which loss-of-function mutations predispose to different types of rare tumors in humans, the consequences of chemical inactivation of SDH by SDHi remain largely unknown, particularly regarding their carcinogenic potential. Here, we investigated the metabolic and cellular impact of SDHi on human non-cancer and transformed colon cells. We show that SDHi inhibit SDH activity and increase the level of succinate, known to act as an oncometabolite in SDH-deficient cancers. SDHi exposure also induces a Warburg-like metabolic reprogramming typical of cancer cells, associated with transcriptomic and morphological changes promoting cell migration and invasion. These effects are enhanced in transformed colon cells carrying mutations in colorectal cancer (CRC) driver genes. These findings provide the first evidence that SDHi-mediated chemical inactivation of SDH mimics some metabolic and phenotypic features previously described in human tumors with SDH genetic deficiencies. Given that loss of SDH expression in CRC patients correlates with a poor prognosis, these patients could represent a population sensitive to SDHi exposure. Therefore, it would be wise to include them in biomonitoring programs. Finally, our work highlights the need to improve regulatory assessment procedures to take better account of SDHi mode of action, by developing relevant tests to cover the multiple key events linked to SDH inactivation and assess the resulting mitochondrial toxicity.

Keywords:  Cancer; Metabolic reprogramming; Mitochondria; Oncometabolite; Pesticides

DOI:  https://doi.org/10.1016/j.envint.2025.109503
Methods Mol Biol. 2025 ;2920 173-202

Real-Time Measurement of Mitochondrial Function and Glycolysis in Lymphoblastoid Cell Lines.

Tina Katsaros, Daniel Missailidis, Sarah J Annesley.

  Cells require energy in the form of ATP to function. The two main ways in which cells generate energy in mammalian cells is through glycolysis and oxidative phosphorylation (OXPHOS). Glycolysis takes place in the cytosol and involves the breakdown of glucose molecules, generating ATP and pyruvate, while OXPHOS takes place in the mitochondria and is responsible for producing the majority of ATP for the cell. A dysregulation of these cellular processes has been reported in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In order to understand the mechanisms of the disease, it is imperative to understand how the bioenergetic pathways are altered in ME/CFS. Here we describe a method for measuring mitochondrial function and glycolytic function using the Agilent Seahorse Extracellular Flux Analyzer. We have optimized these assays for use in actively proliferating lymphoblastoid cell lines that are generated from blood cells. This assay measures oxygen consumption rate and extracellular acidification rates providing an overview of mitochondrial function and efficiency and glycolytic rate and capacity, respectively. These assays are performed on live, intact cells, and enable us to view different components and measurements of energy metabolism through the injection of different compounds that stimulate or inhibit various sections of these pathways. The below method details an optimized glycolysis and mitochondrial assay for 96-well plates with modifications noted for use in 24-well plates.

Keywords:  Agilent seahorse XF analyzer; Glycolysis; Lymphoblastoid cell lines; Mitochondria; Myalgic encephalomyelitis/chronic fatigue syndrome

DOI:  https://doi.org/10.1007/978-1-0716-4498-0_11
Mol Med Rep. 2025 Jul;pii: 197. [Epub ahead of print]32(1):

Glucose, glutamine, lactic acid and α‑ketoglutarate restore metabolic disturbances and atrophic changes in energy‑deprived muscle cells.

Miu Ikeda, Moe Matsumoto, Miki Tamura, Masaki Kobayashi, Kaoruko Iida.

  Skeletal muscle atrophy is often triggered by catabolic conditions such as fasting, malnutrition and chronic diseases; however, the efficacy of nutritional supplementation in maintaining muscle mass and preventing muscle atrophy remains controversial. The present study aimed to compare the inhibitory effects of various nutritional substrates on starvation‑induced catabolic changes and muscle cell atrophy. C2C12 muscle cells were starved for up to 24 h in medium lacking serum and main nutrients (glucose, glutamine and pyruvate). To assess the effects of exogenous substrates, the cells were incubated in starvation medium and individually supplemented with each of the following nutrients: Glucose, amino acids, fatty acids, lactate or ketone bodies. The expression of each gene and protein was analyzed by reverse transcription‑quantitative PCR and western blotting, respectively. Mitochondrial activity was determined by MTT assay and cell morphology was observed by immunofluorescence staining. The results revealed that starvation for >3 h suppressed mitochondrial activity, and after 5 h of starvation, the expression levels of several metabolic genes were increased; however, the levels of most, with the exception of Scot and Cpt‑1b, were suppressed after 24 h. Protein degradation and a decrease in protein synthesis were observed after 5 h of starvation, followed by autophagy with morphological atrophy at 24 h. Supplementation with specific substrates, with the exception of leucine, such as glucose, glutamine, lactic acid or α‑ketoglutarate, attenuated the suppression of mitochondrial activity, and altered gene expression, protein degradation and myotube atrophy in starved myotubes. Furthermore, the decrease in intracellular ATP production after 24 h of starvation was reversed by restoring glycolysis in glucose‑treated cells, and via an increase in mitochondrial respiration in cells treated with glutamine, lactic acid or α‑ketoglutarate. In conclusion, increasing the availability of glucose, glutamine, lactic acid or α‑ketoglutarate may be beneficial for countering muscle atrophy associated with inadequate nutrient intake.

Keywords:  atrophy; metabolism; muscle cells; nutrient substrates; starvation

DOI:  https://doi.org/10.3892/mmr.2025.13562
Cells. 2025 Apr 29. pii: 653. [Epub ahead of print]14(9):

Targeted Redox Regulation α-Ketoglutarate Dehydrogenase Complex for the Treatment of Human Diseases.

Ryan J Mailloux.

  α-ketoglutarate dehydrogenase complex (KGDHc) is a crucial enzyme in the tricarboxylic acid (TCA) cycle that intersects monosaccharides, amino acids, and fatty acid catabolism with oxidative phosphorylation (OxPhos). A key feature of KGDHc is its ability to sense changes in the redox environment through the reversible oxidation of the vicinal lipoic acid thiols of its dihydrolipoamide succinyltransferase (DLST; E2) subunit, which controls its activity and, by extension, OxPhos. This characteristic inculcates KGDHc with redox regulatory properties for the modulation of metabolism and mediating of intra- and intercellular signals. The innate capacity of KGDHc to participate in the regulation of cell redox homeodynamics also occurs through the production of mitochondrial hydrogen peroxide (mtH2O2), which is generated by the dihydrolipoamide dehydrogenase (DLD; E3) downstream from the E2 subunit. Reversible covalent redox modification of the E2 subunit controls this mtH2O2 production by KGDHc, which not only protects from oxidative distress but also modulates oxidative eustress pathways. The importance of KGDHc in modulating redox homeodynamics is underscored by the pathogenesis of neurological and metabolic disorders that occur due to the hyper-generation of mtH2O2 by this enzyme complex. This also implies that the targeted redox modification of the E2 subunit could be a potential therapeutic strategy for limiting the oxidative distress triggered by KGDHc mtH2O2 hyper-generation. In this short article, I will discuss recent findings demonstrating KGDHc is a potent mtH2O2 source that can trigger the manifestation of several neurological and metabolic diseases, including non-alcoholic fatty liver disease (NAFLD), inflammation, and cancer, and the targeted redox modification of the E2 subunit could alleviate these syndromes.

Keywords:  KGDHc; NAFLD; hydrogen peroxide; metabolic diseases; mitochondria; oxidative distress; oxidative eustress; succinate

DOI:  https://doi.org/10.3390/cells14090653
Cancer Cell Int. 2025 May 14. 25(1): 176

BCR::ABL1 expression in chronic myeloid leukemia cells in low oxygen is regulated by glutamine via CD36-mediated fatty acid uptake.

Caterina Mancini, Giulio Menegazzi, Silvia Peppicelli, Giampaolo Versienti, Daniele Guasti, Giuseppe Pieraccini, Elisabetta Rovida, Matteo Lulli, Laura Papucci, Persio Dello Sbarba, Alessio Biagioni.

   BACKGROUND: Chronic myeloid leukemia (CML) is influenced by microenvironmental nutrients, glucose (Glc), and glutamine (Gln) which regulate cell proliferation, viability, and the expression of the driver oncoprotein (BCR::ABL1).
RESULTS: Our study revealed that Glc, while partially supporting alone cell growth in normoxia, is essential in low oxygen conditions, whereas Gln is ineffective. Under low oxygen, Gln reduced oxidative respiratory activity while enhancing glycolysis. In these conditions, fatty acid (FA) metabolism becomes crucial, as evidenced by increased lipid droplets (LD) accumulation when Glc was absent. Gln, in particular, drives CD36-mediated FA uptake, suppressing the BCR::ABL1 oncoprotein and facilitating cell survival. By co-culturing leukemia cells with adipocytes, one of the main bone marrow (BM) cell components, we observed an enhanced FA release, suggesting a link between FA, microenvironmental BM cells, and the maintenance of leukemic stem cells (LSC).
METHODS: K562 and KCL22 cell lines were subjected to Glc and/or Gln deprivation under hypoxic conditions (96 h at 0.1% O2). Metabolic profiling was conducted through the Seahorse XFe96 analyzer, and the contribution of L-Glutamine-13C5 to FA de novo synthesis was determined via GC/MS. Intracellular neutral LD were measured using BODIPY 493/503 in confocal microscopy and flow cytometry, with their presence and morphology further examined via transmission electron microscopy. BCR::ABL1 as well as several FA-related markers were evaluated via Western Blotting, whilst CD36 was determined through flow cytometry. LC2 assay was used for measuring leukemia stem cell potential by inhibiting FA uptake via the usage of the Sulfo-N-Succinimidyl Oleate, a CD36 inhibitor. qPCR was exploited to detect markers of FA secretion in CML-adipocytes co-culture together with Nile Red staining to assess free FA in the media.
CONCLUSIONS: These findings underscore the central role of FA in the regulation of the LSC compartment of CML, highlighting the importance of Gln in facilitating CML cell survival under restrictive metabolic conditions and preparing the cell population for expansion upon the release of these restrictions.

Keywords:  BCR:ABL1; Chronic myeloid leukemia; Fatty acids; Hypoxia

DOI:  https://doi.org/10.1186/s12935-025-03805-y
Nat Immunol. 2025 May 12.

Inhibition of ENT1 relieves intracellular adenosine-mediated T cell suppression in cancer.

Theodore J Sanders, Christopher S Nabel, Margreet Brouwer, Annelise L Hermant, Lucas Chaible, Jean-Philippe Deglasse, Nicolas Rosewick, Angélique Pabois, Wilfried Cathou, Aurore Smets, Michael Deligny, João Marchante, Quentin Dubray, Marie-Claire Letellier, Chiara Martinoli, Reece Marillier, Olivier De Henau, Yvonne McGrath, Matthew G Vander Heiden, Erica Houthuys.

The benefit of immune checkpoint blockade for cancer therapy is limited to subsets of patients because of factors including the accumulation of immunosuppressive metabolites, such as adenosine, within tumors. Pharmacological inhibition of adenosine generation and signaling is an active area of clinical investigation, but only limited clinical benefit has been reported. Here, we show that adenosine suppresses anti-cancer T cell responses following uptake into activated T cells by equilibrative nucleoside transporter 1 (ENT1) and inhibition of de novo pyrimidine nucleotide synthesis. We identify EOS301984 as a potent ENT1 antagonist that restores pyrimidine levels in activated T cells in adenosine-rich environments, resulting in enhanced tumor cell killing by memory T cells and increased ex vivo expansion of functional human tumor-infiltrating lymphocytes. A combination of EOS301984 with anti-PD-1 led to synergistic control of tumor growth in a humanized mouse model of triple-negative breast cancer. ENT1 inhibition, therefore, augments anti-cancer immune responses through the restoration of pyrimidine nucleotide synthesis in T cells suppressed by adenosine.

DOI: https://doi.org/10.1038/s41590-025-02153-3
Small. 2025 May 09. e2504554

Discovery of Cu(II)-Dipyridophenazine Complex for Synergistic Cuproptosis/Chemodynamic Therapy via Disrupting the Tricarboxylic Acid (TCA) Cycle in Metastatic TNBC.

Ayushi Chaudhary, Ashwini Kumar, Ankit Ankit, Ritika Gautam Singh.

  Cuproptosis, a recently recognized regulated cell death, distinct from established death mechanisms, offers promising cancer therapy. However, its efficacy relies on intracellular copper availability and homeostasis. Herein, a novel Copper(II) dipyridohenazine complex, Cu(L1)2Cl acts as an oxidative stress amplifier and glutathione (GSH) disrupter for synergistic cuproptosis/chemodynamic anticancer therapy for the treatment of challenging triple negative breast cancer. Cu(L1)2Cl followed the endocytosis pathway to enter tumor cells and depleted GSH to release Cu+ ions which result in the production of.OH radicals generated from H2O2, leading to chemodynamic therapy. The spike in ROS generation disrupts cellular redox homeostasis, causing impaired mitochondrial function, ATP depletion, and endoplasmic reticulum stress generation. ATP depletion directly affects the function of copper-transporting ATPase 1 (ATP7A), resulting in a large amount of Cu+ trapped inside cancer cells, causing oligomerization of dihydrolipoamide S-acetyltransferase (DLAT), and depletion of Lipoyl synthase (LIAS), and leading to cellular cuproptosis. Subsequently, Cu(L1)2Cl interrupts tumor metastasis and evokes immunogenic cell death (ICD) by promoting high mobility group protein (HMGB1), ATP and lactate dehydrogenase (LDH) release, calreticulin (CRT) exposure, and inhibiting programmed death ligand 1 (PD-L1). The in vivo studies on 4T1 tumor bearing Balb/c mice validate its potent antitumor efficacy, thereby providing a new therapeutic paradigm to augment cuproptosis-related therapies.

Keywords:  chemodynamic therapy; cuproptosis; immunogenic cell death; metastasis; synergistic therapy

DOI:  https://doi.org/10.1002/smll.202504554
Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2415779122

Mutant IDH1 cooperates with NPM1c or FLT3ITD to drive distinct myeloid diseases and molecular outcomes.

Takashi Sakamoto, Julie Leca, Xin Zhang, Cem Meydan, Jonathan Foox, Parameswaran Ramachandran, Liam D Hendrikse, Wenjing Zhou, Thorsten Berger, Jerome Fortin, Steven M Chan, Ming-Feng Chiang, Satoshi Inoue, Wanda Y Li, Mandy F Chu, Gordon S Duncan, Andrew Wakeham, François Lemonnier, Chantal Tobin, Ryan Mcwilliam, Isabelle Colonna, Christophe Bontoux, Soode Moghadas Jafari, Robert L Bowman, Brandon Nicolay, Sebastien Ronseaux, Rohini Narayanaswamy, Ross L Levine, Ari M Melnick, Christopher E Mason, Mark D Minden, Tak W Mak.

  In human acute myeloid leukemia (AML), mutations of isocitrate dehydrogenase-1 (IDH1) often co-occur with NPM1 mutations, and less frequently with FLT3 mutations. To investigate whether the effects of IDH1 mutation differ according to the specific co-occurring mutation, we generated two strains of double knock-in mutant mice. Idh1R132H combined with Npm1c induced overt AML, whereas Idh1R132H plus Flt3ITD resulted in Flt3ITD-driven myelo- or lymphoproliferation that was minimally affected by Idh1R132H and rarely generated AML. Gene expression profiling revealed differences between Idh1R132H;Npm1c cells and Idh1R132H;Flt3ITD cells and suggested altered heme metabolism and immune responses in the former. The profile of Idh1R132H;Npm1c cells corresponded to that of human IDH-mutated AML cells, particularly those resistant to inhibitors of mutant IDH. Compared to treatment with a menin inhibitor, IDH1-targeted therapy of Idh1R132H;Npm1c AML-bearing mice was less efficacious in improving cell differentiation and extending survival. The differential cooperation of Idh1R132H with Npm1c vs. Flt3ITD may have implications for the devising of subtype-specific treatments for human AML.

Keywords:  FLT3; IDH1; NPM1; acute myeloid leukemia; preclinical mouse model

DOI:  https://doi.org/10.1073/pnas.2415779122
ESMO Open. 2025 May 12. pii: S2059-7029(25)00405-3. [Epub ahead of print]10(5): 104536

A phase I/II study of the safety and efficacy of telaglenastat (CB-839) in combination with nivolumab in patients with metastatic melanoma, renal cell carcinoma, and non-small-cell lung cancer.

M A Gouda, M H Voss, H Tawbi, M Gordon, S S Tykodi, E T Lam, U Vaishampayan, N M Tannir, J Chaves, P Nikolinakos, A Fan, R Lee, D McDermott, G I Shapiro, L Gandhi, S Bhatia, V Katragadda, F Meric-Bernstam.

   BACKGROUND: Telaglenastat (CB-839) is a glutaminase 1 inhibitor that targets the dysregulation in glutamine metabolism in cancer cells and the tumor microenvironment. Preclinical data suggested that the combination of telaglenastat with programmed cell death protein 1 (PD-1) or programmed cell death-ligand 1 (PD-L1) antibodies can lead to enhanced immune response against cancer.
PATIENTS AND METHODS: We designed a phase I/II trial to investigate the safety and efficacy of telaglenastat combined with nivolumab in patients with advanced solid tumors. Dose escalation was carried out using a 3 + 3 design with two dose levels for telaglenastat (600 mg and 800 mg twice daily). Nivolumab was given at a fixed dose of 240 mg by intravenous infusion on days 1 and 15 of a 28-day cycle in all patients. Expansion in phase II was planned using Simon's two-stage design in disease- and prior therapy-specific cohorts.
RESULTS: We included a total of 118 patients across different cohorts. The most frequently reported adverse events were fatigue (42.4%; n = 50), nausea (39%; n = 46), and photophobia (32.2%; n = 38). In the response-assessable analysis set (including 107 patients in dose expansion and recommended phase II dose of dose escalation), the overall response rate (ORR) was 8.4% (n = 9). The ORR was 24% in 25 patients with clear-cell renal cell carcinoma (ccRCC) who were checkpoint inhibitor-naïve, 5.9% in 17 patients with ccRCC after nivolumab, 0% in 9 patients with ccRCC after other prior anti-PD-1/PD-L1, 5.4% in 37 patients with melanoma after anti-PD-1/PD-L1, and 0% in 19 patients with non-small-cell lung cancer after anti-PD-1/PD-L1.
CONCLUSIONS: Telaglenastat in combination with nivolumab was generally well tolerated. The combination did not show a pattern of efficacy across different study cohorts.

Keywords:  CB-839; clinical trials; glutaminase inhibitor; nivolumab

DOI:  https://doi.org/10.1016/j.esmoop.2025.104536
Arch Pharm (Weinheim). 2025 May;358(5): e70002

Structural Optimization and MD Simulation Study of Benzimidazole Derivatives as Potent Mutant FLT3 Kinase Inhibitors Targeting AML.

Nada Alaa El-Deen, RosaAnna DeFilippis, Amal Kamal Abdel-Aziz, Sandra N Milik, Suhana Patel, Muhammad I Ismail, Omar Khaled, Tarek Erfan Ahmed, Ayatullah Gamal Abdelfattah, Eslam M H Ali, Maiy Y Gaballah, Martin J McPhillie, Khaled A M Abouzid, Rabah A T Serya, Maged Henary, Saverio Minucci, Neil P Shah, Eman M E Dokla.

  Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor survival rates in adults, posing a significant economic burden. FMS-like tyrosine kinase 3 (FLT3) mutations are linked to poor prognosis in AML and resistance to clinically approved FLT3 inhibitors. Previously, we reported a novel benzimidazole-based FLT3 inhibitor, 4ACP, with nanomolar activities against FLT3-ITD and FLT3-TKD mutants, showing selective cytotoxicity against FLT3-ITD+ AML cell lines. In this study, we synthesized 31 derivatives by modifying the 4-acetamidophenyl group and varying substituents at N1-phenyl and C2 positions. We identified compound 21l (3-acetamidophenyl) as the most potent derivative (FLT3-TKD(D835Y) IC50 = 1.47 nM). Linking 21l to a solvent-accessible group yielded compound 22b, which exhibited a sub-nanomolar activity against FLT-TKD(D835Y) mutant with an IC50 value of 0.48 nM. Compound 22b showed preferential antiproliferative activities against MOLM-14, MV4-11, MOLM-14-D835Y, and MOLM-14-F691L AML cell lines with IC50 values of 16.1, 10.5, 26.5, and 160.3 nM, respectively. 22b induced dose-dependent inhibition of FLT3, ERK, STAT5, and S6 phosphorylation, G0/G1 cell-cycle arrest, and apoptotic cell death at low nanomolar concentrations in MOLM-14 and MOLM-14-D835Y cells. It was more selective for FLT3-dependent cell lines, showing about 80-fold selectivity toward FLT3-TKD(D835Y) over KIT, indicating relative safety and lower myelosuppression potential. The molecular dynamics study of 4ACP and 22b was conducted to explain the significant changes in activity resulting from subtle structural alterations. Altogether, these findings establish 22b as a potent mutant FLT3 inhibitor, warranting further investigation and optimization to target resistant AML.

Keywords:  acute myeloid leukemia; benzimidazole; kinase inhibitor; molecular dynamics; mutant FLT3

DOI:  https://doi.org/10.1002/ardp.70002
Nutrition. 2025 Apr 10. pii: S0899-9007(25)00117-0. [Epub ahead of print]136 112799

Altered free fatty acids levels and the onset of metabolic syndrome in childhood cancer survivors.

Katarzyna Konończuk, Katarzyna Muszyńska-Rosłan, Karolina Konstantynowicz-Nowicka, Adrian Chabowski, Eryk Latoch.

  Childhood cancer survivors (CCS) are at increased risk for various health issues, including obesity, insulin resistance, hypertension, and dyslipidemia, resulting in the development of metabolic syndrome (MetS) later in life. It has been suggested that anticancer treatment may lead to alterations in lipid metabolism, which play a role in the pathogenesis of metabolic syndrome among CCS. The prospective study included 110 CCS, with a follow-up time of 6.39 years since the end of treatment. Fasting serum of fourteen fatty acids concentrations were measured in all children using gas-liquid chromatography. Among the study group, 41 CCS (37%) met 1 or more criteria for metabolic syndrome and exhibited higher concentrations of myristic (P = 0.002), palmitic (P = 0.003), stearic (P = 0.017), oleic (P = 0. 019), arachidonic (P = 0.002), lignoceric (P = 0.005), docosahexaenoic (P = 0.005), and total fatty acids compared to CCS without metabolic syndrome factors. Additionally, overweight or obese CCS presented higher levels of myristic (P = 0.048), palmitic (P = 0.016), oleopalmitic (P = 0.019), stearic (P = 0.024), oleic (P = 0.020), α-linoleic (P = 0.023) and behenic (P = 0.036) acids compared to survivors with a normal BMI. Childhood cancer survivors develop abnormalities in lipid metabolism, which may contribute to an earlier onset of metabolic syndrome. Additionally, overweight or obesity significantly exacerbates changes in lipid metabolism.

Keywords:  Childhood cancer survivors; Children; FFA; Free fatty acids; Metabolic syndrome; Obesity

DOI:  https://doi.org/10.1016/j.nut.2025.112799
Cancers (Basel). 2025 May 07. pii: 1586. [Epub ahead of print]17(9):

Unraveling Venetoclax Resistance: Navigating the Future of HMA/Venetoclax-Refractory AML in the Molecular Era.

Theodora Chatzilygeroudi, Theodoros Karantanos, Vasiliki Pappa.

  Acute myeloid leukemia (AML) has traditionally been linked to a poor prognosis, particularly in older patients who are ineligible for intensive chemotherapy. The advent of Venetoclax, a powerful oral BH3 mimetic targeting anti-apoptotic protein BCL2, has significantly advanced AML treatment. Its combination with the hypomethylating agent azacitidine (AZA/VEN) has become a standard treatment for this group of AML patients, demonstrating a 65% overall response rate and a median overall survival of 14.7 months, compared to 22% and 8 months with azacitidine monotherapy, respectively. However, resistance and relapses remain common, representing a significant clinical challenge. Recent studies have identified molecular alterations, such as mutations in FLT3-ITD, NRAS/KRAS, TP53, and BAX, as major drivers of resistance. Additionally, other factors, including metabolic changes, anti-apoptotic protein expression, and monocytic or erythroid/megakaryocytic differentiation status, contribute to treatment failure. Clinical trials are exploring strategies to overcome venetoclax resistance, including doublet or triplet therapies targeting IDH and FLT3 mutations; novel epigenetic approaches; menin, XPO1, and MDM2 inhibitors; along with immunotherapies like monoclonal antibodies and antibody-drug conjugates. A deeper understanding of the molecular mechanisms of resistance through single-cell analysis will be crucial for developing future therapeutic strategies.

Keywords:  AML; clinical trials; resistance; venetoclax

DOI:  https://doi.org/10.3390/cancers17091586
Nature. 2025 May 14.

Taurine from tumour niche drives glycolysis to promote leukaemogenesis.

Sonali Sharma, Benjamin J Rodems, Cameron D Baker, Christina M Kaszuba, Edgardo I Franco, Bradley R Smith, Takashi Ito, Kyle Swovick, Kevin Welle, Yi Zhang, Philip Rock, Francisco A Chaves, Sina Ghaemmaghami, Laura M Calvi, Archan Ganguly, W Richard Burack, Michael W Becker, Jane L Liesveld, Paul S Brookes, Joshua C Munger, Craig T Jordan, John M Ashton, Jeevisha Bajaj.

Signals from the microenvironment are known to be critical for development, stem cell self-renewal and oncogenic progression. Although some niche-driven signals that promote cancer progression have been identified1-5, concerted efforts to map disease-relevant microenvironmental ligands of cancer stem cell receptors have been lacking. Here, we use temporal single-cell RNA-sequencing (scRNA-seq) to identify molecular cues from the bone marrow stromal niche that engage leukaemia stem-enriched cells (LSCs) during oncogenic progression. We integrate these data with our human LSC RNA-seq and in vivo CRISPR screen of LSC dependencies6 to identify LSC-niche interactions that are essential for leukaemogenesis. These analyses identify the taurine-taurine transporter (TAUT) axis as a critical dependency of aggressive myeloid leukaemias. We find that cysteine dioxygenase type 1 (CDO1)-driven taurine biosynthesis is restricted to osteolineage cells, and increases during myeloid disease progression. Blocking CDO1 expression in osteolineage cells impairs LSC growth and improves survival outcomes. Using TAUT genetic loss-of-function mouse models and patient-derived acute myeloid leukaemia (AML) cells, we show that TAUT inhibition significantly impairs in vivo myeloid leukaemia progression. Consistent with elevated TAUT expression in venetoclax-resistant AML, TAUT inhibition synergizes with venetoclax to block the growth of primary human AML cells. Mechanistically, our multiomic approaches indicate that the loss of taurine uptake inhibits RAG-GTP dependent mTOR activation and downstream glycolysis. Collectively, our work establishes the temporal landscape of stromal signals during leukaemia progression and identifies taurine as a key regulator of myeloid malignancies.

DOI: https://doi.org/10.1038/s41586-025-09018-7
Anal Chem. 2025 May 13.

Improved MALDI-MS Imaging of Polar and 2H-Labeled Metabolites in Mouse Organ Tissues.

Siva Swapna Kasarla, Antonia Fecke, Karl William Smith, Vera Flocke, Ulrich Flögel, Prasad Phapale.

Imaging small polar metabolites and analyzing their in vivo dynamics with stable isotope-labeled (SIL) tracing through various biochemical pathways, including the citric acid (TCA) cycle, glycolysis, and amino acid metabolism, have gained substantial interest over the years. However, imaging these small polar metabolites across different tissue types is limited due to their lower ionization efficiencies and ion suppression from larger abundant biomolecules. These challenges can be further exacerbated with SIL studies, which require improvements in sample preparation and method sensitivity. Solvent pretreatments before matrix application on a tissue section have the potential to improve the sensitivity of metabolite imaging; however, they are not yet widely optimized across tissue types. Furthermore, there is a recurring concern about metabolite delocalization from such wash treatments that require "spatial validation". Here, we optimized a simple "basic hexane" wash method that improved sensitivity up to several folds for a broad range of polar and 2H-labeled metabolites across five different mouse organ tissues (kidney, heart, brain, liver, and brown adipose tissue). Notably, we provided region-specific quantification of 51 metabolites using laser microdissection (LMD)-LC-MS/MS to validate their localization observed in MALDI-MSI analysis after the basic hexane wash. Overall, we reported an improved MALDI-MSI sample pretreatment method with a "spatial validation" workflow for sensitive and robust imaging of polar metabolite distributions in mouse organs.

DOI: https://doi.org/10.1021/acs.analchem.5c00620
Drug Dev Res. 2025 May;86(3): e70084

Augmenting the Anti-Leukemic Activity of the BCL-2 Inhibitor Venetoclax Through Its Transformation Into Polypharmacologic Dual BCL-2/HDAC1 and Dual BCL-2/HDAC6 Inhibitors.

Alexandria M Chan, Christian Eberly, Brandon Drennen, Christopher C Goodis, Zoe Wuyts, Curt I Civin, Steven Fletcher.

  Motivated by the anti-leukemic synergy between histone deacetylase (HDAC) inhibitors and the FDA-approved BCL-2 inhibitor venetoclax, coupled with our interests in polypharmacology, we sought to bolster the anti-leukemic efficacy of the clinical drug by grafting HDAC1-selective or HDAC6-selective inhibitor motifs onto a solvent-accessible domain of venetoclax. We discovered multiple polypharmacological agents that both retained the potent BCL-2 inhibitory activity of venetoclax and effectively inhibited either HDAC1 or HDAC6 with excellent (up to 80-fold) selectivities for the desired HDAC isoform. In addition, relative to parental venetoclax, two of our lead compounds, BD-4-213 and AMC-4-154, exhibited superior activities against the acute myeloid leukemia cell line MV4;11 and an MV4;11 cell line engineered to overexpress BCL-2. Annexin-V assay results confirmed an on-target mechanism of apoptosis for these novel chimeric molecules. Efforts to further boost the HDAC1 or HDAC6 binding affinities and/or selectivities proved unsuccessful due to synthetic chemistry challenges and solubility problems, which may underscore the difficulties of polypharmacology approaches involving a large inhibitor, such as venetoclax.

Keywords:  AML; BCL‐2; HDAC; cancer; venetoclax

DOI:  https://doi.org/10.1002/ddr.70084
Mol Immunol. 2025 May 09. pii: S0161-5890(25)00122-1. [Epub ahead of print]183 93-103

Gastric cancer cells shuttle lactate to induce inflammatory CAF-like phenotype and function in bone marrow-derived mesenchymal stem cells.

Feng Huang, Xiaoli Cao, Jingyu Mei, Chen Wu, Wei Zhu, Li Sun, Chun Dai, Mei Wang.

  Metabolic reprogramming, exemplified by the "Warburg effect," is a hallmark of human cancers, leading to lactate buildup in tumors. Bone marrow-derived mesenchymal stem cells (BM-MSCs), key contributors to cancer-associated fibroblasts (CAFs), integrate into gastric cancer stroma through interactions with cancer cells. However, the role of lactate in activating BM-MSCs in this context remains unclear. Herein, exogenous lactate induced a pro-tumorigenic phenotype in BM-MSCs, which was blocked by AZD3965. Gastric cancer cells released more lactate under hypoxia than normoxia. While normoxic gastric cancer cells could educate BM-MSCs, hypoxic cells were more effective. However, the effects of the supernatant from gastric cancer cells in both conditions were significantly reduced by AZD3965. Similarly, prevention of lactate production by oxamic acid sodium significantly reduced the effects observed. Lactate-activated BM-MSCs showed NF-κB signaling activation, increased IL-8 secretion, and no change in TGF-β signaling. These activated BM-MSCs promoted gastric cancer cell migration and invasion through IL-8 secretion and enhanced resistance to CD8 + T cell cytotoxicity by upregulating PD-L1. Collectively, gastric cancer cells induce an iCAF-like phenotype and function in BM-MSCs through a lactate shuttle mechanism, emphasizing the role of metabolic reprogramming in cellular communication that fosters a supportive tumor microenvironment. Targeting lactate-related pathways may provide new therapeutic strategies to hinder BM-MSCs' supportive roles in gastric cancer.

Keywords:  Bone marrow-derived mesenchymal stem cells; Cancer-associated fibroblasts; Gastric cancer; Lactate; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.molimm.2025.05.002
J Hepatobiliary Pancreat Sci. 2025 May 14.

Efficacy and Safety of Surgical Treatment Among Older Adult Patients (80 Years) With Pancreatic Cancer: A Systematic Review and Meta-Analysis.

Naoki Ikenaga, Takao Ohtsuka, Eiji Mitate, Koji Tamura, Masayuki Sho, Masafumi Nakamura.

   BACKGROUND: With rapid population aging, the number of older adult patients presenting with pancreatic cancer is increasing. This meta-analysis aimed to clarify the efficacy and safety of surgical interventions for pancreatic cancer among older adult patients.
METHODS: Literature published in PubMed, Cochrane Library, and ICHUSHI databases until January 2024 was systematically searched. Comparative studies reporting outcomes of pancreatic cancer resection among patients aged 80 years or older were included in the analysis. Fifteen retrospective studies involving 22 647 patients were included in the meta-analysis: 2930 patients aged 80 years or older who underwent pancreatic resection, 2059 patients aged 80 years or older treated with chemotherapy, and 17 658 patients under 80 years old.
RESULTS: Surgical treatment had a higher two-year survival rate than chemotherapy among patients with pancreatic cancer aged 80 years or older. These patients experienced similar morbidity, higher mortality, and lower three-year survival rates than those younger than 80 years.
CONCLUSIONS: Surgical treatment for pancreatic cancer improves survival rates even among patients aged 80 years or older; however, these patients may have a lower chance of recovering from complications. Patients should be informed of these objective findings to ensure shared decision-making regarding the best treatment strategy.

Keywords:  non‐surgical treatment; older adults; overall survival; pancreatectomy; pancreatic cancer

DOI:  https://doi.org/10.1002/jhbp.12151
J Leukoc Biol. 2025 May 16. pii: qiaf065. [Epub ahead of print]

Hypoxia-Activated CBS/H2S Signaling Drives Drug Resistance in AML through CD36-Mediated Fatty Acid metabolism.

Qianpeng Li, Qin Li, Haifeng Han, Maowen Liu, Nannan Lyu, Zhiyuan Qiu, Rui Zhang, Xuehong Ran, Xiaofeng Li.

  Hypoxia-associated H2S accumulation promotes chemotherapy resistance in solid tumor cells. This study delved into the mechanism by which CBS/H2S signaling is involved in the development of acute myeloid leukemia (AML) resistance to cytarabine (ara-C) under hypoxic conditions. The levels of CBS and H2S in AML cells and ara-c-resistant AML cells were evaluated. Subsequently, the expression of CBS and H2S under normoxic and hypoxic conditions in ara-c-resistant AML cells were further scrutinized. Sh-CBS or sh-THBS1 was transfected into ara-c-resistant AML cells, which were then exposed to 1% oxygen and/or ara-C. The cell viability, apoptosis, lipid metabolism level were evaluated by CCK-8, flow cytometry, kit and qPCR. Simultaneously, the methylation of THBS1 was detected via methylation-specific PCR analysis. The expression of CBS and H2S is elevated in ara-C-resistant AML cells, rising proportionally with diminishing oxygen concentration. In ara-C-resistant AML cells, hypoxia stimulated cell viability, suppressed apoptosis, augmented total cholesterol and triacylglycerol levels, upregulated the levels of CD36 and CPT1α as well as downregulated SCAD and PPARα levels, while these effects of hypoxia were all reversed by sh-CBS. Sh-CBS notably decreases the hypermethylation level of THBS1 in ara-C-resistant AML cells. Sh-THBS1 reversed the regulatory effect of sh-CBS on lipid metabolism, cell viability, and apoptosis in ara-C-resistant AML cells. Conversely, sh-CD36 effectively overrode the reversal impact of sh-THBS1. Activation of CBS/H2S signaling in a hypoxic environment participates in the ara-C resistance of AML cells by facilitating CD36-mediated fatty acid metabolism through mediation of THBS1 methylation.

Keywords:  Acute myeloid leukemia; cytarabine resistance; hydrogen sulfide; hypoxia; thrombospondin 1

DOI:  https://doi.org/10.1093/jleuko/qiaf065
Nutrients. 2025 Apr 27. pii: 1478. [Epub ahead of print]17(9):

Database Analysis of Application Areas and Global Trends in Ketogenic Diets from 2019 to 2024.

Marc Assmann, Isabel Albrecht, Marius Frenser, Thorsten Marquardt, Tobias Fischer.

  Background: After being developed in the 1920s, the ketogenic diet fell into disuse, only to make a comeback at the end of the 20th century. In addition to its original use in the treatment of epilepsy, research on the ketogenic diet is now focusing on many other indications. Methods: Based on a systematic literature analysis according to the PRISMA guidelines, an overview of the current research on specific topics in the last five years (2019 to August 2024) was compiled. Results: A total of 290 trials were included. In total, 32 topics were analyzed, most of which were related to overweight and obesity, as well as exercise and epilepsy. The articles included 1981 authors from 47 countries, who published their results from intervention and observational studies in 153 journals. In total, 227 studies lasted less than six months, while 61 studies lasted more than six months. Conclusions: The results and the increasing amount of research underline the growing scientific attention and potential of the ketogenic diet to offer new therapeutic and individual preventive approaches. These trends indicate that the ketogenic diet remains an important international research topic.

Keywords:  database analysis; global trends; ketogenic diet; ketogenic nutrition; literature analysis; nutrition trends; research areas

DOI:  https://doi.org/10.3390/nu17091478
Mol Metab. 2025 May 08. pii: S2212-8778(25)00072-9. [Epub ahead of print] 102165

Off-target depletion of plasma tryptophan by allosteric inhibitors of BCKDK.

Caitlyn E Bowman, Michael D Neinast, Ryo Kawakami, Nicholas Forelli, Cholsoon Jang, Jiten Patel, Megan C Blair, Michael C Noji, Emily T Mirek, William O Jonsson, Qingwei Chu, Lauren Merlo, Laura Mandik-Nayak, Tracy G Anthony, Joshua D Rabinowitz, Zolt Arany.

The activation of branched chain amino acid (BCAA) catabolism has garnered interest as a potential therapeutic approach to improve insulin sensitivity, enhance recovery from heart failure, and blunt tumor growth. Evidence for this interest relies in part on BT2, a small molecule that promotes BCAA oxidation and is protective in mouse models of these pathologies. BT2 and other analogs allosterically inhibit branched chain ketoacid dehydrogenase kinase (BCKDK) to promote BCAA oxidation, which is presumed to underlie the salutary effects of BT2. Potential "off-target" effects of BT2 have not been considered, however. We therefore tested for metabolic off-target effects of BT2 in Bckdk-/- animals. As expected, BT2 failed to activate BCAA oxidation in these animals. Surprisingly, however, BT2 strongly reduced plasma tryptophan levels and promoted catabolism of tryptophan to kynurenine in both control and Bckdk-/- mice. Mechanistic studies revealed that none of the principal tryptophan catabolic or kynurenine-producing/consuming enzymes (TDO, IDO1, IDO2, or KATs) were required for BT2-mediated lowering of plasma tryptophan. Instead, using equilibrium dialysis assays and mice lacking albumin, we show that BT2 avidly binds plasma albumin and displaces tryptophan, releasing it for catabolism. These data confirm that BT2 activates BCAA oxidation via inhibition of BCKDK but also reveal a robust off-target effect on tryptophan metabolism via displacement from serum albumin. The data highlight a potential confounding effect for pharmaceutical compounds that compete for binding with albumin-bound tryptophan.

DOI: https://doi.org/10.1016/j.molmet.2025.102165
EXCLI J. 2025 ;24 433-449

Using novel oxidative phosphorylation inhibitors to attenuate drug resistance in human gliomas.

Chia-Kuang Tsai, Chin-Yu Lin, Yung-Lung Chang, Fu-Chi Yang, Chung-Hsing Chou, Yu-Chian Huang, Dueng-Yuan Hueng.

  Glioblastoma multiforme (GBM) is an aggressive brain tumor with a poor prognosis, worsened by resistance to temozolomide (TMZ). TMZ-induced DNA damage is counteracted by the repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT), promoting tumor recurrence. Targeting oxidative phosphorylation (OXPHOS), essential for cellular energy production, offers a potential therapeutic strategy to overcome TMZ resistance and improve GBM treatment outcomes. Gboxin, a small-molecule drug, selectively inhibits OXPHOS by targeting complex V, with minimal toxicity to normal cells. It accumulates in the mitochondria of GBM cells, exploiting their high membrane potential and pH, thereby inhibiting cell proliferation. This study evaluates Gboxin's efficacy in TMZ-resistant (TMZ-R) GBM. Results show that Gboxin suppresses the growth of both TMZ-sensitive and TMZ-R GBM cells by inhibiting proliferation, inducing apoptosis, and reducing OXPHOS activity. These findings were confirmed in an in vivo model, highlighting Gboxin as a promising therapeutic for both TMZ-sensitive and TMZ-R GBM. See also the graphical abstract(Fig. 1).

Keywords:  Gboxin; PLK2; glioblastoma; oxidative phosphorylation capacity

DOI:  https://doi.org/10.17179/excli2025-8193