bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2026–06–21
eleven papers selected by
Brett Chrest, Wake Forest University
  1. Emerging insights into the role of BDH1 in the pathogenesis of human cancer.
  2. High-fat, low-carb diet reduces tumor growth and induces liver metabolism remodeling in a breast cancer mouse model.
  3. Short-changed: Limited short-chain fatty acid oxidative capacity in skeletal muscle mitochondria.
  4. Development of new liquid chromatography-tandem mass spectrometry methods for the quantification of seven metabolites in three related breast cancer cell lines.
  5. Ketogenic diet as a metabolic vehicle enhancing the therapeutic efficacy of mebendazole and devimistat in juvenile syngeneic high-grade glioma.
  6. Venetoclax and hypomethylating agents synergize to increase cell death and metabolic remodeling in acute B-lymphoblastic leukemia cells.
  7. Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
  8. Editorial: Beyond energy production: exploring mitochondrial dynamics and disease.
  9. Detection of NADH/NAD+ dysregulation in MELAS via diazo-carboxyl click derivatization mass spectrometry.
  10. Peroxisomal Lipid Metabolism as a Therapeutic Target in Leukemia.
  11. A minimal chemo-mechanical Markov model for rotary catalysis of F1-ATPase.
  1. Front Oncol. 2026 ;16 1785200
    Emerging insights into the role of BDH1 in the pathogenesis of human cancer.
    Penghui Wang, Yunmeng Yan, Zhengrong Liu, Guoxun Feng, Wei Yu.
      β-Hydroxybutyrate dehydrogenase 1 (BDH1) encodes a key enzyme in the metabolism of ketone bodies and plays a critical role in maintaining cellular energy homeostasis. As a member of the short-chain dehydrogenase/reductase (SDR) family, BDH1 catalyzes the reversible conversion of β-hydroxybutyrate (BHB) to acetoacetate (AcAc), a process that is particularly vital during states of metabolic stress, such as fasting or prolonged exercise. Beyond normal physiology, BDH1 functions as a context-dependent metabolic rheostat in human cancers, supporting altered neoplastic energy metabolism and conferring stress resistance. Its dysregulation is associated with tumor microenvironment adaptation, malignant progression, and differential therapeutic responses, positioning BDH1 as both a potential prognostic biomarker and a promising therapeutic target in precision oncology.
    Keywords:  BDH1; cancer; ketone body metabolism; metabolic reprogramming; pathogenesis
    DOI:  https://doi.org/10.3389/fonc.2026.1785200
  2. Am J Physiol Cell Physiol. 2026 Jun 16.
    High-fat, low-carb diet reduces tumor growth and induces liver metabolism remodeling in a breast cancer mouse model.
    Anouk Charlot, Anthony Bringolf, Joris Mallard, Amélie Jaulin, Emilie Crouchet, Delphine Duteil, Fabien Alpy, Catherine-Laure Tomasetto, Thomas Baumert, Joffrey Zoll.
      Cancer cells require large quantities of glucose to ensure sufficient ATP production through glycolysis, and the liver may facilitate this glucose supply. A high-fat low-carbohydrate ketogenic diet (KD) could represent a strategy to reduce tumor growth. However, the molecular effects of carbohydrate restriction mediated by the KD and its hepatic impact remain poorly understood. To address this question, 6-week-old FVB/N-Tg(MMTV-PyVT)634Mul/J mice, which develop spontaneous mammary tumors, were fed a standard chow diet (SD group) or a KD diet (KD group) until reaching the age of 12 weeks. The effects of carbohydrate restriction were assessed by plasma analyses, as well as histological staining, RT-qPCR and Western Blotting in tumors and liver. We found that carbohydrate restriction reduced tumor growth by 46% and was associated with decreased expression of pro-tumorigenic factors (Ang2, Hgf, Mki67). Moreover, a decrease of metabolic enzymes (Pfk, Bdh1, Scot1) highlighted the lack of metabolic flexibility of the tumor cells and underscored their strong dependency on glucose. Conversely, the liver exhibited a strong adaptive response with enhanced ketogenesis and gluconeogenesis, evidenced by elevated blood glucose and upregulation of Pepck, Foxo1, and CREB. A high-fat, low-carbohydrate diet exerts a dual metabolic effect: it suppresses tumor progression through local metabolic reprogramming but simultaneously enhances hepatic glucose production. This highlights the pivotal role of systemic glucose availability in tumorigenesis and underscores the need to consider liver metabolism when designing dietary interventions for cancer therapy.
    Keywords:  Breast cancer; Warburg effect; carbohydrate restriction; gluconeogenesis; ketogenic diet
    DOI:  https://doi.org/10.1152/ajpcell.00878.2025
  3. J Physiol. 2026 Jun 19.
    Short-changed: Limited short-chain fatty acid oxidative capacity in skeletal muscle mitochondria.
    Daniel G Sadler.
      
    Keywords:  exercise; high‐fat diet; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1113/JP291630
  4. J Pharm Biomed Anal. 2026 Jun 13. pii: S0731-7085(26)00280-3. [Epub ahead of print]280 117612
    Development of new liquid chromatography-tandem mass spectrometry methods for the quantification of seven metabolites in three related breast cancer cell lines.
    Marziyeh Ghanbarian, Deborah Michel, Maryam Alyari, Amir Khajavinia, Oleg Y Dmitriev, Anas El-Aneed.
      Metabolites of the tricarboxylic acid (TCA) cycle play crucial roles in cancer biology, and their accurate quantification is essential for understanding energy metabolism, signaling dynamics, and identifying metabolic vulnerabilities in cancer cells. However, traditional liquid chromatograph-tandem mass spectrometry (LC-MS/MS) methods for these polar metabolites often encounter challenges, such as limited retention on reversed-phase columns and ion suppression. This study developed and validated two LC-MS/MS methods for the accurate quantification of seven key TCA cycle metabolites in MDA-MB-231, M67-2 (MEMO1 knockdown), and M67-9 (MEMO1 knockout) breast cancer cell lines. For five metabolites, namely citrate (CA), L-malate (MA), fumarate (FA), α-ketoglutarate (AKG), and glutamate (GA), an isotope-coded derivatization approach utilizing 12C/13C-labeled dimethylaminophenacyl (DmPA) bromide was employed to develop a targeted high-performance liquid chromatography (HPLC)-MS/MS method. Inefficient DmPA derivatization in aqueous matrices was addressed by optimizing sample preparation in non-aqueous conditions, and the presence of multiple peaks of AKG was resolved by selecting triethanolamine (TEOA) as the reaction base to improve specificity. Conversely, due to persistent interferences with DmPA derivatization, pyruvic acid (PA) and succinic acid (SA) were quantified using another novel hydrophilic interaction liquid chromatography (HILIC)-MS/MS method in their native underivatized forms. Both methods were validated according to regulatory bodies, ensuring linearity, accuracy, precision, selectivity, and stability. The methods ensured the utilization of two multiple reaction monitoring (MRM) transitions to enhance specificity. The validation approach was adjusted to fit tissue culture studies. The validated methods were successfully used to measure the TCA metabolites in tested cell lines, providing valuable tools for investigating metabolic dynamics in cancer research.
    Keywords:  Cancer cells; DmPA derivatization; HILIC-MS/MS; HPLC-MS/MS; LC-MS/MS; TCA cycle metabolites; Targeted metabolomics
    DOI:  https://doi.org/10.1016/j.jpba.2026.117612
  5. Cell Rep Med. 2026 Jun 16. pii: S2666-3791(26)00262-4. [Epub ahead of print]7(6): 102845
    Ketogenic diet as a metabolic vehicle enhancing the therapeutic efficacy of mebendazole and devimistat in juvenile syngeneic high-grade glioma.
    Purna Mukherjee, Jack Maurer, Sylwia A Stopka, Bennett Greenwood, Juan J Aristizabal-Henao, Srada Karmacharya, Alexandra Chimento, Nathan Ta, Derek C Lee, Tomas Duraj, Roderick T Bronson, Michael A Kiebish, Thomas N Seyfried.
      Invasive pediatric high-grade gliomas (HGGs) are associated with poor clinical outcomes, and current therapies often cause significant long-term toxicities. This study investigates the influence of nutritional ketosis on the therapeutic efficacy of mebendazole (MBZ) and devimistat (CPI-613) in invasive VM-M3 and non-invasive CT-2A glioblastoma models in juvenile syngeneic mice. Both drugs were also evaluated in the human pediatric glioma cell line SF-188. Mesenchymal-origin VM-M3 tumors exhibited extensive invasion throughout the brain and spinal cord, whereas neural stem cell-derived CT-2A and VM-NM1 tumors did not show distal spread. The greatest reductions in tumor invasion and progression, together with prolonged survival, occurred when drug treatment was combined with a ketogenic diet (KD). MBZ inhibited glycolysis and glutaminolysis in VM-M3 cells and reduced proliferation and viability of SF-188 cells. KD-enabled combination therapy allowed lower drug dosing, reduced toxicity, and improved survival, supporting further investigation of metabolically informed diet-drug strategies for pediatric gliomas.
    Keywords:  childhood brain cancer; glucose; glutamine; glutaminolysis; glycolysis; ketones; metabolic therapy; press-pulse; spinal cord
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102845
  6. Mol Metab. 2026 Jun 17. pii: S2212-8778(26)00086-4. [Epub ahead of print] 102402
    Venetoclax and hypomethylating agents synergize to increase cell death and metabolic remodeling in acute B-lymphoblastic leukemia cells.
    Patricia Maass, Sandra Lange, Felix Wittig, Nares Trakooljul, Frieder Hadlich, Anett Sekora, Christian Schmidt, Hugo Murua Escobar, Klaus Wimmers, Burkhard Hinz, Christian Junghanss, Anna Richter.
      Overexpression of anti-apoptotic protein BCL-2 and hypermethylation are hallmarks of acute lymphoblastic leukemia (ALL) and can be pharmacologically addressed by venetoclax (VEN) and hypomethylating agents (HMA) such as azacytidine (AZA) or decitabine (DEC). Combined VEN and HMA application was recently successfully implemented into the clinical treatment regimen of acute myeloid leukemia but has so far not been investigated in ALL. We therefore analyzed the anti-leukemic potential of VEN+HMA in four ALL cell lines and identified potential modes of synergy to overcome mono-drug-induced resistance. All substances influenced cell proliferation and induced apoptosis in a subset of the tested cell lines. Investigating potential ways of synergy, combined VEN and HMA application resulted in significantly reduced metabolic activity in all investigated cell lines. In contrast, no synergistic effects were observed regarding the BCL-2 protein and methyltransferase expression or global methylation. Single cell RNAseq of a patient-derived xenograft model revealed that VEN interferes with both main energy supply routes, oxidative phosphorylation as well as glycolysis, to impede the cells' metabolism and mitochondrial activity. The addition of HMA, especially DEC, further increased anti-metabolic effects, leading to a strong reduction of basal and maximal respiration, ATP production and proton leakage. AZA-induced metabolic suppression as well as overall anti-leukemic activity alone and in combination with VEN was generally weaker compared to DEC. Altogether, we herein demonstrate that combined VEN and HMA application acts synergistically and significantly reduces the leukemic burden in ALL cell lines via impairment of tumor cell metabolism and mitochondrial function.
    DOI:  https://doi.org/10.1016/j.molmet.2026.102402
  7. J Clin Invest. 2026 Jun 16. pii: e196687. [Epub ahead of print]
    Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
    Matthew Tcheng, Veronique Voisin, Geethu Emily Thomas, Anastasija A Piric, Marcela Gronda, Rose Hurren, Dakai Ling, Yongran Yan, Lan Xin Zhang, Yue Feng, Ali Chegini, Nathan Duong, Ross S Mancini, Stefan Quinn W Currie, Zaynab Mamai, Brady Stock, Shahbaz Khan, Yulia Jitkova, Chaitra Sarathy, Edward Ayoub, Po Yee Mak, Andrea Arruda, Thomas Kislinger, Mark Reed, Bing Z Carter, Michael Andreeff, Steven M Kornblau, Mark D Minden, Siavash Vahidi, Aaron D Schimmer.
      Most mitochondrial proteins are nuclear encoded, translated in the cytosol, and imported into the mitochondria. Through gene expression analysis and functional assays, we demonstrated that mitochondrial protein import is increased in acute myeloid leukemia (AML) cells compared to normal hematopoietic cells. Increased mitochondrial protein import was positively correlated with increased mitochondrial unfolded protein response (UPRmt), a stress activated pathway of mitochondrial proteases and chaperones that maintains protein solubility and prevents the formation of toxic aggregates. The UPRmt protease LONP1 (Lon Peptidase 1) was upregulated in AML and positively correlated with increased mitochondrial protein import and UPRmt. Genetically or chemically inhibiting the LONP1 ATPase domain induced mitochondrial protein aggregation and selectively killed AML cells with high LONP1 expression while sparing AML cells with low LONP1 expression and normal hematopoietic cells in vitro and in vivo. Thus, we uncovered a critical role of the UPRmt protease LONP1 in buffering stress from mitochondrial protein import in AML.
    Keywords:  Cancer; Cell biology; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI196687
  8. Front Cell Dev Biol. 2026 ;14 1872916
    Editorial: Beyond energy production: exploring mitochondrial dynamics and disease.
    Nahid A Khan, Ruben Torregrosa-Muñumer.
      
    Keywords:  cell fate regulation; metabolic signaling; mitochondria; mitochondrial disease; mitochondrial dynamics; mitochondrial quality control; mitochondrial therapy; redox metabolism
    DOI:  https://doi.org/10.3389/fcell.2026.1872916
  9. Clin Chim Acta. 2026 Jun 13. pii: S0009-8981(26)00354-2. [Epub ahead of print]591 121172
    Detection of NADH/NAD+ dysregulation in MELAS via diazo-carboxyl click derivatization mass spectrometry.
    Jiaqi Hu, Tongling Liufu, Cong Li, Qijin Zhao, Meng Yu, Yun Yuan, Li Quan, Zhixing Chen, Zhaoxia Wang.
       OBJECTIVES: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disorder driven by mutations in mitochondrial or nuclear DNA, involving an altered NADH/NAD+-associated redox metabolism as a key pathological mechanism. The traditional metabolomic analyses in MELAS face sensitivity and sample volume limitations, particularly for carboxylic acid metabolites. This study employed a recently established diazo-carboxyl/hydroxylamine-ketone double-click derivatization (DQmB-HA) mass spectrometry method to overcome these barriers, enabling highly sensitive quantification of NADH/NAD+-related serum metabolites in minimal sample volumes.
    METHODS: Using DQmB-HA mass spectrometry, we analyzed lactate, pyruvate, β-hydroxybutyrate, acetoacetate, α-hydroxybutyrate, and malate in 5-μL serum samples from each of the MELAS patients (n = 70), healthy controls (n = 29), and CPEO patients (n = 17). Individual metabolite levels were quantified, and the lactate/pyruvate ratio and β-hydroxybutyrate/acetoacetate ratio were used as surrogate indicators of cytoplasmic and mitochondrial NADH/NAD+ redox states, respectively. Following this, analyses were performed to assess between-group differences in these indicators and to determine their correlations with disease duration.
    RESULTS: MELAS patients exhibited significantly elevated lactate, β-hydroxybutyrate, α-hydroxybutyrate, and malate levels, together with increased lactate/pyruvate and β-hydroxybutyrate/acetoacetate ratios compared with healthy controls. Among the evaluated biomarkers, the lactate/pyruvate ratio achieved the highest diagnostic performance (AUC = 0.993, 95% CI = 0.979-1.000), followed by lactate (AUC = 0.976) and β-hydroxybutyrate (AUC = 0.864). Although the β-hydroxybutyrate/acetoacetate ratio showed high sensitivity (95.7%), its overall diagnostic accuracy was limited by lower specificity. However, none of these serum markers show a significant correlation with the disease duration course in MELAS patients. Relative to MELAS, lower concentrations of α-hydroxybutyrate (p < 0.001) and malate (p = 0.026) and elevated lactate/pyruvate ratio (p < 0.001) were observed in CPEO.
    CONCLUSION: The DQmB-HA method enabled high-sensitivity metabolomic profiling in low-volume clinical samples and revealed broad alterations in metabolites and metabolite ratios associated with NADH/NAD + -related redox metabolism in MELAS, providing a useful framework for metabolomic screening in mitochondrial diseases.
    Keywords:  MELAS; Metabolic dysfunction; Mitochondrial disease; NADH/NAD(+) ratio
    DOI:  https://doi.org/10.1016/j.cca.2026.121172
  10. Mol Nutr Food Res. 2026 Jun;70(11): e70530
    Peroxisomal Lipid Metabolism as a Therapeutic Target in Leukemia.
    Ekaterina N Parfenova, Paul A Spagnuolo.
      Lipid delivery and metabolism profoundly shape cancer cell fate, energy balance, redox control, and therapy resistance. Peroxisomes regulate fatty acid oxidation (FAO) and oxidative homeostasis with growing relevance in hematologic malignancies. Recent studies show peroxisomal FAO (pFAO) is selectively elevated in acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), sustaining cancer cell survival under metabolic and therapeutic stress. Elevated ACOX1, ABCD1/2, CROT, and PEX5 expression underscores leukemia-specific peroxisomal vulnerability; their pharmacologic or genetic inhibition disrupts lipid homeostasis, induces very-long-chain fatty acid accumulation, and drives oxidative stress and lipotoxicity. This selectively kills leukemia cells while sparing normal progenitors. pFAO blockade synergizes with chemotherapy drugs such as venetoclax and cytarabine, enabling exploitation of metabolic vulnerabilities to improve therapeutic outcomes. Upstream, PPAR isoforms transcriptionally link lipid ligand sensing to peroxisomal gene expression, though their precise role in governing pFAO in leukemia remains undefined. Integrating solid tumor and leukemia insights, peroxisomes emerge as dynamic lipid-processing organelles coupling FAO, redox buffering, and inter-organelle exchange to cancer persistence. Targeting peroxisome-mediated lipid delivery offers a frontier for overcoming metabolic resilience and therapeutic resistance in leukemia.
    Keywords:  acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); fatty acid oxidation (FAO); lipid metabolism; peroxisomes
    DOI:  https://doi.org/10.1002/mnfr.70530
  11. Nat Commun. 2026 06 15. pii: 5310. [Epub ahead of print]17(1):
    A minimal chemo-mechanical Markov model for rotary catalysis of F1-ATPase.
    Yixin Chen, Helmut Grubmüller.
      F1-ATPase, the catalytic domain of ATP synthase, is pivotal for mechano-chemical energy conversion in mitochondria. Aiming at a minimal yet quantitative and thermodynamically consistent model for its rotary catalysis mechanism, here we developed a chemo-mechanical Markov model incorporating essential conformational and chemical degrees of freedom. By systematically evaluating over 14,000 model variants via Bayesian inference and cross-validation, we find that a fully functional minimal model requires four functionally distinct β -subunit conformations. Our model reconciles the decade-long bi-site versus tri-site controversy, showing that both pathways contribute depending on ATP concentration. Furthermore, our model suggests a Brownian-ratchet-like mechanism that explains the observation that one ATP hydrolysis event can trigger larger than 120º rotations, thereby explaining seemingly over 100% efficiency. Beyond this prototypic example of a complex biomolecular machine, our approach should enable one to study other enzymatic mechanisms that implement close coupling between conformational motions, substrate binding, and chemical reactions.
    DOI:  https://doi.org/10.1038/s41467-026-73844-0
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