bims-medica 2026-07-12 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–07–12
thirty papers selected by
Brett Chrest, Wake Forest University

Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.
Succinate and lactate produced as conserved biomarkers through chronic and transient substrate-level phosphorylation: from microorganisms to cancer.
In Vivo Quantification of Histone Acetylation Turnover and Acetyl-CoA Sources Using ²H₂O Metabolic Labeling and High-Resolution Mass Spectrometry.
Skeletal muscle biomass as an underappreciated fate of glucose.
Lactate-induced H3K4me3 histone mark promotes PLOD1-driven prostate cancer invasion.
Chemical-induced colitis lowers mitochondrial bioenergetic function in colonic tissue with minimal impacts on the proteome.
Venetoclax with intensive chemotherapy in acute myeloid leukemia.
Control theory analysis of dynamic metabolic response elucidates mitochondrial-cytoplasmic coupling and nutrient partitioning.
Mitochondria produce lactate to vent redox pressure.
Dynamic control of nucleotide metabolism in physiology and disease.
Submicromolar imaging of intrinsic chromophores by two-photon photothermal microscopy captures mitochondrial response to chemotherapy.
Methionine restriction plus vitamin B12 antagonism overcomes methionine independence for cancer therapy.
Six Dehydrogenase Gatekeepers of Carbohydrate Metabolism: Metabolic Integration in Health and Disease.
Back to the future: "7+3" joins the venetoclax plus intensive chemotherapy movement.
N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase.
De novo synthesis of cardiolipin controls respiratory chain biogenesis in neonatal mouse hearts.
A method to synthesize analytical rhodoquinone standards for quantitative analysis in tissue specimen.
Metabolomics of healthy hematopoietic stem cells and leukemic stem cells.
TCA-controlled histone succinylation identifies IDH3B as a prognostic and therapeutic target in AML.
Oxygen relief for a proteostasis-driven disease associated with mitochondrial complex I dysfunction.
Tricarboxylic Acid (TCA) Cycle Enzyme Alpha-Ketoglutarate Dehydrogenase (KGDH) as a Nexus for the Regulation of Macrophage Polarization.
Discovery of SD-2301 as a Highly Potent and Selective PROTAC STAT3 Degrader Capable of Achieving Complete Tumor Regression with Single Administration.
Sex-Specific Relationships between Cerebral Cortex Metabolism, Behavior, and ECG Parameters in Rats under Physiological Conditions and after Pyruvate Dehydrogenase Inhibition.
Targeting ribonucleotide reductase to enhance the antileukemic activity of gilteritinib against chemoresistant FLT3- internal tandem duplication acute myeloid leukemia.
Kinetic Lipidomics: Quantifying in vivo changes in lipid metabolism using metabolic labeling.
The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart.
Distinct metabolic dependency on BCAA defines cancer stemness and malignancy in human triple-negative breast cancer.
BCAAs, LAT1, and the Metabolic Competition between Tumor and Peripheral Tissues during Cancer Cachexia.
Targeting Warburg effect in Chinese hamster ovary cell culture with pyruvate dehydrogenase kinase inhibitors.
A bioenergetic understanding of "aerobic glycolysis".

Elife. 2026 07 08. pii: RP107953. [Epub ahead of print]14

Dynamic assembly of malate dehydrogenase-citrate synthase multienzyme complex in the mitochondria.

Joy Omini, Inga Krassovskaya, Taiwo Adeolu Dele-Osibanjo, Connor Pedersen, Toshihiro Obata.

  The tricarboxylic acid (TCA) cycle enzymes malate dehydrogenase (MDH1) and citrate synthase (CIT1) form a multienzyme complex, referred to as a metabolon, that channels intermediate oxaloacetate between their reaction centers. Given that the MDH1-CIT1 metabolon enhances pathway reactions in vitro, its dynamic assembly is hypothesized to contribute to TCA cycle regulation in response to cellular metabolic demands. Here, we demonstrated that yeast mitochondrial MDH1 and CIT1 dissociated when aerobic respiration was suppressed by the Crabtree effect and associated when the respiratory activity was enhanced by acetate. Pharmacological TCA cycle inhibition dissociated the complex, whereas electron transport chain inhibition enhanced the interaction. The multienzyme complex assembly was related to the mitochondrial matrix acidification and oxidation, as well as cellular levels of malate, fumarate, and citrate. These factors significantly affected the MDH1-CIT1 complex affinity in vitro. Especially, variations in buffer pH within the physiological pH range between 6.0 and 7.0 in the mitochondrial matrix significantly impacted the MDH1-CIT1 affinity. These results demonstrate the dynamic association and dissociation of the MDH1-CIT1 metabolon and its relationship with respiratory activity, supporting metabolon dynamics as an integral factor in metabolic regulation governed by multiple factors such as mitochondrial pH and metabolite levels.

Keywords:  S. cerevisiae; biochemistry; chemical biology; citrate synthase; malate dehydrogenase; metabolon; mitochondria; oxidative respiration; tricarboxylic acid cycle

DOI:  https://doi.org/10.7554/eLife.107953
J Bioenerg Biomembr. 2026 Jul 06. pii: 36. [Epub ahead of print]58(1):

Succinate and lactate produced as conserved biomarkers through chronic and transient substrate-level phosphorylation: from microorganisms to cancer.

Derek C Lee, Tomas Duraj, Christos Chinopoulos, Thomas N Seyfried.

  ATP is the primary energy currency required by living organisms. Mitochondrial oxidative phosphorylation (OxPhos) produces most of the ATP in quiescent and differentiated cells. OxPhos interruption results in analogous bioenergetic adaptations across divergent evolutionary taxa, yet this adaptation is poorly recognized. Oxygen availability is a major determinant of the source of ATP generation across most eukaryotic cell types. Acute oxygen deprivation, mitochondrial dysfunction, high energy demand, or other metabolic cues can shift relative ATP production from OxPhos to high-throughput fermentation via substrate-level phosphorylations (SLPs). Glucose-derived lactate and glutamine-derived succinate are biomarkers of cytosolic and mitochondrial SLP, respectively. The extracellular accumulation of these metabolites is observed in a broad range of biological systems, including unicellular bacteria and yeast to more complex mammalian cells, including those of the immune system, retina, and muscle. Unsurprisingly, many cancer cells accumulate excess lactate and succinate due to chronic OxPhos insufficiency. This review links ostensibly unique cases of metabolic disruption to the accumulation of lactate and succinate as biomarkers of compensatory fermentative metabolism through cytosolic and mitochondrial SLP. Fundamental principles of cellular energy and environmental adaptation are reviewed that span a broad range of biological complexity.

Keywords:  ATP; Fermentation; Lactate; Substrate-level phosphorylation; Succinate

DOI:  https://doi.org/10.1007/s10863-026-10117-x
bioRxiv. 2026 Jun 29. pii: 2026.06.26.734905. [Epub ahead of print]

In Vivo Quantification of Histone Acetylation Turnover and Acetyl-CoA Sources Using ²H₂O Metabolic Labeling and High-Resolution Mass Spectrometry.

Andrea Arias-Alvarado, Usman Sabir, Serguei Ilchenko, Spencer Parrish, Mirjavid Aghayev, Wentao He, Tsung-Heng Tsai, Guo-Fang Zhang, Takhar Kasumov.

Dysregulated histone acetylation links cellular metabolism to gene expression, but measuring its in vivo turnover remains technically challenging. Here, we introduce a 2 H2O -based metabolic labeling method coupled with high-resolution Orbitrap mass spectrometry to quantify in vivo histone acetylation dynamics. The approach leverages differing deuterium incorporation rates between fast-labeling acetyl groups and slow-labeling peptide backbones. A two-tier analytical workflow uses full-scan mass spectrometry for mono-acetylated peptides, combined with parallel reaction monitoring (PRM) to resolve site-specific turnover and stoichiometry. Furthermore, monitoring acetyl-group plateau 2 H enrichment enables the evaluation of specific substrate contributions to the acetyl-CoA pool supporting histone acetylation. To demonstrate biological utility, we applied this approach to mice maintained on a high-carbohydrate diet or subjected to 48-h fasting to assess nutrient-dependent histone acetylation dynamics. Acetyl-group labeling reflected the metabolic origin of acetyl-CoA, showing greater 2 H enrichment in the fed state and reduced enrichment during fasting due to increased utilization of unlabeled fatty acid-derived acetyl-CoA. Fasting accelerated acetylation turnover across multiple histone sites and reduced overall acetylation stoichiometry. Quantitative tracing revealed that fatty acid oxidation becomes an important contributor to histone acetylation during fasting, whereas glucose remains the predominant source of nucleo-cytosolic acetyl-CoA (supplying > 60% of acetylation used carbon). This approach enables simultaneous in vivo assessment of histone acetylation turnover, site occupancy, and acetyl-CoA substrate utilization, offering a robust platform to investigate metabolic-epigenetic crosstalk in health and disease.

DOI: https://doi.org/10.64898/2026.06.26.734905
Am J Physiol Cell Physiol. 2026 Jul 06.

Skeletal muscle biomass as an underappreciated fate of glucose.

Henning Wackerhage, Moritz Eggelbusch, Juha J Hulmi, Sakari Mäntyselkä.

  Glucose is traditionally viewed as a substrate for ATP production and glycogen storage in skeletal muscle. Here, we review evidence that glucose also serves as a building block for biomass synthesis in proliferating muscle satellite (stem) cells and hypertrophying skeletal muscle fibers, drawing parallels to anabolic metabolic reprogramming in cancer cells. In cancer and other growing cells, increased glucose uptake, aerobic glycolysis (Warburg effect), and the TCA cycle provide substrates for anabolic pathways that generate macromolecules required for growth and proliferation. Radiotracer studies in mammalian cancer and muscle cells demonstrate that approximately 8-15% of the cell dry mass originates from glucose. Mechanistic insights, obtained predominantly from cell culture models, indicate that glucose-derived glycolytic and TCA cycle intermediates provide substrates for serine synthesis and the pentose phosphate pathway, glycine and one-carbon metabolism, non-essential amino acid synthesis, nucleotide and lipid synthesis as well as for epigenetic methylation and acetylation. We further review evidence that human resistance training, hypertrophy through muscle-specific expression of Akt1 in mice, loss or inhibition of myostatin/activin signaling, and other hypertrophy-inducing interventions improve glucose homeostasis under conditions of obesity, insulin resistance, and type 2 diabetes. We discuss the possibility that glucose incorporation into biomass contributes to this effect.

Keywords:  Glucose; Warburg effect; cancer; diabetes mellitus; serine biosynthesis; skeletal muscle; skeletal muscle hypertrophy

DOI:  https://doi.org/10.1152/ajpcell.00295.2026
Cell Death Dis. 2026 Jul 07.

Lactate-induced H3K4me3 histone mark promotes PLOD1-driven prostate cancer invasion.

Marta Iozzo, Luigi Ippolito, Erica Pranzini, Simone Romagnoli, Giulia Gangarossa, Caterina Grillo, Sara Roccabianca, Giada Sandrini, Matteo Benelli, Giuseppina Comito, Elisa Giannoni, Paola Chiarugi.

Prostate cancer (PCa) progression is strongly influenced by the metabolites available in the tumor microenvironment (TME), including lactic acid (LA), which is actively imported by PCa cells to boost mitochondrial metabolism and drive de novo collagen synthesis, sustaining increased malignancy. LA exploitation promotes the unbalance of tricarboxylic acid (TCA) cycle intermediates, particularly succinate and fumarate, well-known epigenetic modifiers for histone (de)methylation. Here, we show that the LA-induced increase in succinate levels affects the activating H3K4me3 methylation mark in PCa cells, promoting a pro-invasive phenotype. Notably, pharmacological targeting of H3K4me3 using OICR-9429 reduces LA-enhanced PCa cell invasiveness. Moreover, LA-induced H3K4me3 enrichment regulates the expression of procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 1 (PLOD1), a key enzyme involved in collagen maturation. Genetic impairment of PLOD1 reduces the LA-driven invasive potential of PCa cells, thereby highlighting PLOD1 as a crucial epigenetically regulated mediator of tumor invasion. Overall, our findings uncover a novel LA-fuelled metabolic-epigenetic axis that promotes the H3K4me3-mediated PLOD1 upregulation, consequently fostering PCa aggressiveness and unveiling a potential therapeutic vulnerability.

DOI: https://doi.org/10.1038/s41419-026-09091-4
Sci Rep. 2026 Jul 06.

Chemical-induced colitis lowers mitochondrial bioenergetic function in colonic tissue with minimal impacts on the proteome.

McLane M Montgomery, Masara A Al Obaidi, Raphael T Aruleba, Polina Krassovskaia, Emely A Pacheco, Edziu Franczak, Brett R Chrest, Thomas D Green, Tonya N Zeczycki, Joeseph M McClung, Kelsey H Fisher-Wellman.

  Dextran sulfate sodium (DSS) is widely used to chemically-induce both colitis and colorectal cancer when administered alongside azoxymethane (AOM). DSS functions by disrupting the colonic epithelial barrier, triggering widespread inflammation within the colon. While DSS is a valuable tool for studying colitis-related diseases, its impact on mitochondrial bioenergetics and the proteomic landscape of colonic tissue remains poorly understood. To assess the chronic effects of DSS-induced colitis, we administered three rounds of 3% DSS in drinking water (5-day treatment periods) to C57BL/6 J mice and analyzed resected colonic tissue from DSS-treated and control (non-DSS treated) mice. Longitudinally opened colon segments were cleaned and subjected to high-resolution respirometry and mass spectrometry-based proteomic profiling. DSS treatment led to a global lowering of mitochondrial respiration, with the most pronounced impairments observed in complex I-supported respiration. Proteomic analysis revealed that these functional deficits occurred largely independently of changes in the mitochondrial proteome, except for an apparent upregulation of NIPSNAP1, a mitophagy-related protein. However, lentiviral knockdown of NIPSNAP1 in HCT116 cells did not rescue the observed bioenergetic defects, suggesting it is not the primary driver. Collectively, our findings show that DSS impairs mitochondrial respiration in the colon, most notably at complex I, without major alterations to the mitochondrial proteome. Given the role of mitochondrial dysfunction in various diseases, these effects should be carefully considered when using DSS-based models to study colitis pathophysiology.

Keywords:  DSS; Energy transduction; Epithelial barrier; Inflammation; Mitochondrial respiration

DOI:  https://doi.org/10.1038/s41598-026-61224-z
Chin Clin Oncol. 2026 06;15(3): 54

Venetoclax with intensive chemotherapy in acute myeloid leukemia.

Logan Shaver, Omer Jamy.



Keywords:  7+3; Acute myeloid leukemia (AML); intensive chemotherapy (IC); venetoclax

DOI:  https://doi.org/10.21037/cco-2026-1-0005
bioRxiv. 2026 Jul 01. pii: 2026.06.28.735091. [Epub ahead of print]

Control theory analysis of dynamic metabolic response elucidates mitochondrial-cytoplasmic coupling and nutrient partitioning.

Xingbo Yang, Daniel J Needleman.

Cells adjust their internal circuits in response to changes in their environment. Hence, exposing cells to changing conditions provides a way to probe the intrinsic dynamics of cellular internal circuits. Metabolic networks are examples of such circuits since metabolic fluxes dynamically adjust when environmental conditions are transiently altered. Most existing theoretical frameworks focus on cellular metabolic steady states and do not consider the dynamics of changes in metabolic fluxes. In this work, we applied transfer function analysis from control theory to analyze the changes of NADH oxidative fluxes in the mitochondria and cytoplasm in mouse oocytes in response to dynamical perturbations of oxygen depletion and recovery. We observed an overshoot of NADH oxidative flux in the cytoplasm upon oxygen recovery which is absent in the mitochondrial NADH oxidative flux. Metabolic perturbation experiments and transfer function analysis indicate that this cytoplasmic NADH overshoot results from the coupling of the mitochondrial and cytoplasmic NADH cycles. The degree of overshoot is determined by competing timescales associated with the exchange rates of lactate and pyruvate with the media and their interconversion rates catalyzed by lactate dehydrogenase. Applying control theory to the data enables the inference of the exchange and conversion rates of pyruvate and lactate, allowing predictions of the contribution of lactate to mitochondrial respiration. Our work indicates that the oocytes maintain a homeostatic respiration rate across nutrient conditions by modulating the contribution of lactate to mitochondrial respiration.

DOI: https://doi.org/10.64898/2026.06.28.735091
Trends Endocrinol Metab. 2026 Jul 04. pii: S1043-2760(26)00149-9. [Epub ahead of print]

Mitochondria produce lactate to vent redox pressure.

Serwah A Danquah, Lucas B Sullivan.

Conventionally viewed as a waste product or a cytosolic pyruvate source, recent findings suggest that lactate may also directly contribute to mitochondrial oxidative metabolism. Using an intramitochondrial lactate biosensor, Rauseo et al. instead find that energized mitochondria are producers of lactate, which buffers mitochondrial redox to mitigate reactive oxygen species production.

DOI: https://doi.org/10.1016/j.tem.2026.06.005
Nat Cell Biol. 2026 Jul 08.

Dynamic control of nucleotide metabolism in physiology and disease.

Dohun Kim, Gerta Hoxhaj.

Nucleotides are essential for life, serving not only as the building blocks of the genome but also as cellular energy providers, metabolic cofactors and signalling molecules. To sustain cellular function and proliferation, cells must continuously generate, recycle and precisely balance nucleotide pools in response to fluctuating metabolic and environmental demands. Nucleotide metabolism is therefore not a static biosynthetic pathway, but a dynamic system tightly integrated with cell signalling and physiology. Here we highlight the regulatory logic of nucleotide metabolism, from acute post-translational regulation to transcriptional scaling, feedback control and higher-order spatial organization into multi-enzyme assemblies and filaments. Through the lens of human genetic disorders and cancer, we examine how nucleotide depletion, pool imbalance or intermediate toxicity produce striking tissue-selective pathologies. Together, these principles position nucleotide metabolism as a central regulatory axis linking cellular metabolism, signalling and fate in health and disease.

DOI: https://doi.org/10.1038/s41556-026-02004-9
Sci Adv. 2026 Jul 10. 12(28): eaee7678

Submicromolar imaging of intrinsic chromophores by two-photon photothermal microscopy captures mitochondrial response to chemotherapy.

Nathaniel Hai, Chinmayee Vallabh Prabhu Dessai, Dingcheng Sun, Jianpeng Ao, Pin-Tian Lyu, Yifan Zhu, Ji-Xin Cheng.

Intracellular chromophores {e.g., NADH [reduced form of nicotinamide adenine dinucleotide (oxidized form)] and FAD (flavin adenine dinucleotide)} play a central role in regulation of cellular metabolism. Although autofluorescence has been extensively used for label-free mapping of chromophores inside a cell, its sensitivity and molecular specificity are constrained by the low quantum yield and the fluorescence spectral overlap. Here, we address these challenges by using a photothermal approach to measure the optical absorption of chromophores rather than its autofluorescence. Our two-photon photothermal (2PPT) microscope exploits localized thermal transients generated through two-photon absorption, enabling detection of chromophore-specific signatures beyond the reach of autofluorescence. We demonstrate submicromolar limits of detection for the metabolic coenzymes NADH and FAD of 0.87 and 0.99 μM, respectively. Such high sensitivity enables differentiating the influence of mitochondrial shapes on metabolism. 2PPT can identify the biomolecular source of contrast from cellular mitochondria in a label-free manner on the basis of spectroscopy. 2PPT microscopy is used to study metabolic alterations of mitochondria in cancer under chemotherapy at the single-organelle level.

DOI: https://doi.org/10.1126/sciadv.aee7678
Cancer Lett. 2026 Jul 09. pii: S0304-3835(26)00487-8. [Epub ahead of print] 218723

Methionine restriction plus vitamin B12 antagonism overcomes methionine independence for cancer therapy.

Valentin Lacombe, Jade Aurrière, Adélie Mellinger, Salim Khiati, Nicolas Giachetti, Flavien Bessaguet, Sarah Bellal, Pascal Reynier, Franck Geneviève, Geoffrey Urbanski, Guy Lenaers.

  Methionine dependence represents a well-known metabolic vulnerability in cancer. Despite promising preclinical results, methionine restriction is impaired by the presence of methionine-independent cancer cells. After confirming both inter- and intra-tumoral heterogeneity in methionine dependence, we demonstrate that "methionine-independent" cells are rather "methionine self-sufficient," relying on the vitamin B12 (B12)-dependent methionine synthase (MTR) to sustain growth without exogenous methionine, which renders them highly vulnerable to B12 deprivation. Dual methionine and B12 deprivation produced synergistic cytotoxicity, inhibiting proliferation and inducing apoptosis across multiple cancer types and primary tumor cells, while sparing fibroblasts. This synergy persisted under moderate nutrient restriction, supporting translational potential. Moreover, dual therapy prevented the adaptive metabolic shift seen with methionine deprivation alone, avoiding rebound proliferation and resistance. In vivo, a methionine-restricted diet plus a synthesized B12 antagonist significantly suppressed growth of methionine-independent pancreatic xenografts without hematologic toxicity. These findings uncover a selective, synergistic anticancer strategy targeting methionine self-sufficiency.

Keywords:  Dietary Restriction; Methionine; Methionine synthase; Neoplasms; Vitamin B12

DOI:  https://doi.org/10.1016/j.canlet.2026.218723
Front Biosci (Landmark Ed). 2026 Jun 25. 31(6): 49369

Six Dehydrogenase Gatekeepers of Carbohydrate Metabolism: Metabolic Integration in Health and Disease.

Christos Papaneophytou, Christos Petrou.

  Dehydrogenases function as metabolic gatekeepers, regulating carbon flux, redox balance, and biosynthetic capacity at critical branch points in cellular metabolism. This narrative review examines six key dehydrogenases, namely glyceraldehyde-3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase (LDH), pyruvate dehydrogenase complex (PDHC), malate dehydrogenase (MDH1/2), isocitrate dehydrogenase (IDH1/2/3), and glucose-6-phosphate dehydrogenase (G6PDH), that collectively orchestrate the partitioning of nutrients among energy production, biosynthesis, and redox homeostasis. These enzymes share common features, including cofactor-dependent catalysis (NAD+/NADH or NADP+/NADPH), strategic positioning at metabolic nodes, and integration of compartmentalized metabolism between the cytosol and mitochondria. Under physiologic conditions, these dehydrogenases enable metabolic flexibility, allowing cells to adapt nutrient utilization to changing energetic demands and biosynthetic requirements. However, their dysregulation drives pathogenesis across diverse human diseases. In cancer, altered dehydrogenase activity supports metabolic reprogramming, exemplified by the Warburg effect mediated by LDHA, oncometabolite production (mutant IDH1/2), and enhanced biosynthetic capacity associated with G6PDH activity. Metabolic syndrome and diabetes feature PDHC suppression via pyruvate dehydrogenase kinase (PDK) upregulation, contributing to metabolic inflexibility and impaired glucose oxidation. Inherited enzymopathies, including G6PDH and PDHC deficiencies, underscore the essential roles of these enzymes and their tissue-specific requirements. In neurodegenerative disorders, oxidative modification of GAPDH promotes protein aggregation, whereas age-related decline in NAD+ compromises the activity of multiple NAD+-dependent dehydrogenases in a tissue- and context-dependent manner. The central importance of these enzymes has generated substantial therapeutic interest. Successful clinical translation includes mutant IDH inhibitors that reverse oncometabolite-driven epigenetic reprogramming in cancer. However, targeting essential metabolic enzymes presents challenges, including narrow therapeutic windows, metabolic compensation, and tissue-specific toxicities. Future therapeutic strategies will likely focus on exploiting disease-specific vulnerabilities, developing isoform-selective inhibitors, and combining metabolic interventions with conventional therapies. Understanding these six dehydrogenase gatekeepers provides crucial insights into metabolic regulation and highlights opportunities for precision-medicine approaches targeting the metabolic dependencies of human disease.

Keywords:  dehydrogenases; glucose-6-phosphate dehydrogenase; glyceraldehyde-3-phosphate dehydrogenase; isocitrate dehydrogenase; lactate dehydrogenase; malate dehydrogenase; oxidoreductases; pyruvate dehydrogenase complex

DOI:  https://doi.org/10.31083/FBL49369
Chin Clin Oncol. 2026 Jun;15(3): 49

Back to the future: "7+3" joins the venetoclax plus intensive chemotherapy movement.

Michael Canonico, Somedeb Ball.



Keywords:  B-cell lymphoma 2 (BCL2); PARADIGM; Venetoclax (VEN); acute myeloid leukemia (AML); “7+3”

DOI:  https://doi.org/10.21037/cco-2026-1-0021
bioRxiv. 2026 Jul 02. pii: 2026.06.29.735215. [Epub ahead of print]

N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase.

Narayanan Puthillathu, John R Moffett, Barbara S Slusher, Aryan M Namboodiri.

N-acetylaspartate (NAA) is the most abundant neuron-enriched acetylated metabolite in the mammalian brain, but its metabolic purpose remains unresolved. We developed a simplified kinetic model of mitochondrial aspartate metabolism to test whether NAA synthesis by aspartate N-acetyltransferase (ASPNAT) acts as a thermodynamic "relief valve" for mitochondrial aspartate aminotransferase (AAT) under the low-oxaloacetate (OAA) conditions expected in neuronal mitochondria. In the mitochondrial-compartment model, ASPNAT lowered steady-state mitochondrial aspartate from 141 to 105 µ M and increased net forward AAT flux by 30.9%. The relative AAT-relief effect was largest when OAA and aspartate-glutamate carrier 1 (AGC1/Aralar1)-mediated export were both low, whereas acetyl-CoA availability controlled the substrate-supported capacity for NAA synthesis. That places the relief effect in a narrow regime where product removal matters most. ASPNAT titration produced a graded, concentration-dependent response rather than a binary on/off response. Energetic comparisons showed that the gain in AAT-linked support comes at a modest acetyl-CoA cost, which makes NAA synthesis easier to sustain in carbon-replete states than in carbon-poor ones. Some studies have suggested a secondary cytoplasmic site of NAA synthesis, and we therefore examined how the network response changed with a change in ASPNAT topology. Mitochondrial matrix ASPNAT increased forward AAT flux by 53.32%, whereas cytoplasmic ASPNAT decreased ASPNAT flux by 17.8%. Allowing OAA to vary preserved the positive ASPNAT-dependent relief of AAT flux, but because this simplified extension produced unrealistically low absolute fluxes, it is interpreted as a robustness check on the direction of the mechanism rather than as a prediction of physiological metabolic rates. These results identify mitochondrial NAA synthesis as a plausible thermodynamic relief valve for mitochondrial AAT and define a directional prediction that could test whether severe metabolic stress reroutes effective ASPNAT-linked aspartate metabolism.

DOI: https://doi.org/10.64898/2026.06.29.735215
EMBO Rep. 2026 Jul 07.

De novo synthesis of cardiolipin controls respiratory chain biogenesis in neonatal mouse hearts.

Mindong Ren, Yang Xu, Colin K L Phoon, Hediye Erdjument-Bromage, Thomas A Neubert, Michael Schlame.

Postnatal maturation of the mammalian heart requires a vast increase in respiratory enzymes. The mitochondria-specific lipid cardiolipin (CL) is essential for respiratory chain integrity but has no defined function in heart maturation. Here, we determined how the two steps of CL biogenesis, de novo synthesis and acyl chain remodeling, affect the maturation of cardiac mitochondria in mice. Cardiomyocyte-restricted deletion of the CL synthase Crls1 in late gestation does not affect CL levels at birth but blocks the increase in the tissue concentration of CL observed during normal postnatal maturation. Deletion of Crls1 prevents the postnatal rise in cristae density and in the intramitochondrial concentration of respiratory proteins. This inhibits cardiac development, precipitates heart failure, and causes death by the age of 2 weeks. In contrast, ablation of CL remodeling by cardiomyocyte-restricted deletion of Tafazzin does not disrupt mitochondrial maturation or cardiac development, although it has a similar effect on the CL concentration and profoundly alters the CL species composition. Our data show that CL synthesis, but not CL remodeling, controls expression of the respiratory chain by a mechanism independent of the CL concentration.

DOI: https://doi.org/10.1038/s44319-026-00864-8
J Lipid Res. 2026 Jul 09. pii: S0022-2275(26)00129-X. [Epub ahead of print] 101099

A method to synthesize analytical rhodoquinone standards for quantitative analysis in tissue specimen.

Thang Do, Akbar Ali, Jessica B Spinelli.

  Rhodoquinone (RQ) is a recently discovered component of the mammalian electron transport chain (ETC) with a high degree of tissue-specificity. Currently, a lack of pure analytical standards limits efforts to precisely quantify its levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and interrogate its biochemical functions within mammalian ETC complexes. Here, rhodoquinone-9 (RQ-9) and rhodoquinone-10 (RQ-10), and their isomeric by-products isorhodoquinone-9 (isoRQ-9) and isorhodoquinone-10 (isoRQ-10), were synthesized from ubiquinone-9 and ubiquinone-10 starting materials. Isomers were separated and purified by flash chromatography and structurally confirmed with nuclear magnetic resonance (NMR) spectroscopy. The chromatographic and fragmentation patterns of both the oxidized and reduced forms of these electron carriers were further characterized by LC-MS/MS, establishing signatures for their confident identification in lipidomics studies. LC-MS/MS analysis of murine kidney tissue with RQ-9 analytical standard spike-in corroborate the identity of the endogenous murine RQ-9 and enable absolute quantification of its levels. Thus, we synthesized and purified RQ-9 and RQ-10 analytical standards that will enable absolute quantification in mammalian tissues and in vitro reconstitution studies on RQ-9 and RQ-10 in the mammalian ETC.

Keywords:  Electron Transport Chain; Mass spectrometry; Mitochondria; Rhodoquinone

DOI:  https://doi.org/10.1016/j.jlr.2026.101099
J Clin Transl Res. 2025 Oct 29. 11(5): 50-68

Metabolomics of healthy hematopoietic stem cells and leukemic stem cells.

Gavin M Traber, Emely A Pacheco, Ansh Kumar, Edziu Franczak, Kelsey H Fisher-Wellman, Kathleen M Sakamoto.

  Background. Hematopoietic stem cells (HSCs) reside in the bone marrow and are responsible for the life-long production of blood cells by balancing quiescence, self-renewal, and differentiation. A major feature distinguishing quiescent HSCs from their activated counterparts is a shift in the metabolic profile including changes in glycolytic flux and mitochondrial oxidative metabolism. Disruptions to HSC homeostasis can lead to hematologic diseases such as bone marrow failure or clonal hematopoiesis and even oncogenic transformation to form leukemic stem cells (LSCs). Like that of HSCs, LSCs retain stem-like characteristics but also gain features of malignancy including drug resistance and a hijacked metabolism that exhibit distinct metabolic profiles that can underlie their pathogenesis. The aim of this review is to summarize the key metabolic characteristics that distinguish healthy quiescent and active HSCs as well as oncogenic LSCs. Here we also explore the modern tools used to investigate the metabolome and how they can reveal novel metabolites, metabolic interactions and pathways, and targets for diagnosis or therapeutic intervention of hematologic diseases. Understanding and interrogating changes to the metabolic profiles of healthy and leukemic stem cells may lead to the development of innovative techniques, technologies, and therapeutics. In turn, these advances can be used for the identification, treatment, and prevention of hematologic disease. By better understanding their metabolome, therapies can be designed to target the unique metabolic pathways, dependencies, and resistance mechanisms of LSCs.

Keywords:  hematopoietic stem cells; leukemic stem cells; metabolism; metabolomics

DOI:  https://doi.org/10.36922/jctr025320053
Clin Epigenetics. 2026 Jul 05.

TCA-controlled histone succinylation identifies IDH3B as a prognostic and therapeutic target in AML.

Minhui Shi, Kepeng Yang, Hao Ding, Na Zhao, Jiewen Ma, Aijie Huang, Yun Wang, Xiaoyu Zhu, Domenico Iuso, Mengqing Gao.

   BACKGROUND: Mitochondrial metabolism-driven epigenetic modifications have emerged as crucial regulators for acute myeloid leukemia (AML) progression, linking metabolic activity in leukemic stem cells to epigenetically controlled transcriptional programs that drive oncogenic gene expression.
RESULTS: Here, by integrating proteomic and transcriptomic data, we identified six genes whose expression were able to predict outcome in AML. Among these, IDH3B was highly expressed in leukemic stem cells and associated with poor prognosis. Functional studies revealed that IDH3B deletion in KMT2A-rearranged AML increased global protein succinylation, reduced acetylation, and sensitized cells to the menin-KMT2A inhibitor, both in vitro and in vivo. Mechanistically, loss of IDH3B, by increasing histone succinylation and reducing H3K79 methylation at the MYC promoter, amplified Revumenib-induced transcriptional repression of MYC.
CONCLUSIONS: These findings establish IDH3B as a key metabolic-epigenetic regulator in AML and highlight it as a potential synergistic target to enhance menin inhibition therapy.

Keywords:  Acute myeloid leukemia; IDH3B; Menin–KMT2A inhibition; Mitochondrial metabolism; Succinylation

DOI:  https://doi.org/10.1186/s13148-026-02197-8
Nat Metab. 2026 Jul 08.

Oxygen relief for a proteostasis-driven disease associated with mitochondrial complex I dysfunction.

Anthony S Grillo.

DOI: https://doi.org/10.1038/s42255-026-01569-x
J Cell Biochem. 2026 Jul;127(7): e70104

Tricarboxylic Acid (TCA) Cycle Enzyme Alpha-Ketoglutarate Dehydrogenase (KGDH) as a Nexus for the Regulation of Macrophage Polarization.

Meijing Li, Ryan J Mailloux.

Macrophage metabolism has been increasingly studied in recent years for its potential as a therapeutic target across multiple pathologies. In this article, we propose that the tricarboxylic acid (TCA) cycle enzyme alpha-ketoglutarate (KG) dehydrogenase (KGDH) serves as a nexus for regulating macrophage polarization toward pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes. This is achieved through modulation of mitochondrial hydrogen peroxide (mtH2O2) and the availability of the TCA cycle metabolites KG and succinate, which are important immunomodulatory molecules. We discuss the evidence showing KGDH is a potent source of mtH2O2 in various cell types and how it could use this reactive oxygen species (ROS) to modulate signaling pathways involved in macrophage differentiation. Coupled to this, we describe emerging evidence showing that KG and succinate exert opposite signaling effects in macrophages, with the former metabolite inducing an anti-inflammatory phenotype and the latter (succinate) promoting inflammation. This occurs through the regulation of dioxygenases involved in hypoxic signaling and epigenetic programming and the activation of G-protein coupled receptor 91 (GPR91) by succinate. Importantly, we contend that regulating KGDH influences the availability of these two metabolites, which, along with controlling mtH2O2 availability, helps control macrophage polarization. Collectively, increased mtH2O2 generation and succinate are known to induce a pro-inflammatory phenotype, whereas low mtH2O2 and high KG have the opposite effect. This suggests that KGDH is a key regulator of macrophage polarization by controlling the availabilities of these immunomodulatory metabolites.

DOI: https://doi.org/10.1002/jcb.70104
J Med Chem. 2026 Jul 05.

Discovery of SD-2301 as a Highly Potent and Selective PROTAC STAT3 Degrader Capable of Achieving Complete Tumor Regression with Single Administration.

Ranjan Kumar Acharyya, Longchuan Bai, Haibin Zhou, Dimin Wu, Mi Wang, Hoda Metwally, Donna McEachern, Meilin Wang, Bo Wen, Duxin Sun, Shaomeng Wang.

STAT3 is a promising therapeutic target for human cancers and other diseases. Herein, we report our development of novel STAT3 proteolysis-targeting chimera degraders using high-affinity STAT3 and Von Hippel-Lindau 1 ligands, which led to the discovery of SD-2301 as a highly potent, selective, and efficacious STAT3 degrader. SD-2301 achieved DC50 = 4 nM and Dmax of >95% and is >100 times more potent than SD-36 and SD-91. SD-2301 is highly selective for inducing STAT3 degradation over other Signal Transducer and Activator of Transcription members. SD-2301 inhibited cell growth with IC50 = 5-11 nM in the SU-DHL-1 and SUP-M2 lymphoma cell lines. SD-2301 displayed an excellent pharmacokinetic profile in mice and achieved rapid and persistent depletion of STAT3 protein in native and xenograft tumor tissues in mice. SD-2301 was capable of achieving complete and long-lasting tumor regression in vivo and is a promising STAT3 degrader for the treatment of human cancers and other human diseases.

DOI: https://doi.org/10.1021/acs.jmedchem.6c00743
Biochemistry (Mosc). 2026 Jun;91(6): 1006-1022

Sex-Specific Relationships between Cerebral Cortex Metabolism, Behavior, and ECG Parameters in Rats under Physiological Conditions and after Pyruvate Dehydrogenase Inhibition.

Anastasia V Graf, Alexey V Kazantsev, Victoria I Bunik.

  Sex-specific interactions between neurosignaling systems, which generate, propagate, and terminate signals in nervous tissue, and metabolic pathways that support these processes may underlie sex differences in adaptation and therapeutic efficacy. This study aimed to characterize these interactions as systemic indicators of sex-specific adaptive responses in a rat model of metabolic stress induced by the inhibition of pyruvate dehydrogenase complex (PDC), which catalyzes the key reaction linking anaerobic glycolysis to aerobic glucose oxidation. To inhibit brain PDC, we used a single intranasal administration of methyl acetylphosphinate (MeAcP), a phosphinate analog of pyruvate, or dimethyl acetylphosphonate (AcPMe2), a membrane-permeable precursor of phosphonate pyruvate analogs. Effects were assessed 24 h post-administration by measuring biochemical and physiological parameters in the cerebral cortex, including glutamate levels, glutamine synthetase (GS) activity, and activities of enzymes in the tricarboxylic acid (TCA) cycle and affiliated pathways. Neurosignaling was evaluated using surrogate indicators: ECG (electrocardiogram) parameters and spontaneous behavior in the open field test. Relationships between measured parameters were analyzed using Spearman's rank correlation coefficients, with the correlation strength classified according to the Chaddock's scale. In control animals, no sex differences were observed in the mean values of biochemical or ECG parameters. However, behavioral parameters (e.g., grooming and locomotion) and the overall structure of correlations between the studied parameters exhibited marked sex dependence. In control females, strong correlations were detected between ECG parameters and GS activity, whereas in males, ECG parameters were strongly associated with malic enzyme (ME) activity. Male controls also showed strong correlations between locomotor/exploratory behavior and activities of ME, PDC, and 2-oxoglutarate dehydrogenase complex (OGDC). Administration of PDC inhibitors induced a sex-specific reorganization of relationships between neurosignaling indicators and glutamate metabolism, which eliminated pronounced sex differences in locomotor activity observed in controls, while revealing new sex-related differences in glutamate levels, glutamate dehydrogenase (GDH) and ME activities, grooming bout duration, and freezing time. The reduction in glutamate levels observed in females following PDC inhibition was consistent with the established decrease in de novo glutamate synthesis from glucose under conditions of impaired substrate flux through the TCA cycle. Overall, these findings demonstrate that the relationships among metabolic, behavioral, and ECG parameters are inherently sex-specific. Moreover, the homeostatic response of the cerebral cortex to PDC inhibition reshapes these relationships, thereby modifying sex-dependent biochemical and behavioral characteristics observed under control conditions.

Keywords:  2-oxoglutarate dehydrogenase complex; behavior; correlation analysis; dimethyl acetylphosphonate; glutamate; glutamate dehydrogenase; glutamine synthetase; heart rate variability; malic enzyme; methyl acetyl phosphinate; pyruvate dehydrogenase complex; pyruvate dehydrogenase inhibition; sex differences; tricarboxylic acid cycle

DOI:  https://doi.org/10.1134/S0006297926600444
ASPET Discov. 2025 ;pii: 100014. [Epub ahead of print]1

Targeting ribonucleotide reductase to enhance the antileukemic activity of gilteritinib against chemoresistant FLT3- internal tandem duplication acute myeloid leukemia.

Nibal Eid, Jianlei Zhao, Jenna Thibodeau, Holly Edwards, Jing Li, Xun Bao, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Steven A Buck, Jessica B Back, Paul M Stemmer, Maurgan Lee, Seongho Kim, Jeffrey W Taub, Yubin Ge.

  Acute myeloid leukemia (AML) cases harboring FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (FLT3-ITD) mutations have poor clinical outcomes. Gilteritinib is a United States Food and Drug Administration-approved FLT3 inhibitor for treating relapsed/refractory (R/R) FLT3-mutated AML; however, monotherapy shows short-lived responses, highlighting the need for combination therapies. Increased ribonucleotide reductase regulatory subunit M2 (RRM2) was detected in cytarabine-resistant (AraC-R) FLT3-ITD AML cell lines and patient-derived xenograft (PDX) cells, accompanied by increased dNDPs determined by proteomics, western blotting, and metabolomics studies. shRNA knockdown of RRM2 significantly enhanced cell death induced by the ribonucleotide reductase inhibitor, hydroxyurea (HU). Treatment of MV4-11/AraC-R and the PDX cells with variable concentrations of gilteritinib (25-1000 nM) almost completely abolished RRM2 in the cells even at the lowest concentration and was accompanied by a plateau of cell death. Pretreatment with HU (12.5-500 μM) for 48 hours followed by gilteritinib (25-100 nM) for another 24 hours had a strong synergistic effect on the AraC-R FLT3-ITD AML cell lines and the PDX cells. Increasing gilteritinib concentrations by 10-fold did not result in further increased cell death. HU treatment induced RRM2 which was abolished by gilteritinib treatment, whereas gilteritinib treatment induced FLT3 which was canceled by HU, demonstrating reciprocal overcoming of drug resistance. Given that both drugs are Food and Drug Administration approved, and HU is well tolerated in both pediatric and adult populations as well as being cost-effective, establishing in vivo models could pave the path to clinical trials, ultimately providing a bridge to transplantation for R/R FLT3-ITD AML while minimizing toxicity.

Keywords:  Acute myeloid leukemia; Cytarabine-resistant; FMS-like tyrosine kinase 3-internal tandem duplication; Gilteritinib; Hydroxyurea

DOI:  https://doi.org/10.1016/j.aspetd.2025.100014
bioRxiv. 2026 Jul 01. pii: 2026.06.29.735310. [Epub ahead of print]

Kinetic Lipidomics: Quantifying in vivo changes in lipid metabolism using metabolic labeling.

Coleman O Nielsen, Russell L Denton, Chad R Quilling, Kenneth L Virgin, Kyle J Cutler, Spencer S Gates, Martin D Sorensen, Mitchel F Poulson, Tayler C Hilton, Benjamin K Driggs, Zabdi Hernandez, Parker M Snedaker, Bradley C Naylor, Mark K Transtrum, John C Price.

Lipid metabolism reflects the dynamic balance between metabolic turnover and concentration. Kinetic mass spectrometry (MS) enables direct quantification of molecular turnover in vivo. Previous work has shown that MS-based kinetic proteomics has provided powerful insights into proteome regulation. Analogous lipidome-wide kinetic measurements remain limited by challenges in defining molecule-specific labeling behavior. Here, we extend kinetic MS to untargeted lipidomics. Isotope labeling with deuterated water ( 2 H 2 O) is commonly used for monitoring turnover of palmitate and other select lipids by measuring labeling of stable C-H positions with deuterium ( 2 H). Here, we extend the deuterium-incorporation model underlying these targeted lipid turnover assays to support untargeted analysis of all detectable lipids. This allows us to empirically quantify the effective fraction of endogenous synthesis ( A syn ) and the turnover rate ( k ) across hundreds of lipid species simultaneously. One central barrier to lipidome-wide kinetic modeling is determining the endogenous number of deuterium-labeling sites for each molecule ( n L ) which is required to estimate A syn and k accurately. The n L value is an essential component of biological kinetic assays. In kinetic proteomics, curated amino acid n L libraries enable peptide-level modeling by summing sequence-specific labeling-site values, but comparable resources are lacking for lipids and may not generalize across metabolic states or non-mammalian systems. Yet, gaps remain for lipids and for amino acids in modified metabolic conditions or non-mammalian biologies. Here, we empirically determine lipid n L values and validate the process with peptides against an n L library. To evaluate this strategy in a biologically relevant setting, we applied it to brain tissue from transgenic mice expressing human ApoE isoforms, where altered lipid transport and metabolism are implicated in Alzheimer's disease risk. These data validate the method in a clinically relevant context and suggest that genotype-dependent metabolism can alter empirically determined lipid n L values.

DOI: https://doi.org/10.64898/2026.06.29.735310
Sci Adv. 2026 Jul 10. 12(28): eaeb2695

The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart.

Kelsey H Fisher-Wellman, Richard D Lutze, Logan G Kirkland, Ju Youn Beak, Mansi Goyal, Raghu Nagalingam, Samantha M Morrissey, Peyton B Sandroni, Wei Huang, Julian D Bailon, Melissa A Schroder, Lars A Albrecht, Ethelyn Ofei, Andrew L Chin, Thomas D Green, Joseph M McClung, McLane M Montgomery, James T Hagen, Brett R Chrest, Edziu M Franczak, Polina Krassovkaia, Raphael T Aruleba, Jon S Zawistowski, Timothy J Stuhlmiller, Shawn M Gomez, Nanthip Prathumsap, Qing Zhang, Jing Zhang, Weiyi Xu, Lilei Zhang, Jeremy A Meier, Lisa A Carey, Jonathan C Schisler, Gary L Johnson, Brian C Jensen.

Trametinib (Trm) is a highly selective mitogen-activated protein kinase kinase (MEK) inhibitor that potently and persistently abrogates extracellular signal-regulated kinase 1/2 activation. Trm initially was used to treat BRAF Val600→Glu (V600E)-mutated melanoma, but its Food and Drug Administration-approved indications are expanding rapidly. Trm generally is well tolerated, but it can cause dose-limiting cardiomyopathy and heart failure. Here, we characterize a mouse model of Trm cardiotoxicity using complementary in vitro approaches to show that Trm induces mitochondrial dysfunction in cardiomyocytes and some cancer cell types. In vivo, Trm caused contractile dysfunction within 3 days and heart failure within 2 weeks. High-resolution respirometry using isolated cardiac mitochondria revealed that Trm compromises oxidative metabolism, in part, through blunted activity of electron transport system complexes. Trm-mediated mitochondrial injury led to the release of mitochondrial damage-associated molecular patterns including mitochondrial DNA in both mice and humans, triggering activation of canonical innate immune pathways including cGAS-STING. In multiple rodent and human cardiomyocyte platforms, Trm diminished mitochondrial respiratory capacity at nanomolar concentrations, but this lesion was reversed by expression of a phosphomimetic signal transducer and activator of transcription 3-S727 construct. We also found that Trm induced mitochondrial dysfunction in some but not all cancer cell lines, identifying a previously unrecognized effect that could contribute to Trm's anticancer efficacy.

DOI: https://doi.org/10.1126/sciadv.aeb2695
Cell Rep. 2026 Jul 08. pii: S2211-1247(26)00708-4. [Epub ahead of print]45(7): 117630

Distinct metabolic dependency on BCAA defines cancer stemness and malignancy in human triple-negative breast cancer.

Kenkyo Matsuura, Ririko Shinonaga, Mizuki Yamamoto, Yoshiki Yamamoto, Hsin Chen, Ayaka Maeno, Kayo Okuda, Haruki Inoue, Sota Imotani, John Glushka, Koji Miki, Yukako Watanabe, Mamoru Takada, Hironori Kaji, Jun-Ichiro Inoue, Ayuna Hattori, Hiromi Imamura, Takahiro Ito.

  Triple-negative breast cancer (TNBC) lacks effective molecularly targeted therapies. Here, we identify branched-chain amino acid (BCAA) metabolism as a selective vulnerability in human TNBC, particularly in the claudin-low subtype. TNBC cells show greater dependence on BCAAs than other breast cancer subtypes, and intracellular BCAA levels are heterogeneous within tumors in vivo. Cells with high BCAA levels exhibit enhanced sphere formation and cancer stem cell potential in xenograft models. BCAT1, a cytoplasmic BCAA aminotransferase, is upregulated in claudin-low TNBC and enables tumor growth by promoting BCAA production from branched-chain ketoacids. BCAT1 knockdown impairs TNBC growth in vivo, and high BCAT1 expression predicts poor prognosis in patient cohorts. Conversely, BCAA catabolism via the BCKDH complex is suppressed in TNBC, and reactivation of BCKDH by BCKDK knockout blocks clonogenic growth. These findings reveal BCAA metabolic balance as a key regulator of TNBC stemness and malignancy.

Keywords:  CP: cancer; TNBC; branched-chain amino acid; claudin-low; metabolic vulnerability; metabolite imaging

DOI:  https://doi.org/10.1016/j.celrep.2026.117630
Am J Physiol Regul Integr Comp Physiol. 2026 Jul 09.

BCAAs, LAT1, and the Metabolic Competition between Tumor and Peripheral Tissues during Cancer Cachexia.

Jessica L Halle, Benjamin F Miller.



Keywords:  BCAA; Cancer Cachexia; Colorectal Cancer; LAT1; Metabolism

DOI:  https://doi.org/10.1152/ajpregu.00219.2026
Biotechnol Prog. 2026 Jul 08. e88536

Targeting Warburg effect in Chinese hamster ovary cell culture with pyruvate dehydrogenase kinase inhibitors.

Geetanjali Basavaraj Hubli, Richa Katiyar, Vrinda Kapoor, Girish H Rajacharya, Anurag S Rathore.

  Production of monoclonal antibodies (mAbs) in Chinese hamster ovary (CHO) cells is affected by the "Warburg effect" which is characterized by high lactate accumulation. Therefore, the present study explores the use of pyruvate dehydrogenase kinase (PDK) inhibitors dichloroacetate (DCA), metformin (M), (S)-3,3,3-trifluoro-2-hydroxy-2-methyl propionic acid (TPP), and 4-phenylbutyrate (PB) to counteract this metabolic bottleneck. To achieve optimal mAb yields, individual inhibitors (0.5-10 mM) were screened, followed by evaluation of their combinatorial effects. A combination of 5 mM DCA and 1 mM TPP (DCA + TPP) revealed ~2-fold enhancement in mAb yield (1.2 g/L) under fed-batch conditions, accompanied by a marked reduction in lactate accumulation as compared to control. The optimized DCA + TPP combination also exhibited 15%-20% enhancement in the mAb yield as compared to a single PDK inhibitor that is, DCA (5 mM) and TPP (1.0 mM) at the same concentration. Metabolic analysis revealed a 19.5-fold increase in pyruvate flux and a 2-fold increase in intracellular acetyl-CoA. The critical product quality attributes exhibited insignificant impact on charge variant (<3%), aggregation, and glycosylation of mAb. The amino acid consumption profiles predominantly showed depletion of glycine and tryptophan, whereas threonine and aspartic acid were primarily consumed in the control. Proteomic analysis exhibited upregulation and downregulation of various proteins, which significantly contribute to mAb's yield. Validation in Trastuzumab-producing CHO-S cells confirmed a 30% increase in mAb yield and a 10% improvement in cell density. These outcomes demonstrate that the combination of DCA + TPP is a promising metabolic intervention to mitigate the Warburg effect and enhance recombinant protein production in mammalian systems.

Keywords:  CHO cell culture; Warburg effect; lactate inhibition; monoclonal antibody (mAbs); proteomics analysis; pyruvate dehydrogenase kinase (PDK) inhibitors

DOI:  https://doi.org/10.1002/btpr.88536
Commun Biol. 2026 Jul 09. pii: 928. [Epub ahead of print]9(1):

A bioenergetic understanding of "aerobic glycolysis".

Valerie L Wasem, Shona A Mookerjee.

"Aerobic glycolysis" is a widely used term whose current meaning has drifted from its original usage in a way that has created confusion and inaccuracy. This drift has weakened "aerobic glycolysis" as a hypothesis-testing framework, despite the critical importance of glycolysis in understanding cellular bioenergetic behavior. Here, we examine the historical and contemporary uses of "aerobic glycolysis" and the related "Warburg effect". We argue that "aerobic glycolysis" as originally investigated was essentially a bioenergetic phenomenon. We review the bioenergetic model of glycolysis and mitochondrial respiration as ATP supply pathways operating together to meet cellular ATP demand. A bioenergetic view of aerobic glycolysis clarifies that it is not a less desirable contingency or indicator of pathology, but rather a part of a kinetically regulated system of cellular energy supply. On this basis, the operation of glycolysis under many different physiological and pathological conditions can be better interrogated and understood.

DOI: https://doi.org/10.1038/s42003-026-10601-5