bims-medica 2025-11-16 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–11–16
thirty-two papers selected by
Brett Chrest, Wake Forest University

Hyperpolarized Carbon-13 Metabolic Imaging Differentiates Distinctive Molecular Phenotypes in Diffuse Midline Gliomas.
ATP Metabolism of Astrocytes: Consumption, Regeneration and Restoration.
Time-restricted feeding induces white adipose browning and improves metabolic health independent of weight loss: an integrative multi-omics study.
NHANES data are irrelevant for ketogenic diet research - Comment on "Ketogenic diets are associated with an elevated risk of hypertension: Insights from a cross-sectional analysis of the NHANES 2007-2018″.
Single-cell imaging of liver metabolic dynamics using fluorescent biosensors.
iGlucoSnFR2: A genetically encoded fluorescent sensor for measuring intracellular or extracellular glucose in vivo in mouse brain.
Increasing Infusion Times of Hyperpolarized [1-13C]Pyruvate in a Mouse Brain Maintain Lactate Generation and Approach Pseudo-Steady State Metabolism.
Beyond the Warburg Effect: Modeling the Dynamic and Context-Dependent Nature of Tumor Metabolism.
The SLC1A1/EAAT3 dicarboxylic amino acid transporter is an epigenetically dysregulated nutrient carrier that sustains oncogenic metabolic programs.
Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation.
Tumour growth and chemotherapy alter skeletal muscle, cardiac, and hepatic amino acid pools in mice.
Olutasidenib for mutated IDH1 acute myeloid leukemia: final five-year results from the phase 2 pivotal cohort.
Tumour sampling conditions perturb the metabolic landscape of clear cell renal cell carcinoma.
qMaLioffG: a genetically encoded green fluorescence lifetime-based indicator enabling quantitative imaging of intracellular ATP.
Impaired mitochondrial ketone body oxidation in insulin resistant states.
Therapeutic remodeling of the ceramide backbone prevents kidney injury.
GLS1 inhibitor CB-839 inhibits the malignant progression of 5-FU resistant hepatoma cells by regulating glutamine metabolism.
Venetoclax combined with cladribine, idarubicin, cytarabine (CLIA-VEN) results in higher remission rates over conventional 7 + 3 chemotherapy without increased toxicity in newly diagnosed acute myeloid leukaemia.
13C metabolic tracing in human SGBS cells provides a potential new approach methodology for assessing metabolism-disrupting properties of environmental chemicals.
Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis.
Primary-Stage Colon Cancer Impairs Muscle Energy Metabolism by Suppressing Mitochondrial Complex I Activity.
Navigating an Imposed Diet: What Dietetic Students Learned From a Food Intervention Experience.
Ketone ester supplementation protects from experimental colitis via improved goblet cell differentiation and function.
The effect of triclosan uncovers the possible involvement of complex II in the oxidation of glycerol-3-phosphate in brain mitochondria.
Metabolite maps reveal spatial gradients in liver and intestinal tissue.
Nutritional strategies against skeletal muscle wasting in cancer-associated cachexia: the role of β-hydroxybutyrate and polyunsaturated fatty acids.
What is the Prognostic Relevance of Responses Less Than a CR to Initial AML Treatment?
Evaluation of an enzymatic one-step assay for Beta-Hydroxybutyrate blood testing on clinical chemistry platforms using HILIC-MS/MS as a non-enzymatic reference method.
Universal consensus 3D segmentation of cells from 2D segmented stacks.
The genotypic and phenotypic landscape of PDHA1-related pyruvate dehydrogenase complex deficiency.
Robust calibration and quantification of FRET signals using multiplexed biosensor barcoding.
Validation of a Multiplex mRNA- and gDNA-Based Droplet Digital PCR Assay in Acute Myeloid Leukemia Patients with an NPM1 Mutation.

Molecules. 2025 Oct 24. pii: 4175. [Epub ahead of print]30(21):

Hyperpolarized Carbon-13 Metabolic Imaging Differentiates Distinctive Molecular Phenotypes in Diffuse Midline Gliomas.

Ilwoo Park, Rintaro Hashizume, Joanna Phillips.

  Despite a specific histone mutation defining the unique genetic makeup, diffuse midline gliomas are heterogeneous tumors with a wide range of morphologic and molecular spectrum. We investigated the feasibility of using hyperpolarized carbon-13(13C) MR metabolic imaging to differentiate distinctive molecular features from two H3K27M-mutant, biopsy-originated diffuse midline glioma xenografts. 13C MR metabolic imaging data were acquired on a 3T scanner from 12 rats that had been implanted with SF8628 or SF7761 diffuse midline glioma cells in brainstem, following injection of hyperpolarized [1-13C]pyruvate. Despite the two tumors' similar appearance of T2-hyperintensity throughout the cerebellum and pons without contrast enhancement, 13C metabolic imaging data revealed that SF8627 had significantly higher ratios of lactate to pyruvate, lactate to total carbon, and normalized lactate than SF7761. Elevated lactate levels in SF8628 were associated with large amounts of lactate dehydrogenase (LDH)-A and carbonic anhydrase-IX staining in SF8628 compared to SF7761, which implied that the highly hypoxic condition in SF8628 appeared to contribute to the high level of LDH-A enzyme activity, which, in turn, induced the large conversion from hyperpolarized pyruvate to lactate. Our findings suggest that this advanced metabolic imaging technique may be used for the noninvasive characterization of molecular hypoxia and lactate dehydrogenase-A activity in these pediatric brainstem gliomas.

Keywords:  diffuse midline glioma; hyperpolarized carbon-13; magnetic resonance imaging; metabolic imaging; pediatric brain tumor

DOI:  https://doi.org/10.3390/molecules30214175
Neurochem Res. 2025 Nov 12. 50(6): 357

ATP Metabolism of Astrocytes: Consumption, Regeneration and Restoration.

Ralf Dringen, Gabriele Karger, Ulrike Winkler, Johannes Hirrlinger.

  Astrocytes are essential partners of neurons and have many important functions in the brain. Almost all of these astrocytic functions require energy that is provided by cellular adenosine triphosphate (ATP). Accordingly, astrocytes contain a millimolar concentration of cellular ATP that is maintained by continuous and rapid regeneration from adenosine diphosphate (ADP) and adenosine monophosphate (AMP), the main products of cellular energy-consuming reactions. In this article we describe the current knowledge on the cellular content, the consumption and the metabolic regeneration of ATP in astrocytes, explore the consequences of an application of metabolic inhibitors on astrocytic ATP metabolism and summarize the importance of endogenous energy stores and exogenous energy substrates for the maintenance of a high cellular ATP content. In addition, we give insight in recent studies on the visualization of ATP in astrocytes by genetically encoded ATP sensors, summarize the importance of astrocytic ATP release and extracellular ATP processing and discuss recent data on the restoration of ATP in ATP-deprived astrocytes. The current knowledge on the ATP metabolism of astrocytes clearly demonstrates the high potential of this important brain cell type to flexibly use different metabolic pathways and a broad range of endogenous and exogenous sources to maintain, regenerate and restore cellular ATP levels. These processes secure that ATP is continuously available for the many ATP consuming processes that enable astrocytes to perform their functions in the healthy brain.

Keywords:  ATP; Astrocytes; Energy metabolism; Glycolysis; Oxidative phosphorylation

DOI:  https://doi.org/10.1007/s11064-025-04604-7
Life Sci. 2025 Nov 07. pii: S0024-3205(25)00713-1. [Epub ahead of print]383 124077

Time-restricted feeding induces white adipose browning and improves metabolic health independent of weight loss: an integrative multi-omics study.

Yixuan Zheng, Jingya Wang, Meng Zhang, Ziyi Chen, Yue Wang, Jing Sui, Wei Qiang, Hui Guo, Leigang Jin, Guixue Hou, Bingyin Shi, Mingqian He.

   AIMS: Time-restricted feeding (TRF) exerts beneficial effects against metabolic disorders via adipocyte thermogenesis; however, the precise tissue-specific mechanisms and key molecular mediators remain incompletely characterized.
MATERIALS AND METHODS: C57BL/6J male mice were subjected to a 9-week high-fat, high-fructose diet (HFHFD) before being randomized into one of three groups for an additional 9 weeks: continued HFHFD group, high-fat diet (HFD) group, or TRF group fed with HFD. Body weight, adipose tissue mass, and serum lipids and glucose levels were measured. Proteomic analysis of inguinal white adipose tissue (iWAT) was conducted in the HFD and TRF groups, and plasma metabolome and lipidome profiles were analyzed across all three groups.
KEY FINDINGS: Compared to HFD, TRF significantly reduced serum low-density lipoprotein cholesterol, total cholesterol, fasting blood glucose, and resistin levels, without accompanying weight loss. TRF reduced iWAT mass and upregulated mRNA expression of thermogenic genes (PGC-1a and UCP-1). Proteomic analysis revealed that TRF upregulated mitochondrial electron transport chain (ETC) complex I proteins and activated iWAT oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle. TRF notably altered the plasma lipidome and metabolite profiles, with polyunsaturated phosphatidylcholines (PUFA-PCs) accounting for approximately half of the differential lipids and D-2-hydroxyglutaric acid (D2HG) being significantly decreased.
SIGNIFICANCE: In summary, multi-omics profiling reveals that TRF improves metabolic health in HFHFD-fed mice independent of weight loss by enhancing iWAT thermogenesis through mitochondrial OXPHOS, with specific upregulation of ETC complex I proteins. Additionally, TRF remodels plasma lipidome and metabolite signatures, including reduced D2HG and PUFA-PCs, which may serve as novel biomarkers of TRF efficacy.

Keywords:  Lipidome; Metabolome; Proteome; Time-restricted feeding; White adipose browning

DOI:  https://doi.org/10.1016/j.lfs.2025.124077
Int J Cardiol Cardiovasc Risk Prev. 2025 Dec;27 200534

NHANES data are irrelevant for ketogenic diet research - Comment on "Ketogenic diets are associated with an elevated risk of hypertension: Insights from a cross-sectional analysis of the NHANES 2007-2018″.

Rainer J Klement.

  In a recent study titled "Ketogenic diets are associated with an elevated risk of hypertension: Insights from a cross-sectional analysis of the NHANES 2007-2018", Qu et al. have used data from the NHANES, a large survey of American citizens, to correlate the participants' dietary ketogenic ratio (DKR) to hypertension. They find a significant positive correlation and conclude, as the title of their article suggests, that ketogenic diets (KDs) are associated to hypertension risk. However, their basic assumption that the participants' DKR has anything to do with a KD constitutes a serious mistake, as I argue in this Commentary. The reason is that even the highest quartile of DKR corresponds to a non-ketogenic diet. In conclusion, the data utilized by Qu et al. are irrelevant to their research question and cannot be used to support the hypothesis that KDs increase the risk of hypertension.

Keywords:  Ketogenic diet; Ketone bodies; Nutritional epidemiology

DOI:  https://doi.org/10.1016/j.ijcrp.2025.200534
Trends Endocrinol Metab. 2025 Nov 10. pii: S1043-2760(25)00224-3. [Epub ahead of print]

Single-cell imaging of liver metabolic dynamics using fluorescent biosensors.

Israel Pérez-Chávez, Eduardo H Gilglioni, Daria Ezeriņa, Joris Messens, Esteban N Gurzov.

  Traditional metabolic studies rely on bulk tissue analyses, masking the cellular heterogeneity that underlies disease progression. Genetically encoded fluorescent biosensors now enable real-time, single-cell imaging of dynamic metabolic processes in the liver. These tools provide insights into the metabolic reprogramming in conditions such as chronic obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). By tracking specific metabolites involved in glycolysis, lipid oxidation, and the tricarboxylic acid (TCA) cycle, biosensors can reveal how these pathways respond to diverse stimuli. In this review we outline the core principles of fluorescent biosensors, provide specific recommendations for their usage, suggest possible applications in liver metabolism research, and discuss current technical challenges as well as emerging opportunities in this rapidly advancing field.

Keywords:  HCC; MASLD; fluorescent genetically encoded biosensors; liver metabolism; microscopy; single-cell resolution

DOI:  https://doi.org/10.1016/j.tem.2025.10.003
Sci Adv. 2025 Nov 14. 11(46): eadz3889

iGlucoSnFR2: A genetically encoded fluorescent sensor for measuring intracellular or extracellular glucose in vivo in mouse brain.

Jonathan S Marvin, Philipp Mächler, Chengbo Meng, Tayfun Ates, Ronak H Patel, Raghabendra Adhikari, Monika A Makurath, Zaneta Ku, Daniel Feliciano, Deniz Atasoy, Guohong Cui, David Kleinfeld, Timothy A Brown.

Continuous glucose monitors have proven invaluable for monitoring blood glucose levels for diabetics, but they are of limited use for observing glucose dynamics at the cellular (or subcellular) level. We have developed a second generation, genetically encoded intensity-based glucose sensing fluorescent reporter (iGlucoSnFR2). We show that when it is targeted to the cytosol, it reports intracellular glucose consumption and gluconeogenesis in cell culture, along with efflux from the endoplasmic reticulum. It outperforms the original iGlucoSnFR in vivo when observed by fiber photometry in mouse brain and reports transient increase in glucose concentration when stimulated by noradrenaline or electrical stimulation. Last, we demonstrate that membrane localized iGlucoSnFR2 can be calibrated in vivo to indicate absolute changes in extracellular glucose concentration in awake mice. We anticipate iGlucoSnFR2 facilitating previously unobservable measurements of glucose dynamics with high spatial and temporal resolution in living mammals and other experimental organisms.

DOI: https://doi.org/10.1126/sciadv.adz3889
Magn Reson Med. 2025 Nov 11.

Increasing Infusion Times of Hyperpolarized [1-13C]Pyruvate in a Mouse Brain Maintain Lactate Generation and Approach Pseudo-Steady State Metabolism.

Paola Porcari, Vesselin Miloushev, Saket Patel, Thasin Peyear, Marjan Berishaj, Kayvan R Keshari.

   PURPOSE: To investigate whether varying delivery times of hyperpolarized [1-13C]pyruvate, enabled by the increased apparent T1 dissolved in deuterium oxide (D2O), affects the observed kinetics of glycolytic brain metabolism in vivo.
METHODS: Eighteen healthy mice were injected with 300 μL of hyperpolarized [1-13C]pyruvate dissolved in D2O at increasing injection times (15 s, 60s, 90s, 120 s). After collecting T2-weighted scans, slab dynamic 13C MRS data were acquired. Time-course curves of [1-13C]pyruvate, [1-13C]lactate and [1-13C]lactate/total carbon ratio were calculated. Mean full-width-half-maximum (FWHM) and area-under-curve (AUC) values were compared across injection times. A simplified one-compartment model of pyruvate metabolism was fit using the conversion rate constant (kPL) and effective lactate decay rate (R1eff). Dynamic EPSI images, acquired using an injection time of 15 s and 60 s for comparison.
RESULTS: The mean FWHM values of the time-course curves of [1-13C]pyruvate and [1-13C]lactate showed a significant increase (p < 0.01) with increasing injection times, while no statistical significance was found across the AUC values. The time-course curves of lactate/total carbon ratio showed elongated plateaus with increased injection times. Kinetic modeling showed good agreement between fitted and acquired lactate data, with AUC of normalized lactate profile remaining constant across infusion times. Dynamic EPSI images acquired with a longer infusion time (60 s) showed the ability to monitor brain metabolism as it approached pseudo-steady state.
CONCLUSIONS: Increased delivery times of hyperpolarized [1-13C]pyruvate dissolved in D2O approaches pseudo-steady state metabolism in vivo and allowing for the potential to cater new acquisition and reconstruction approaches for enhanced imaging.

Keywords:  deuterium oxide; hyperpolarized 13C‐pyruvate; injection time; murine brain

DOI:  https://doi.org/10.1002/mrm.70175
Cancers (Basel). 2025 Nov 03. pii: 3563. [Epub ahead of print]17(21):

Beyond the Warburg Effect: Modeling the Dynamic and Context-Dependent Nature of Tumor Metabolism.

Pierre Jacquet, Angélique Stéphanou.

  Background: The Warburg effect, historically regarded as a hallmark of cancer metabolism, is often interpreted as a universal metabolic feature of tumor cells. However, accumulating experimental evidence challenges this paradigm, revealing a more nuanced and context-dependent metabolic landscape. Methods: In this study, we present a hybrid multiscale model of tumor metabolism that integrates cellular and environmental dynamics to explore the emergence of metabolic phenotypes under varying conditions of stress. Our model combines a reduced yet mechanistically informed description of intracellular metabolism with an agent-based framework that captures spatial and temporal heterogeneity across tumor tissue. Each cell is represented as an autonomous agent whose behavior is shaped by local concentrations of key diffusive species-oxygen, glucose, lactate, and protons-and governed by internal metabolic states, gene expression levels, and environmental feedback. Building on our previous work, we extend existing metabolic models to include the reversible transport of lactate and the regulatory role of acidity in glycolytic flux. Results: Simulations under different environmental perturbations-such as oxygen oscillations, acidic shocks, and glucose deprivation-demonstrate that the Warburg effect is neither universal nor static. Instead, metabolic phenotypes emerge dynamically from the interplay between a cell's history and its local microenvironment, without requiring genetic alterations. Conclusions: Our findings suggest that tumor metabolic behavior is better understood as a continuum of adaptive states shaped by thermodynamic and enzymatic constraints. This systems-level perspective offers new insights into metabolic plasticity and may inform therapeutic strategies targeting the tumor microenvironment rather than intrinsic cellular properties alone.

Keywords:  environmental stress; metabolic plasticity; systems biology; tumor metabolism

DOI:  https://doi.org/10.3390/cancers17213563
Nat Commun. 2025 Nov 14. 16(1): 10012

The SLC1A1/EAAT3 dicarboxylic amino acid transporter is an epigenetically dysregulated nutrient carrier that sustains oncogenic metabolic programs.

Treg Grubb, Pooneh Koochaki, Sayed Matar, Fatme Ghandour, Marc Machaalani, Eddy Saad, Cerise Tang, Eduard Reznik, Jesminara Khatun, Carleigh Salem, Noah Dubasik, David A Orlando, Matthew G Guenther, Gyanu Parajuli, Raghvendra M Srivastava, Steven R Martinez, Jesse A Coker, Ritesh R Kotecha, A Ari Hakimi, John M Asara, Timothy A Chan, Sakari Vanharanta, Shaun R Stauffer, William G Kaelin, Sabina Signoretti, Toni K Choueiri, Abhishek A Chakraborty.

Epigenetic dysregulation, including accumulation of Histone H3 lysine 27 acetylation (H3K27ac), is a hallmark of pVHL-deficient clear cell Renal Cell Carcinomas (ccRCCs). Using an in vivo positive selection ORF screen in poorly tumorigenic pVHL-proficient cells and mechanistic studies in pVHL-deficient cells, we discovered that the aspartate (Asp) and glutamate (Glu) transporter, SLC1A1/EAAT3, is a metabolic dependency in ccRCC. pVHL loss promotes Hypoxia Inducible Factor (HIF)-independent SLC1A1 expression via H3K27ac dysregulation. SLC1A1 inactivation, genetically or pharmacologically, depletes Asp/Glu-derived metabolites (e.g., Tricarboxylic acid cycle and nucleotide intermediates), impedes ccRCC growth, and sensitizes ccRCCs to anti-metabolite drugs (e.g., glutaminase blockers). In human tumors, higher SLC1A1 expression is associated with reduced immune infiltration, oncogenic metabolic programs, and advanced stage/metastatic disease. Finally, in ccRCC animal models, SLC1A1 inactivation diminishes lung metastasis and the outgrowth of established renal tumors. Altogether, our studies credential SLC1A1 as an actionable, HIF-independent, metabolic dependency in pVHL-deficient ccRCCs.

DOI: https://doi.org/10.1038/s41467-025-64983-x
Blood. 2025 Nov 14. pii: blood.2025028933. [Epub ahead of print]

Glutaredoxin 2 is essential for AML survival through mitochondrial permeability transition pore regulation.

Tianyi Ling, Cristiana O'Brien, Jonathan St-Germain, Vincent Rondeau, Mary Shi, Jacob M Berman, Adrianna Kinga Cepa, Paula Saez Raez, Mark Wunderlich, Katharine Carter, Cody Stillwell, Christina R Sexton, Rachel Culp-Hill, Julie A Reisz, Saeer A Adeel, Andy G X Zeng, Suraj Bansal, Emily Tsao, He Tian Tony Chen, John E Dick, Mark D Minden, Andrea Arruda, Maria L Amaya, Anastasia N Tikhonova, Kristin Hope, Angelo D'Alessandro, Brian Raught, Courtney L Jones.

Acute myeloid leukemia (AML) patients have a poor five-year survival rate highlighting the need for the identification of new approaches to target this disease. AML is highly dependent on glutathione (GSH) metabolism for survival. While the metabolic role of GSH is well-characterized in AML, the contribution of protein glutathionylation-a reversible modification that protects protein thiols from oxidative damage-remains largely unexplored. Therefore, we sought to elucidate the role of protein glutathionylation in AML pathogenesis. Here, we demonstrate that protein glutathionylation is essential for AML cell survival. Specifically, the loss of glutaredoxin 2 (GLRX2), an enzyme that removes glutathione modifications, resulted in selective primary AML cell death while sparing normal human hematopoietic stem and progenitor cells. Unbiased proteomic analysis revealed increased mitochondrial protein glutathionylation upon GLRX2 depletion, accompanied by mitochondrial dysfunction, including impaired oxidative phosphorylation, reduced mitochondrial membrane potential, and increased opening of the mitochondrial permeability transition pore (mPTP). Further investigation identified ATP5PO, a key regulator of mPTP opening and a component of the ATP synthase complex, as a critical GLRX2 target. Disruption of ATP5PO glutathionylation partially restored mPTP function and rescued AML cell viability following GLRX2 depletion. Moreover, both genetic and pharmacologic inhibition of mPTP opening restored the leukemic potential of primary AML specimens in the absence of GLRX2. By disrupting glutathionylation-dependent mitochondrial homeostasis, this study reveals a novel vulnerability in AML that could inform future therapeutic strategies.

DOI: https://doi.org/10.1182/blood.2025028933
Am J Physiol Cell Physiol. 2025 Nov 10.

Tumour growth and chemotherapy alter skeletal muscle, cardiac, and hepatic amino acid pools in mice.

Meghan V McCue, Irena A Rebalka, Miguel L Paquette, Thomas J Hawke, David A MacLean.

  Background: Amino acids (AAs) play structural and metabolic roles in muscle, heart, and liver-tissues impacted by cancer and chemotherapy. Changes in AA profiles within these tissues have not been evaluated in response to tumor growth and chemotherapy. This study investigated how tumor growth with or without Doxorubicin altered tissue-level amino acids. Methods: Female C57bl/6 mice (n = 7-10/group) were randomly assigned to groups: Control, Doxorubicin control at 3 and 7 days, 21-day tumor, 24-day tumor, 28-day tumor, 24-day tumour+Doxorubicin, 28-day tumour+Doxorubicin. Tumor groups were injected with E0771 cells in the right flank on day 0. Doxorubicin was administered once (I.P.) at 10 mg/kg in Doxorubicin control and tumour+Doxorubicin groups on day 21, with endpoints at day 24 and 28. Results: Muscle glutamate and aspartate were significantly depleted by day 28 in both tumor and tumor + Doxorubicin groups (p<0.05), while proline, arginine, leucine, and isoleucine increased (p<0.05). Hepatic aspartate elevated by 21 days, and lysine by 24 days (p<0.05). Cardiac glutamate was depleted at days 21, 24, and 28 (p<0.05). Notably, Doxorubicin did not add to tumor-induced changes in muscle or heart. Tumor AAs remained largely stable. Conclusion: Tumor growth induced profound changes to skeletal muscle AA pools, reflecting impaired handling of As that could serve structural roles, or expand the substrate pool for ATP synthesis. Despite this, most tumor AAs remained stable over tumor growth. These results suggest a link between muscle wasting and skeletal muscle-derived AAs for tumor growth. Further work is needed to characterize the mechanisms mediating the observed changes in AA profiles.

Keywords:  Amino acids; Cachexia; Liver; Muscle; Tumour

DOI:  https://doi.org/10.1152/ajpcell.01003.2024
J Hematol Oncol. 2025 Nov 14. 18(1): 102

Olutasidenib for mutated IDH1 acute myeloid leukemia: final five-year results from the phase 2 pivotal cohort.

Jorge Cortes, Antonio Curti, Pierre Fenaux, Brian A Jonas, Jürgen Krauter, Pau Montesinos, Christian Récher, David C Taussig, Eunice S Wang, Justin Watts, Andrew Wei, Karen Wl Yee, Hua Tian, Aaron Sheppard, Christophe Marzac, Stephane de Botton.

   BACKGROUND: Olutasidenib is an oral, selective inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) based on a registrational, phase 2, open-label, multicenter trial.
METHODS: Results from the pre-planned interim analysis were previously published (data cut-off [DCO]: June 2021). In this final-follow up analysis, we report an additional 2 years of efficacy and safety data (DCO: June 2023).
RESULTS: At study completion, the overall population included 153 patients (median age, 71 years); 66% had received ≥ 2 prior treatment regimens, and 39% with a hypomethylating agent. Among the 147 efficacy-evaluable patients, 51 achieved complete remission (CR) or CR with partial hematologic recovery (CRh), resulting in a CR/CRh rate of 35% (P < 0.001; 95% CI, 27-43), with 32% of responders achieving CR. The median time to CR/CRh was 1.9 months (range, 0.9-5.6 months). Among responders, 33% achieved CR/CRh within 2-4 months and 12% required ≥ 4 months. The overall response rate (ORR) was 48% (n = 71; 95% CI, 40-56.7). Median duration of CR/CRh was 25.3 months (95% CI, 13.5-not reached), and median overall survival (OS) was 11.5 months (95% CI, 8.3-15.5). Patients with 1-2 prior regimens had a higher CR/CRh rate (41%) and longer median OS (13 months) than those with ≥ 3 prior regimens (CR/CRh: 24%; median OS: 8.9 months). CR/CRh rates were higher among patients with R132C (42%) and R132L/G/S mutations (33%) compared with those harboring R132H mutations (17%). Response rates decreased with increasing numbers of co-mutations. Few new adverse events (AEs) and no treatment discontinuations due to AEs occurred beyond Year 3.
CONCLUSION: These 5-year data support the durable efficacy and manageable safety profile of olutasidenib in R/R mIDH1 AML, including heavily pretreated patients. Findings highlight the potential role of olutasidenib in earlier lines of treatment, and support sustaining therapy for at least 6 months to allow for a clinical response. Further research is warranted to optimize treatment sequencing and patient selection.
TRIAL REGISTRATION: NCT02719574.

Keywords:  Mutant IDH1 inhibitor; Olutasidenib; Relapsed/refractory AML; Targeted therapy

DOI:  https://doi.org/10.1186/s13045-025-01751-w
Nat Commun. 2025 Nov 10. 16(1): 9896

Tumour sampling conditions perturb the metabolic landscape of clear cell renal cell carcinoma.

Cissy Yong, Christina Schmidt, Ming Yang, Alexander Von Kriegsheim, Anne Y Warren, Shubha Anand, James N Armitage, Antony C P Riddick, Thomas J Mitchell, Vishal Patil, Kourosh Saeb-Parsy, Sakari Vanharanta, Grant D Stewart, Christian Frezza.

Human isotopic tracer studies are key for in vivo studies of cancer metabolism. Yet, the effects of sampling conditions on the tissue metabolome remain understudied. Here, we perform a 13C-glucose study coupled with metabolomic, transcriptomic, and proteomic profiling in patients with clear cell renal cell carcinoma (ccRCC) to assess the impact of ischaemia on tissues sampled intraoperatively and post-surgical resection, where tissues are exposed to varying degrees of warm ischaemia. Although several metabolic features were preserved, including suppressed TCA cycle activity, ischaemia masked other metabolic phenotypes of ccRCC, such as suppressed gluconeogenesis. Notably, normal kidneys were more metabolically susceptible to ischaemia than the ccRCC tumours. Despite their overall stability, ischaemia caused subtle changes in the proteome and transcriptome. Using orthotopic ccRCC-derived xenografts, we evidenced that prolonged ischaemia disrupted the tissue metabolome stability. Overall, minimising tissue ischaemia is pivotal in accurately profiling cancer metabolism in patient studies.

DOI: https://doi.org/10.1038/s41467-025-65676-1
Nat Commun. 2025 Nov 13. 16(1): 9972

qMaLioffG: a genetically encoded green fluorescence lifetime-based indicator enabling quantitative imaging of intracellular ATP.

Satoshi Arai, Hideki Itoh, Cong Quang Vu, Loan Thi Ngoc Nguyen, Mizuho Nakayama, Masanobu Oshima, Atsuya Morita, Kazuko Okamoto, Satoru Okuda, Aki Teranishi, Madori Osawa, Yoshiteru Tamura, Shigeaki Nonoyama, Megumi Takuma, Toshinori Fujie, Satya Ranjan Sarker, Thankiah Sudhaharan, Akihiro Furube, Tetsuro Katayama, Taketoshi Kiya, E Birgitte Lane, Tetsuya Kitaguchi.

Genetically encoded indicators that can detect concentrations of metabolites and signalling molecules through fluorescence lifetime changes are gaining attention, because they expand the potential for quantitative imaging. These indicators offer advantages over conventional fluorescence intensity-based indicators by minimizing artifacts such as variations in indicator concentration, cellular morphological changes, and focus drift. However, the availability of fluorescence lifetime-based genetically encoded indicators remains limited, particularly those compatible with the widely used conventional 488 nm laser in microscopy. Here, we introduce qMaLioffG, a single green fluorescent protein-based ATP indicator that exhibits a substantial fluorescence lifetime shift (1.1 ns) within physiologically relevant ATP concentrations. This enables quantitative imaging of ATP levels in the cytoplasm and mitochondria under steady-state conditions across various cell types, providing insights into ATP distribution. We demonstrate that qMaLioffG can be used in multicellular systems, applying it to Drosophila brain and HeLa cell spheroids to reveal spatially heterogeneous ATP levels.

DOI: https://doi.org/10.1038/s41467-025-64946-2
EBioMedicine. 2025 Nov 11. pii: S2352-3964(25)00451-7. [Epub ahead of print]122 106007

Impaired mitochondrial ketone body oxidation in insulin resistant states.

Elric Zweck, Sarah Piel, Johannes W Schmidt, Daniel Scheiber, Martin Schön, Sabine Kahl, Volker Burkart, Bedair Dewidar, Ricarda Remus, Alexandra Chadt, Hadi Al-Hasani, Lucia Mastrototaro, Hug Aubin, Udo Boeken, Artur Lichtenberg, Jörg Distler, Amin Polzin, Malte Kelm, Ralf Westenfeld, Robert Wagner, Patrick Schrauwen, Julia Szendroedi, Michael Roden, Cesare Granata.

   BACKGROUND: Reduced mitochondrial respiratory function has been implicated in metabolic disorders like type 2 diabetes (T2D), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD), which are tightly linked to insulin resistance and impaired metabolic flexibility. However, the contribution of the ketone bodies (KBs) β-hydroxybutyrate (HBA) and acetoacetate (ACA) as substrates for mitochondrial oxidative phosphorylation (OXPHOS) in these insulin resistant states remains unclear.
METHODS: Targeted high-resolution respirometry protocols were applied to detect the differential contribution of HBA and ACA to OXPHOS capacity in heart, skeletal muscle, kidney, and liver of distinct human or murine cohorts with T2D, obesity, and MASLD.
FINDINGS: In humans with T2D, KB-driven mitochondrial OXPHOS capacity was ∼30% lower in the heart (p < 0.05) and skeletal muscle (p < 0.05) compared to non-diabetic controls. The relative contribution of KBs to maximal OXPHOS capacity in T2D was also lower in both the heart (∼25%, p < 0.05) and skeletal muscle (∼50%, p < 0.05). Similarly, in kidney cortex from high-fat diet-induced obese mice, both the absolute and relative contribution of KBs to OXPHOS capacity was ∼15% lower (p < 0.05). Finally, hepatic HBA-driven mitochondrial OXPHOS capacity was 29% lower (p < 0.05) in obese humans with hepatic steatosis compared to humans without.
INTERPRETATION: Mitochondrial KB-driven OXPHOS capacity is impaired in insulin resistant states in various organs in absolute and relative terms, likely reflecting impaired mitochondrial metabolic flexibility. Our data suggest that KB respirometry can provide a sensitive readout of impaired mitochondrial function in diabetes, obesity, and MASLD.
FUNDING: German Research Foundation, German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Center for Diabetes Research, German Heart Foundation, German Diabetes Society, Christiane-and-Claudia Hempel Foundation, European Community and Schmutzler Stiftung.

Keywords:  Diabetes mellitus; Ketone bodies; MASLD; Mitochondrial respiration; Obesity

DOI:  https://doi.org/10.1016/j.ebiom.2025.106007
Cell Metab. 2025 Nov 12. pii: S1550-4131(25)00440-1. [Epub ahead of print]

Therapeutic remodeling of the ceramide backbone prevents kidney injury.

Rebekah J Nicholson, Luis Cedeño-Rosario, J Alan Maschek, Trevor Lonergan, Jonathan G Van Vranken, Angela R S Kruse, Chris J Stubben, Liping Wang, Deborah Stuart, Queren A Alcantara, Monica P Revelo, Kate Rutter, Mayette Pahulu, Jacob Taloa, Xuanchen Wu, Juwan Kim, Juna Kim, Isaac Hall, Amanda J Clark, Samir Parikh, Jeffrey Spraggins, Donna Romero, Jeremy T Blitzer, Steven P Gygi, Jared Rutter, William L Holland, Nirupama Ramkumar, Scott A Summers.

  Perturbation of proximal tubule (PT) lipid metabolism fuels the pathological features of acute kidney injury (AKI). We found that AKI induced biosynthesis of lipotoxic ceramides within PTs in humans and mice and that urine ceramides predicted disease severity in children and adults. Mechanistic studies in primary PTs, which included a thermal proteomic profiling screen for ceramide effectors, revealed that ceramides altered assembly of the mitochondrial contact site and cristae-organizing system (MICOS) and respiratory supercomplexes, leading to acute disruption of cristae architecture, mitochondrial morphology, and respiration. These ceramide actions were dependent on the presence of the 4,5-trans double bond inserted by dihydroceramide desaturase 1 (DES1). Genetically ablating DES1 preserved mitochondrial integrity and prevented kidney injury in mice following bilateral ischemia reperfusion. Moreover, novel DES1 inhibitors that are attractive clinical drug candidates phenocopied the DES1 knockouts. These studies describe a new, therapeutically tractable mechanism underlying PT mitochondrial damage in AKI.

Keywords:  ETC; MICOS; acute kidney injury; ceramides; cristae; lipid metabolism; lipidomics; metabolism; mitochondria; proximal tubule; sphingolipids

DOI:  https://doi.org/10.1016/j.cmet.2025.10.006
Chem Biol Interact. 2025 Nov 08. pii: S0009-2797(25)00442-9. [Epub ahead of print] 111812

GLS1 inhibitor CB-839 inhibits the malignant progression of 5-FU resistant hepatoma cells by regulating glutamine metabolism.

Hao Wang, Xiao-Yan Wang, Jian-Bo Ji, Zong-Xue Zheng, Peng-Fei Shang, Xiu-Li Guo.

  Liver cancer, primary hepatocellular carcinoma (HCC), posing a significant threat to human health due to its high prevalence and limited treatment options. As a first-line chemotherapeutic agent for HCC, 5-fluorouracil (5-FU) has demonstrated significant efficacy in suppressing tumor cell proliferation through its cytotoxic mechanisms. Yet, prolonged 5-FU administration often induces chemo-resistant phenotypes in cancer cells, severely compromising the long-term efficacy of 5-FU-based treatment regimens and becoming a major barrier to successful HCC therapy. In this study, we investigated the mechanism underlying 5-FU resistance in Bel7402 hepatoma cells and found that it is closely related to metabolic reprogramming of glutamine. Notably, we demonstrated that CB-839, which is an inhibitor of glutamine metabolism's rate-limiting enzyme (glutaminase), has no notable anti-tumor activity alone but effectively enhances resistant HCC cells' sensitivity to 5-FU both in vitro and in vivo. The mechanism underlying this sensitization involves the disruption of cellular redox homeostasis. Specifically, the combination of CB-839 and 5-FU increases the accumulation of reactive oxygen species (ROS) and induces oxidative stress by consuming intracellular glutathione (GSH) reserves. Furthermore, this combination therapy elevates intracellular Fe2+levels and promotes lipid peroxidation, ultimately triggering ferroptosis. Collectively, these findings tentatively address certain aspects of the unclear mechanism underlying 5-FU resistance in HCC. Specifically, they may suggest targeting glutamine metabolism as a potential avenue for intervention and offer novel perspectives on understanding this resistance. Concurrently, these discoveries provide some support for optimizing chemotherapy regimens, with the aim of surmounting the current clinical challenges in reversing drug resistance.

Keywords:  5-FU resistance; GLS1; GLS1 inhibitor; Glutamine; Hepatocellular carcinoma

DOI:  https://doi.org/10.1016/j.cbi.2025.111812
Br J Haematol. 2025 Nov 12.

Venetoclax combined with cladribine, idarubicin, cytarabine (CLIA-VEN) results in higher remission rates over conventional 7 + 3 chemotherapy without increased toxicity in newly diagnosed acute myeloid leukaemia.

Benjamin J Lee, Shawn P Griffin, Jean Doh, Anthony Quach, Yujiao Sun, Piyatida Chumnumsiriwath, Stefan O Ciurea, Jorge Ramos-Perez, Polina Bellman, Deepa Jeyakumar, Piyanuch Kongtim, Kiran Naqvi.

  Induction chemotherapy in fit de novo acute myeloid leukaemia (AML) patients has historically combined an anthracycline with standard-dose cytarabine ('7 + 3') despite complete response (CR) rates of 50%-70%. In May 2023, our institution adopted the utilization of cladribine, cytarabine, idarubicin and venetoclax (CLIA-VEN) for intensive remission-induction therapy. In this retrospective study, outcomes of newly diagnosed adult AML patients who were consecutively treated with CLIA-VEN (n = 20; 2023-2025) were compared to a historical cohort that received 7 + 3 (n = 42; 2016-2023). The median interquartile range [IQR] age was 54 [42-63] years, 54% were male and 58% had European LeukemiaNet (ELN) 2022 adverse-risk disease. CLIA-VEN was associated with a higher cumulative incidence of composite CR (CCR) (90% vs. 54.8%; p = 0.002) and minimal residual disease (MRD)-negative CCR (93.8% vs. 40.9%; p < 0.001) at 28 days. Any grade ≥ 2 end-organ toxicity (45% vs. 59.5%; p = 0.28) and early mortality (0% vs. 16.7%; p = 0.09) were not increased with CLIA-VEN. Utilizing propensity score guided inverse probability treatment weighting to balance baseline demographics, receipt of CLIA-VEN was associated with improved overall survival (p = 0.002). Acknowledging the limitations of a retrospective single-centre study, our data suggest that CLIA-VEN has higher efficacy without increasing toxicity and the potential to prolong survival compared to the current standard of care in de novo AML patients.

Keywords:  CLIA; MRD; acute myeloid leukaemia; venetoclax; ‘7 + 3’

DOI:  https://doi.org/10.1111/bjh.70253
J Hazard Mater. 2025 Nov 04. pii: S0304-3894(25)03304-7. [Epub ahead of print]500 140384

13C metabolic tracing in human SGBS cells provides a potential new approach methodology for assessing metabolism-disrupting properties of environmental chemicals.

Cornelius Goerdeler, Beatrice Engelmann, Helen Broghammer, Alix Sarah Aldehoff, Martin Wabitsch, Kristin Schubert, Matthias Blüher, John T Heiker, Ulrike Rolle-Kampczyk, Martin von Bergen.

  Human exposure to certain environmental chemicals, including phthalates, is linked to metabolic disruption and may thereby contribute to diseases like obesity. However, regulatory methods to evaluate such effects are lacking. DINCH was introduced as a substitute for banned phthalate plasticizers, but its primary metabolite, MINCH, has been shown to promote adipogenesis in human preadipocytes and alter the lipid metabolism of mature adipocytes. To investigate its potential metabolism-disrupting effects, we assessed changes in the central carbon metabolism activity of human preadipocytes and mature adipocytes by 13C metabolic tracing. In preadipocytes, MINCH increased glycolysis, pentose phosphate pathway activity, acetyl-CoA production from glucose and glutamine, and pyruvate anaplerosis, indicating a metabolic shift toward adipogenesis. In mature adipocytes, MINCH enhanced glycolysis, glyceroneogenesis, fatty acid oxidation, and oxidative TCA cycle activity, pathways associated with the browning of adipocytes. Elevated UCP1 expression confirmed MINCH-induced browning. Most pronounced effects occurred at micromolar concentrations, whereas subtle changes were already observed at nanomolar concentrations in preadipocytes, the biological relevance of which should be further investigated. Overall, our findings demonstrate the utility of 13C metabolic tracing as a New Approach Methodology for detecting chemical-induced metabolic alterations, thus providing a new perspective for the hazard and risk assessment of environmental contaminants.

Keywords:  (13)C metabolic tracing; DINCH; Metabolic disruption; New Approach Methodology; Plasticizer

DOI:  https://doi.org/10.1016/j.jhazmat.2025.140384
Nat Metab. 2025 Nov 13.

Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis.

Abigail Strefeler, Zakery N Baker, Sylvain Chollet, Mads M Foged, Rachel M Guerra, Julijana Ivanisevic, Hector Gallart-Ayala, David J Pagliarini, Alexis A Jourdain.

Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited therapeutic target against cancer, autoinflammatory disorders and viral infections. However, regulation of nucleotide metabolism remains incompletely understood. Here, we reveal regulators of de novo pyrimidine synthesis. Using uridine-sensitized CRISPR-Cas9 screening, we show that coenzyme Q (CoQ) is dispensable for pyrimidine synthesis, in the presence of the demethoxy-CoQ intermediate as alternative electron acceptor. We further report that the ADP-ribose pyrophosphatase NUDT5 directly binds PPAT, the rate-limiting enzyme in purine synthesis, which inhibits its activity and preserves the phosphoribosyl pyrophosphate (PRPP) pool. In the absence of NUDT5, hyperactive purine synthesis exhausts the PRPP pool at the expense of pyrimidine synthesis, which promotes resistance to purine and pyrimidine nucleobase analogues. Of note, the interaction between NUDT5 and PPAT is disrupted by PRPP, highlighting an intricate allosteric regulation. Overall, our findings reveal a fundamental mechanism of nucleotide balance and position NUDT5 as a regulator of nucleobase analogue metabolism.

DOI: https://doi.org/10.1038/s42255-025-01419-2
J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70117

Primary-Stage Colon Cancer Impairs Muscle Energy Metabolism by Suppressing Mitochondrial Complex I Activity.

COMUNEX group

   BACKGROUND: Colon cancer (CC), the third most common cancer worldwide, is accompanied by cachexia in 30% of patients. Its associated muscle loss directly impairs therapeutic response and survival. Early intervention is crucial, yet the underlying mechanisms of early-stage muscle dysfunction remain unclear. This study investigates mitochondrial function in skeletal muscle across different CC stages to identify early metabolic alterations.
METHODS: The present study investigated mitochondrial function in rectus abdominus muscle biopsies from 30 patients with primary CC (83% male, mean age 67 ± 8 years), 10 patients with colorectal cancer with liver metastases (50% male, mean age 69 ± 6 years), and 17 age-matched controls (65% male, mean age 66 ± 7 years). Mitochondrial oxygen consumption was assessed using high-resolution respirometry, and transcriptional profiles were analysed via RNA sequencing.
RESULTS: Patients with primary CC exhibited reduced complex I activity compared to controls (9.02 vs. 12.47 pmol/s/mg, p < 0.001), accompanied by transcriptional upregulation of oxidative phosphorylation (OXPHOS)-related genes. In contrast, patients with liver metastases showed more severe mitochondrial dysfunction, with reductions in both complex I (7.38 vs. 9.65 pmol/s/mg, p < 0.01) and complex II (8.36 vs. 19.73 pmol/s/mg, p < 0.05), but without the compensatory transcriptional upregulation seen in primary CC. These mitochondrial impairments occurred before detectable declines in physical function or systemic inflammation (C-reactive protein, albumin).
CONCLUSIONS: Our findings reveal stage-specific mitochondrial dysfunction in CC, with early complex I impairment and a transient transcriptional adaptation in primary CC. These alterations precede clinical cachexia, suggesting mitochondrial dysfunction as a potential early biomarker for cancer-induced muscle loss and a target for early intervention.

Keywords:  colon cancer; mitochondria oxidative respiration; mitochondrial function; skeletal muscle function

DOI:  https://doi.org/10.1002/jcsm.70117
J Nutr Educ Behav. 2025 Nov 14. pii: S1499-4046(25)00423-3. [Epub ahead of print]

Navigating an Imposed Diet: What Dietetic Students Learned From a Food Intervention Experience.

Ethel Kautto, Agneta Hörnell, Jonas Burén, Anna Sjödin.

   OBJECTIVE: To explore the experiences of female dietetic students strictly following 2 different isocaloric diets.
DESIGN: A qualitative study as part of a randomized controlled feeding trial with a crossover design. Data were collected through individual interviews conducted 1-35 days after the intervention.
SETTING: A university in Sweden.
PARTICIPANTS: Normal-weight, healthy female dietetic students (n = 17), aged 18-30 years, who completed the full intervention.
INTERVENTION: Two 4-week diet periods with a washout period in between. Participants followed either a diet based on the Nordic Nutrition Recommendations or a ketogenic low-carb high-fat diet, consuming preprepared meals.
PHENOMENON OF INTEREST AND VARIABLES: Participants' experiences of following the imposed diets.
ANALYSIS: Data were analyzed using content analysis techniques, resulting in 1 main theme, 2 categories, and 5 subcategories.
RESULTS: Participants reported challenges with loss of control over food choices, unexpected effects of diet restrictions, and social visibility. They also highlighted the importance of contributing to science and the benefits for their future careers.
CONCLUSIONS AND IMPLICATIONS: First-hand experiences of strict diets provided valuable insights into the complexities of dietary adherence, enhancing empathy and competence in future dietetic practice. Integrating practical diet experiences into education could improve dietary counseling skills.

Keywords:  craving; food and nutrition; ketogenic diet; portion size; public health professional

DOI:  https://doi.org/10.1016/j.jneb.2025.09.002
Eur J Nutr. 2025 Nov 12. 64(8): 316

Ketone ester supplementation protects from experimental colitis via improved goblet cell differentiation and function.

Nadine Rohwer, Anika Sander, Soeren Ocvirk, Michelle Wiebel, Anja A Kühl, Nils Helge Schebb, Tilman Grune, Karsten-H Weylandt.

   PURPOSE: A ketogenic diet (KD), high in fat and low in carbohydrates, induces ketosis characterized by elevated circulating ketone bodies. While both KD and ketone bodies have demonstrated therapeutic potential in various pathophysiological conditions, their effect on inflammatory bowel diseases remains controversial. This study aimed to investigate the impact of a KD and ketone ester (KE), an ingestible form of ketone bodies, on intestinal inflammation.
METHODS: Acute dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced murine colitis models were used to evaluate and compare the effects of KD feeding and KE supplementation on intestinal inflammation, the mucus barrier and gut microbiota composition.
RESULTS: KD feeding did not significantly affect colitis activity, whereas KE supplementation alleviated colitis in both models investigated. KE-induced mitigation of colitis was associated with increased mucin2 expression, indicating enhanced colonic mucus barrier integrity. KE supplementation also improved goblet cell function and differentiation, as evidenced by increased goblet cell numbers and the upregulation of goblet cell differentiation markers. Furthermore, 16S rRNA sequencing analysis revealed that KE supplementation resulted in higher abundances of mucus-degrading Akkermansia, a genus believed to play a key role in maintaining intestinal homeostasis.
CONCLUSION: The present study suggests that KE represent an effective anti-inflammatory dietary supplement in the context of acute colitis, potentially by modulating mucin2 expression, goblet cell differentiation, and the abundance of Akkermansia. Although promising, these findings remain preliminary, and further investigations are needed to explore the therapeutic potential of KE as a dietary supplement in patients with inflammatory bowel disease.

Keywords:  Colitis; Goblet cell; Inflammatory bowel disease; Ketogenic diet; Ketone ester; Microbiome

DOI:  https://doi.org/10.1007/s00394-025-03833-4
Free Radic Biol Med. 2025 Nov 06. pii: S0891-5849(25)01343-7. [Epub ahead of print]242 589-600

The effect of triclosan uncovers the possible involvement of complex II in the oxidation of glycerol-3-phosphate in brain mitochondria.

Alexey G Kruglov, Anna B Nikiforova, Marina V Akulenko.

  Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) links the oxidative phosphorylation, glycolysis, and phospholipid biosynthesis and essentially contributes to ROS production by mitochondria in certain tissues. The pattern of biological effects of mGPDH dysregulation resembles that of chronic exposure to triclosan (Tcs), an unusual complex II inhibitor. Here we propose a hypothesis that the membrane-embedded regions of mGPDH and complex II form a common ubiquinone-binding center, which would be disturbed by Tcs. In this context, we test the potential of Tcs to inhibit mGPDH-related activities (respiration and ROS production) in isolated rat brain mitochondria (RBM). In the presence of moderate concentrations of glycerol-3-phosphate (G3P) and Ca2+, RBM demonstrated a limited ability to support oxidative phosphorylation and generation of superoxide anion and H2O2 via the reversed and transmembrane electron transport (from mGPDH to the flavins of complexes I and II). Tcs suppressed G3P- and 3-hydroxybutyrate (3-HB)-supported respiration and induced high-amplitude mitochondrial swelling. Exogenous cytochrome c restored the respiration in the presence of 3-HB but not G3P. In the presence of rotenone and thenoyltrifluoroacetone, the inhibitors of complexes I and II, Tcs inhibited antimycin A-activated and G3P-supported ROS production, which was accompanied by the oxidation of cytochromes b/heme b of complexes III/II. The 3-HB-supported ROS production and the extent of the reduction of cytochromes b were not affected by Tcs directly. These data confirm our hypothesis. However, for its rigorous assessment, we propose several approaches. Confirmation of this hypothesis will be of great importance for the development of promising mGPDH-targeted anticancer drugs.

Keywords:  Common ubiquinone-binding site; GPD2; ROS; Succinate dehydrogenase; Superoxide anion; Triclosan

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.11.008
Nature. 2025 Nov 12.

Metabolite maps reveal spatial gradients in liver and intestinal tissue.



Keywords:  Imaging; Metabolism; Physiology

DOI:  https://doi.org/10.1038/d41586-025-03457-y
Transl Oncol. 2025 Nov 10. pii: S1936-5233(25)00327-4. [Epub ahead of print]63 102596

Nutritional strategies against skeletal muscle wasting in cancer-associated cachexia: the role of β-hydroxybutyrate and polyunsaturated fatty acids.

Benjamin Hay, Aurélien Brun, Anne Fougerat, Vera Mazurak, Olivier Le Bacquer, Jérémie Talvas, Frédéric Capel.

  Cachexia is a multifactorial syndrome that occurs in many cancers, particularly in their advanced stages, decreasing the quality of life and lifespan of patients. One of the hallmarks of cancer-associated cachexia is skeletal muscle wasting. Multiple causes include inflammation, metabolic deregulation, energy utilization, endoplasmic reticulum and oxidative stress. Loss of skeletal muscle is characterised by an imbalance in protein homeostasis, with decreased anabolism (regulated by the Akt/GSK3/eIF2α and Akt/mTORC1 pathways) and increased catabolism (regulated by autophagy and the ubiquitin-proteasome system), as well as an impairment in myogenesis. Accumulating evidence suggests that dietary intervention of β-hydroxybutyrate, the major ketone body produced by ketogenesis, and n-3 polyunsaturated fatty acids may mitigate skeletal muscle wasting. Polyunsaturated fatty acids and β-hydroxybutyrate are able to favourably modulate inflammation, insulin resistance, unfolded protein response and stresses (such as metabolic stress and oxidative stress). A well-adapted nutritional strategy may include a "classic" diet supplemented with β-hydroxybutyrate and polyunsaturated fatty acids to maintain skeletal muscle integrity and reduce wasting.

Keywords:  Cellular stresses; DHA; EPA; Inflammation; Ketogenic diet; Ketones; Myogenesis; Nutrition; Protein homeostasis

DOI:  https://doi.org/10.1016/j.tranon.2025.102596
Clin Lymphoma Myeloma Leuk. 2025 Oct 24. pii: S2152-2650(25)04258-2. [Epub ahead of print]

What is the Prognostic Relevance of Responses Less Than a CR to Initial AML Treatment?

Akhil Rajendra, Elliot Smith, Eshetu G Atenafu, Aniket Bankar, Steven Chan, Marta Davidson, Vikas Gupta, Mark D Minden, Maria Agustina Perusini, Guillaume Richard-Carpentier, Aaron Schimmer, Andre C Schuh, Hassan Sibai, Karen Yee, Dawn Maze.

   BACKGROUND: Achievement of complete remission (CR) has long been one of the goals of acute myeloid leukemia (AML) treatment. Less stringent criteria for defining CR (sub-CR) have been developed to facilitate clinical trials and regulatory approvals. However, the clinical value of sub-CR in the context of advancements in sequencing and measurable residual disease, and non-intensive therapy is incompletely understood.
METHODS: We performed a retrospective analysis of 363 patients with AML (2019-2023) with CR or sub-CR responses. The primary objective was to determine predictors of sub-CR response.
RESULTS: CR was achieved in 227 and sub-CR in 136 patients. Receiving non-intensive chemotherapy (OR 8.80; 95% [4.25-18.20], P < .001) and having spliceosome pathway mutations (OR 3.53; [1.45-8.57], P = .005) were independent predictors for sub-CR response. Consistent with prior studies, patients achieving a sub-CR response following intensive chemotherapy had inferior survival compared to those achieving CR (median OS: not reached (CR) vs. 26 months [18-NA] (sub-CR); P = .002). On MVA, older age (HR 1.75; [1.04-2.95], P = .034) and adverse ELN risk (HR 2.55; [1.53-4.23], P = .001) was associated with inferior OS. But sub-CR response (HR 1.45; [0.91-2.33], P = .119) was not associated with inferior OS. In patients who received non-intensive treatment, there was no significant difference in EFS or OS between the CR and sub-CR populations.
CONCLUSIONS: In patients treated with intensive chemotherapy, achieving a sub-CR response appears to be reflective of poor disease biology. Whereas, in patients treated with non-intensive therapies, sub-CR responses may result from the continuous nature of the treatment and not necessarily portend an inferior outcome. The potential role of spliceosome pathway variants should be further evaluated.

Keywords:  AML; CRh; CRi; MLFS; NGS; Sub-CR response

DOI:  https://doi.org/10.1016/j.clml.2025.10.016
Clin Chim Acta. 2025 Nov 07. pii: S0009-8981(25)00582-0. [Epub ahead of print]580 120703

Evaluation of an enzymatic one-step assay for Beta-Hydroxybutyrate blood testing on clinical chemistry platforms using HILIC-MS/MS as a non-enzymatic reference method.

Max K Steinbach, Holger Müller, Yanik Reichard, Konstantin Eulberg, Tobias Frömel, Alexandra Lein, Christoph Peter, Kai Prager, Matthias Grimmler.

   BACKGROUND: β-Hydroxybutyrate (β-HB), the predominant circulating ketone body, serves as alternative energy source during periods of glucose deprivation. Accurate quantification of β-HB is essential for the clinical assessment and monitoring of ketosis and diabetic ketoacidosis (DKA).
METHODS: We evaluated the analytical performance of the DiaSys β-Hydroxybutyrate 21 FS assay (BHB 21 FS), a one-step enzymatic assay based on β-hydroxybutyrate dehydrogenase-catalyzed oxidation of β-HB to generate NADH, which is photometrically measured at 340 nm. Performance characteristics, including linearity, repeatability, and total precision, were assessed in serum samples following CLSI guidelines. The BHB 21 FS assay was benchmarked against two commercial two-step assays and a non-enzymatic reference method (HILIC-ESI-MS/MS).
RESULTS: The BHB 21 FS assay showed a linear measuring range from 0.05 up to 6.0-8.0 mmol/L and CLSI-compliant total precision (CV ≤3.3 %), notably at the clinically relevant 3 mmol/L cut-off (mean CV: 1.93 %). Method comparison demonstrated excellent correlation with EKF BHB LiquiColor® across three different analyzers (r = 0.999; bias ≤1 %), and high concordance with DiaSys BHB FS (r = 0.998; bias 5.0 %) and the HILIC-MS/MS reference method (r = 0.998; bias 4.0 %). Interference testing indicated robust performance even in highly hemolytic, lipemic, or icteric samples (≤10 % deviation). On platforms with active cooling compartments, calibration and onboard stability were maintained for 10-16 weeks.
CONCLUSION: The DiaSys BHB 21 FS assay combines robust analytical performance and high concordance with both enzymatic and mass spectrometric methods. These features support its use as a reliable one-step assay for routine clinical assessment of ketosis and ketoacidosis.

Keywords:  Diabetic ketoacidosis; Enzyme assay; Ketones; Liquid chromatography; Mass spectrometry; Method validation; Performance evaluation

DOI:  https://doi.org/10.1016/j.cca.2025.120703
Nat Methods. 2025 Nov;22(11): 2386-2399

Universal consensus 3D segmentation of cells from 2D segmented stacks.

Felix Y Zhou, Zach Marin, Clarence Yapp, Qiongjing Zou, Benjamin A Nanes, Stephan Daetwyler, Andrew R Jamieson, Md Torikul Islam, Edward Jenkins, Gabriel M Gihana, Jinlong Lin, Hazel M Borges, Bo-Jui Chang, Andrew Weems, Sean J Morrison, Peter K Sorger, Reto Fiolka, Kevin M Dean, Gaudenz Danuser.

Cell segmentation is the foundation of a wide range of microscopy-based biological studies. Deep learning has revolutionized two-dimensional (2D) cell segmentation, enabling generalized solutions across cell types and imaging modalities. This has been driven by the ease of scaling up image acquisition, annotation and computation. However, three-dimensional (3D) cell segmentation, requiring dense annotation of 2D slices, still poses substantial challenges. Manual labeling of 3D cells to train broadly applicable segmentation models is prohibitive. Even in high-contrast images annotation is ambiguous and time-consuming. Here we develop a theory and toolbox, u-Segment3D, for 2D-to-3D segmentation, compatible with any 2D method generating pixel-based instance cell masks. u-Segment3D translates and enhances 2D instance segmentations to a 3D consensus instance segmentation without training data, as demonstrated on 11 real-life datasets, comprising >70,000 cells, spanning single cells, cell aggregates and tissue. Moreover, u-Segment3D is competitive with native 3D segmentation, even exceeding when cells are crowded and have complex morphologies.

DOI: https://doi.org/10.1038/s41592-025-02887-w
Brain. 2025 Nov 14. pii: awaf430. [Epub ahead of print]

The genotypic and phenotypic landscape of PDHA1-related pyruvate dehydrogenase complex deficiency.

Kajus Merkevicius, Dmitrii Smirnov, Lea D Schlieben, Rebecca Ganetzky, René G Feichtinger, Huafang Jiang, Fang Fang, Tomohiro Ebihara, Kei Murayama, Giulia Ferrera, Anna Ardissone, Dariusz Rokicki, Dorota Wesol-Kucharska, Sabine Schröder, Peter Bauer, Aida Bertoli-Avella, Elsebeth Østergaard, Peter Freisinger, Mirian C H Janssen, Matias Wagner, Omar Abouyousef, Bader Alhaddad, Lama AlAbdi, Fowzan Alkuraya, Charlotte L Alston, Anna Baghdasaryan, Diana Barca, Ivo Barić, Marcello Bellusci, Andrea Bevot, Eugen Boltshauser, Ingo Borggraefe, Juliette Bouchereau, Claudio Bruno, Birute Burnyte, Amy Calhoun, Kari Casas, Mahmut Coker, Ellen Crushell, Pascal De Lonlay, Carlo Dionisi-Vici, Felix Distelmaier, Marni J Falk, Ana Cristina Ferreira, Carlos R Ferreira, Can Ficicioglu, Gulden Fatma Gokçay, Johannes Häberle, Oliver Heath, Albrecht Hellenschmidt, Julia Hoefele, Georg F Hoffmann, Tomas Honzik, Martina Huemer, Patrícia Janeiro, Amel Karaa, Çiğdem Seher Kasapkara, Ilse Kern, Joerg Klepper, Thomas Klopstock, Ina Knerr, Johannes Koch, Zita Krumina, Costanza Lamperti, Elise Lebigot, Zhimei Liu, Esther M Maier, Diego Martinelli, Robert McFarland, Bryce Mendelsohn, Maria Judits Molnar, Helen Mundy, Marie-Cecile Nassogne, Anabela Oliveira, Katrin Õunap, Chiara Panicucci, Sumit Parikh, Heidi Peters, Samia Pichard, Barbara Plecko, Danijela P Ramadža, Gabriela M Repetto, Isabel Rivera, Richard J Rodenburg, Alessandro Rossi, Manuel Schiff, Kathrin Seidemann, Wendy E Smith, Sérgia Soares, Barbara Siri, Katja Steinbrucker, Pasquale Striano, Jolanta Sykut-Cegielska, Galit Tal, Robert W Taylor, Kostas Tsiakas, Sema Kalkan Ucar, Eva Hoytema van Konijnenburg, Mathias Woidy, Joy Yaplito-Lee, Yilmaz Yildiz, Martin Zenker, Petra Zsidegh, Dominik Westphal, Wolfgang Sperl, Thomas Meitinger, Garry K Brown, Holger Prokisch, Johannes A Mayr, Saskia B Wortmann.

  This retrospective study on X-linked PDHA1-related pyruvate dehydrogenase complex (PDHc) deficiency combined a systematic literature review with a multicenter survey exploring genotypes, phenotypes, and survival. Data from 891 individuals (45% unpublished) were included. Of note, 53% of cases were females. Median age at last assessment was six years (range 0-80 years, n = 622). We detected 331 different (118 unpublished) PDHA1 variants of which 75% (305/405) had occurred de novo. Variants in this study were uploaded to ClinVar (SCV006297015 - SCV006297345). The 10 most frequent variants accounted for 36% of the diagnoses. Sixty-nine percent of the variants were private; missense (50%) and frameshift (20%) variants were most common. Frameshift/nonsense (FS/N) variants in males (44/401, 11%) were confined to regions escaping nonsense-mediated decay (NMD) and were significantly less frequent than in females (151/461, 33%). Neonatal or infantile (405/529, 77%) presentations were most frequent, with pre/perinatal abnormalities reported in 47% (159/342). FS/N variants in NMD-predicted region 3.9 (95% Confidence Interval (CI) 1.54-11.04) times increased the odds of fetal findings. Females presented significantly earlier (2 months, interquartile range (IQR) 7.0, n = 224) than males (8 months, IQR 16.6, n = 233), with increased risk of neonatal presentation (odds ratio (OR) 3.01 (95% CI 1.279-7.616) when harboring FS/N variants in NMD-predicted region. The overall (n = 242) mean survival time was 10.9 (95% CI 9.9-11.9) years. On average, females survived 4.5 (95% CI 2.62-6.40) years longer than males despite presenting more severe phenotypes. Poor survival was associated with male sex (hazard ratio (HR) 3.3 (95% CI 1.95-5.62)), neonatal presentation (HR 5.5 (95% CI 2.17-14.09)), FS/N variants in NMD-predicted region (HR 4.0 (95% CI 1.78, 9.16)), and splice variants (HR 2.3 (95% CI 1.15, 4.59)). More severe clinical phenotypes were predicted by neonatal or infantile presentations and by female sex. Developmental delay (DD), intellectual disability (ID), muscle hypotonia, abnormal movements, seizures, feeding difficulties, and microcephaly were the most frequent phenotypes, all occurring in more than half. Corpus callosum or basal ganglia alterations and cerebral atrophy were common. Four percent (36/891) were reported to have mild phenotypes with no DD nor ID (25/36 males). This is the largest dataset on a nuclear-encoded defect of mitochondrial energy metabolism. The genotypic and phenotypic details further defines disease landscape and can be used for variant interpretation. The correlations between genotypes, sex, phenotypes and survival, adds a substantial improvement to counselling.

Keywords:  genotype-phenotype correlation; inborn errors of metabolism; inborn metabolic disease; ketogenic diet; mitochondrial disease; treatment

DOI:  https://doi.org/10.1093/brain/awaf430
iScience. 2025 Nov 21. 28(11): 113743

Robust calibration and quantification of FRET signals using multiplexed biosensor barcoding.

Jhen-Wei Wu, Ming Yang, Chao-Cheng Chen, Gabriel Au, Suyang Wang, Yichu Xu, Gia-Wei Chern, Chuan-Hsiang Huang.

  Förster resonance energy transfer (FRET) between fluorescent proteins (FPs) underpins many genetically encoded fluorescent biosensors for monitoring biochemical activities in live cells. However, the FRET ratio (acceptor-to-donor signal ratio), commonly used as a proxy for FRET efficiency, is highly sensitive to imaging parameters, complicating data interpretation. Using FP-based barcodes, we introduced calibration standards into subsets of cells for normalization of fluorescence signals. Theoretical analysis indicated the need for both high- and low-FRET standards for calibration under different excitation intensities. We validated this prediction using engineered "FRET-ON" and "FRET-OFF" standards, demonstrating that calibrated FRET ratios are independent of imaging conditions. Including donor-only and acceptor-only cells enabled simultaneous determination of FRET efficiency for multiple biosensors. Calibration also restored expected reciprocal changes in donor and acceptor signals, often obscured by imaging fluctuations and photobleaching. Together, our studies introduce a simple strategy for robust, multiplexed FRET biosensor imaging, facilitating cross-experimental and long-term studies.

Keywords:  Biophysical Chemistry; Biotechnology; Methodology in biological sciences; Sensor

DOI:  https://doi.org/10.1016/j.isci.2025.113743
Clin Chem. 2025 Nov 06. pii: hvaf142. [Epub ahead of print]

Validation of a Multiplex mRNA- and gDNA-Based Droplet Digital PCR Assay in Acute Myeloid Leukemia Patients with an NPM1 Mutation.

Albertus T J Wierenga, Lucy B Hesp, Arjan Simpelaar, Linde M Morsink, Carolien M Woolthuis, Jan Jacob Schuringa, Isidor Minovic, Gerwin Huls, André B Mulder.

BACKGROUND: NPM1 is a disease-defining gene in the diagnosis of acute myeloid leukemia (AML) and is important for measurable residual disease (MRD) assessment. Over 50 different NPM1 mutations have been described, but only the 3 most common are routinely monitored during follow-up.
METHODS: We developed a multiplex droplet digital polymerase chain reaction (PCR) assay for measurement of both variant allele frequencies (VAF) and mRNA transcripts of 10 different NPM1 mutations, using one generic probe, one generic NPM1 reverse primer, and 10 mutation-specific NPM1 forward primers. ABL1 expression and AP3B1 VAF were used as references. The performance of the assay was tested in diagnosis and follow-up samples from patients with an NPM1-mutated AML.
RESULTS: Our assay shows negligible false-positive signals and high assay precision, leading to low limits of detection of at least 0.01%. The assay can easily be expanded to cover more NPM1 mutations by adding extra mutation-specific forward primers to the primer mix. Overall, a good correlation between mutant NPM1 expression and VAF was found. However, we also observed discrepant variable ABL1 expression levels, especially in AML patients with fms-related receptor tyrosine kinase 3-internal tandem duplications co-mutations.
CONCLUSION: We developed a robust and extremely flexible mRNA- and gDNA-based multiplex droplet digital PCR NPM1 assay. Because the AML tumor load is better reflected by mutant NPM1 VAF than expression level, we recommend using the gDNA-based mutant NPM1 MRD assay with a VAF detection limit of 0.01%. For MRD signals below 0.01%, our more sensitive mRNA-based method can be used, although further research has to prove its clinical impact.

DOI: https://doi.org/10.1093/clinchem/hvaf142