bims-medica 2026-04-12 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–04–12
nineteen papers selected by
Brett Chrest, Wake Forest University

PHGDH is a targetable driver of PDAC progression.
Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.
Metformin treatment impairs the adenine nucleotide translocator activity and energy metabolism in human clear cell renal carcinoma cells.
Effect of glucose on medium chain triglyceride induced ketosis in healthy adults in a randomized, double-blind, controlled study.
Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation.
SLC13A2-transported citrate remodels transcriptional regulation through protein acetylation to suppress tumor growth.
A high-resolution mass spectrometry-based method for quantifying insulin-stimulated glucose uptake in mice following an intraperitoneal injection of tracer.
Glutamine addiction is a therapeutic target to block emergency myelopoiesis.
Single-Cell Metabolic Profiling in a Glioblastoma Coculture Model Using AP-MALDI-Based Mass Spectrometry Imaging.
Metabolites from plasma-like medium fuel nitrogen metabolism and influence proliferation in Leptospira interrogans.
Isocitrate dehydrogenase mutations as potential tumour agnostic targets.
Protocol for stable isotope tracing of primary human peripheral blood mononuclear cells.
Adapting high-resolution respirometry for adherent brain endothelial cells reveals stable and reproducible mitochondrial respiration.
Cardiometabolic effects of time-restricted eating (tentative).
Tumour trap: engineered enhancer sequences enlisted to kill cancer cells.
Quizartinib and omacetaxine mepesuccinate combination therapy in FLT3-ITD AML: a phase II trial.
Brain glucose extraction is fixed at 10% despite twofold variability in resting cerebral blood flow in healthy humans.
Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells.
Clinical advancement in the management of mutant isocitrate dehydrogenase (IDH) cancers.

bioRxiv. 2026 Mar 14. pii: 2026.03.11.711147. [Epub ahead of print]

PHGDH is a targetable driver of PDAC progression.

Yumi Kim, Le Jin Sun, Meredith Long, Samantha Caldwell, H Carlo Maurer, Kenneth P Olive, Florian Karreth, Gina M DeNicola.

Pancreatic ductal adenocarcinoma (PDAC) arises in a nutrient-deprived microenvironment through progressive stages from pancreatic intraepithelial neoplasia (PanIN) to invasive carcinoma. While serine metabolism supports tumor growth across multiple cancer types, the stage-specific role of de novo serine synthesis in PDAC evolution remains undefined. Here, we show that expression of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of serine biosynthesis, increases progressively from PanIN to invasive PDAC in human and mouse specimens. Using genetically engineered mouse models with inducible PHGDH knockdown, we found that PHGDH loss delayed PDAC development. Unexpectedly, PHGDH-deficient tumors did not increase reliance on exogenous serine, and dietary serine/glycine manipulation had no effect on tumor development. Instead, stable isotope tracing and metabolomic profiling revealed that PHGDH loss suppressed mTOR signaling, reduced expression of the glutamine transporter ASCT2, and impaired glutamine uptake and utilization. Leveraging this metabolic liability, we demonstrated that PHGDH-deficient tumors exhibited selective sensitivity to the glutamine antagonist DRP-104, whereas PHGDH-intact tumors were resistant. These findings reveal an unanticipated connection between serine biosynthesis and glutamine metabolism in PDAC and identify a therapeutic vulnerability that may be exploited through combined metabolic targeting.
Statement of significance: PHGDH supports PDAC progression not primarily through serine provision, but by maintaining glutamine metabolism and mTOR signaling. This unanticipated metabolic crosstalk creates a synthetic lethal vulnerability to glutamine antagonism in PHGDH-deficient tumors, providing a rationale for combining serine synthesis pathway inhibitors with glutamine-targeting therapies in pancreatic cancer.

DOI: https://doi.org/10.64898/2026.03.11.711147
Cancer Lett. 2026 Apr 07. pii: S0304-3835(26)00251-X. [Epub ahead of print] 218488

Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.

Johnvesly Basappa, Aaron R Goldman, Cosimo Lobello, Shengchun Wang, David Rushmore, Olga Melnikov, Neil V Sen, Vinay S Mallikarjuna, Priyanka Jain, Masoud Edalati, David S Nelson, Kathy Q Cai, Pin Lu, Reza Nejati, Hossein Borghaei, Pradeep K Gupta, Kavindra Nath, Kathryn E Wellen, Mariusz A Wasik.

  Acetate serves as an alternative carbon source in nutrient-limited tumors, yet its role in supporting nucleotide biosynthesis remains poorly understood. Here, we identify the mitochondrial enzyme ACSS1 as a key metabolic driver in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). ACSS1 is frequently overexpressed and catalyzes the conversion of acetate to mitochondrial acetyl-CoA, sustaining oxidative metabolism and biosynthesis under nutrient stress. Genetic silencing of ACSS1 impairs mitochondrial respiration and disrupts acetate incorporation into acetyl-CoA, TCA cycle intermediates, glutamate, and aspartate, while markedly reducing 13C-acetate labeling of dihydroorotate and orotate, intermediates in de novo pyrimidine synthesis. Untargeted metabolomics reveal enrichment of pyrimidine biosynthesis pathways in ACSS1-high cells. Notably, acetate or uridine supplementation rescues the growth of ACSS1-deficient cells, confirming a functional link between acetate metabolism and nucleotide synthesis. Importantly, in vivo studies using two different MCL xenografts demonstrate that ACSS1 knockdown profoundly suppresses tumor growth, indicating that ACSS1 is required not only for metabolic adaptation of lymphoma cells in vitro but also in vivo. Collectively, our results uncover an ACSS1-dependent mitochondrial acetate-pyrimidine axis that sustains lymphoma growth and represents a previously unrecognized therapeutic vulnerability.

Keywords:  ACLY; ACSS1; ACSS2; CAD; DHODH; acetate metabolism; cancer metabolism; oncometabolite

DOI:  https://doi.org/10.1016/j.canlet.2026.218488
Sci Rep. 2026 Apr 10.

Metformin treatment impairs the adenine nucleotide translocator activity and energy metabolism in human clear cell renal carcinoma cells.

Lidia de Bari, Mariano Francesco Caratozzolo, Giuseppe Petrosillo, Miriana Calò, Cinzia Antognelli, Tatiana Armeni, Andrea Scirè, Miklós Péter Kalapos.

  Although metformin (MET), the well-known antidiabetic drug, exhibits clear antineoplastic effects and is reported to target mitochondria, several issues are still open in this regard, thus limiting its utilization as an anticancer drug alone or in combination with other molecules. Here a functional investigation was carried out to reveal how MET impacted on mitochondrial functions and cell energy metabolism in human cultured clear cell renal carcinoma cells (ccRCCs), in which the anticancer effect of MET is already known. The in vitro effect of increasing MET concentrations on cell viability, necrosis and apoptosis of ccRCCs was checked and compared to normal immortalized HK2 cells. At the same time, the effect of MET on mitochondrial functions, ATP synthesis via oxidative phosphorylation, cellular ATP level, L-lactate (L-LAC) production and export, glucose consumption and key mitochondrial and cytosolic enzyme activities was also investigated in cancer cells. MET affected ccRCC viability and impaired mitochondrial respiration, membrane potential generation and ATP production by targeting complex I (CI), III and IV of the respiratory chain at a concentration near to the IC50 value (25 mM). Importantly, we first identified a significant inhibition of the adenine nucleotide translocator (ANT) activity in response to MET treatment. Notably, the sensitivity of ANT and CI activity to increasing MET concentrations differed markedly, the former being considerably inhibited already at a low, near-clinically relevant concentrations, while the latter only at concentrations ≥ 1 mM. The drug also induced a glycolytic shift in ccRCCs and increased the activity of the mitochondrial flavoenzymes succinate dehydrogenase (SDH) and D-lactate dehydrogenase (D-LDH), and of the key enzymes of the pay-off phase of glycolysis, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK) and pyruvate kinase (PK). Nevertheless, cellular ATP level dropped markedly, and the intracellular L-LAC amount was almost doubled in the presence of MET. Interestingly, MET-induced glycolytic shift showed a drug concentration dependence similar to that seen for CI inhibition, suggesting not ANT but rather CI inhibition may be the trigger for metabolic rewiring. These findings give new insights into MET mechanisms of action which may potentially improve its application and outcome in cancer as well as in other pathologies.

Keywords:  Adenine nucleotide translocator; Clear cell renal cell carcinoma; Glycolysis; Metformin; Mitochondrial respiratory chain complexes; Oxidative phosphorylation

DOI:  https://doi.org/10.1038/s41598-026-48200-3
Sci Rep. 2026 Apr 09. pii: 12049. [Epub ahead of print]16(1):

Effect of glucose on medium chain triglyceride induced ketosis in healthy adults in a randomized, double-blind, controlled study.

Marius Frenser, Manfred Fobker, Renata Antonina Feuerborn, Thorsten Marquardt, Tobias Fischer.

  Although medium-chain triglycerides (MCT) stimulate and carbohydrates inhibit ketone body synthesis, their quantitative interaction in humans is not well defined. This randomised, controlled, double-blind crossover study investigated how increasing glucose doses affects C8-MCT-induced ketone body synthesis after overnight fasting. Eleven healthy young woman (22.5 ± 1.9 years) received a constant dose of tricaprylin (99% C8; 0.2 g/kg bodyweight) combined with increasing glucose doses (0.2-0.6 g/kg bodyweight). In additional interventions, both C8-MCT and glucose were increased in parallel. Plasma β-hydroxybutyrate (βHB), glucose, and insulin were measured for up to 300 min post-dose. Indirect calorimetry in a subset and side effects were monitored. C8-MCT significantly increased βHB concentrations at low and medium glucose doses compared with control, but not at highest glucose dose. When both substrates were increased equally (1:1 ratio), ketone body synthesis increased. βHB was negative correlated with increasing glucose dosing at constant C8-MCT dosing, while parallel increases in both substrates showed a positive moderate correlation between βHB and C8-MCT doses. No dose-dependent side effects occurred. Overall, ketone body synthesis declines with rising glucose intake. It remains unclear whether a C8-MCT: glucose ratio of 1:3 represents a metabolic cut-off or whether glucose intake becomes excessive due to linear effects.Trial registration This study was prospectively registered in the German Clinical Trials Register (DRKS ID DRKS00035373 https//www.bfarm.de/EN/BfArM/Tasks/GermanClinicalTrialsRegister/_node.html ).

Keywords:  Caprylic acid (C8; C8:0); Glucose; Ketogenic diet; Ketone bodies; Medium-chain triglycerides (MCT); Tricaprylin

DOI:  https://doi.org/10.1038/s41598-026-47702-4
Mol Cell. 2026 Apr 07. pii: S1097-2765(26)00192-9. [Epub ahead of print]

Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation.

Chao Qin, Zhenhao An, Shu Feng, Wen Fu, Xinchi Xie, Ali Can Savas, Taolin Xie, Charles Brenner, Takeshi Saito, Pinghui Feng.

  Rapid cancer cell proliferation requires extensive macromolecular biosynthesis, yet how distinct anabolic pathways are coordinated remains incompletely understood. Here, we report that the trifunctional carbamoyl-phosphate synthase, aspartate transcarbamoylase, and dihydroorotase (CAD) activates key glycolytic enzymes to support biosynthesis and cancer cell proliferation. When cancer proteomics datasets were queried, a CAD activation signature was identified in diverse tumors. Metabolomics analysis revealed that CAD fuels central carbon metabolism, specifically the pentose phosphate pathway (PPP) and serine synthesis pathway (SSP). Mechanistically, CAD deamidates and activates glucose-6-phosphate dehydrogenase (G6PD) and phosphoglycerate dehydrogenase (PHGDH), rate-limiting enzymes of the PPP and SSP, respectively, which are fully recapitulated by the glutaminase domain of CAD. Functional interrogation of cancer-associated CAD mutations and human hepatocellular carcinoma tumors predicts the metabolic signature endowed by G6PD and PHGDH deamidation. Simultaneous inhibition of G6PD and PHGDH effectively impeded tumor formation. This work identifies CAD as a central carbon metabolism signaling node and a potential therapeutic target.

Keywords:  CAD; Cancer metabolism; G6PD; PHGDH; central carbon metabolism; deamidation; pyrimidine synthesis; the pentose phosphate pathway; the serine synthesis pathway

DOI:  https://doi.org/10.1016/j.molcel.2026.03.016
Sci Adv. 2026 Apr 10. 12(15): eaec4368

SLC13A2-transported citrate remodels transcriptional regulation through protein acetylation to suppress tumor growth.

Mengyao Qin, Longcheng Shang, Hao Chen, Li Shi, Chan Liu, Ming Ding, Dandan He, Chang Shao, Shengtao Yuan, Hong Yu, Haiping Hao, Yong Ma, Jing Xiong.

Metabolic reprogramming is a hallmark of cancer, while tricarboxylic acid cycle is increasingly recognized as a multifaceted hub driving tumor metabolism and progression. Integrated analysis of solute carrier (SLC) transporters revealed consistent down-regulation of SLC13A2 in hepatocellular carcinoma (HCC) cells and liver tissues from human patients and mouse models. Adeno-associated virus-mediated liver-specific knockout or overexpression of SLC13A2 (SLC13A2-OE) promoted or ameliorated HCC progression, indicating its protective role. SLC13A2 inhibited HCC proliferation by decreasing mitochondrial function via suppressed glycolysis, respiration, and adenosine 5'-triphosphate production. Flux analysis showed that SLC13A2 imported citrate to generate acetyl-coenzyme A for pyruvate kinase isozyme type M2 acetylation, triggering its degradation. Reduced pyruvate kinase activity limited pyruvate supply, impairing amino acid synthesis and nucleotide metabolism. Moreover, SLC13A2-imported citrate induced intracellular protein acetylation, particularly histone proteins, which provided an epigenetic basis for transcriptional regulation and contributed to tumor suppression. Thus, SLC13A2 perturbs metabolic and transcriptional programs to suppress tumor growth, highlighting potential drug targets for HCC therapy.

DOI: https://doi.org/10.1126/sciadv.aec4368
bioRxiv. 2026 Apr 02. pii: 2026.03.31.714892. [Epub ahead of print]

A high-resolution mass spectrometry-based method for quantifying insulin-stimulated glucose uptake in mice following an intraperitoneal injection of tracer.

Guo-Fang Zhang, Dorothy H Slentz, Louise Lantier, Owen P McGuinness, Deborah M Muoio, Ashley S Williams.

Objective: A catheter-free, non-radiolabeled method that permits in vivo measurement of tissue-specific glucose uptake does not exist. To address this gap, we sought to develop and validate a new, higher throughput mass spectrometry (MS)-based method that combines an injection of insulin with a non-radiolabeled glucose tracer, 2-fluoro-2-deoxyglucose (2FDG), to determine insulin-stimulated tissue-specific glucose clearance in conscious, unrestrained mice.
Methods: Injections of saline or insulin with 2FDG were coupled with LC-Q Exactive Hybrid Quadrupole-Orbitrap (LC) MS-based measures of plasma 2FDG and tissue (2-fluoro-2-deoxyglucose-6-phosphate) 2FDGP to determine glucose clearance in mice under several different conditions.
Results: The newly developed method was first applied to a dose response experiment in mice. Next, the ability of this method to quantify changes in glucose clearance in response to an insulin stimulus was assessed, and glucose clearance was compared between chow and high fat fed mice. Results from these studies showed that insulin-stimulated skeletal muscle and heart glucose clearance can be estimated following a bolus injection of tracer, and these fluxes are blunted in diet-induced obese mice. The broad applicability of this approach was then demonstrated by assessing glucose clearance in a mouse model with anticipated changes in insulin-stimulated skeletal muscle glucose metabolism.
Conclusions: The results validated a new LC-MS method to quantify insulin-stimulated tissue-specific glucose clearance in vivo without the use of catheters or radiolabeled tracers. The method offers great potential because it is designed for application to pre-clinical studies seeking high throughput tests and/or assays that can be coupled with discovery technologies such as genomics, proteomics and metabolomics.
HIGHLIGHTS: In vivo glucose clearance can be estimated by a new non-radiolabeled method. The plasma tracer to tracee ratio is required to determine tissue tracer phosphorylation.Measures of plasma glucose and tracer kinetics are critical for data interpretation.The new method can be combined with 'omics' technologies such as metabolomics.

DOI: https://doi.org/10.64898/2026.03.31.714892
bioRxiv. 2026 Mar 30. pii: 2026.03.26.714544. [Epub ahead of print]

Glutamine addiction is a therapeutic target to block emergency myelopoiesis.

Oakley C Olson, Ruiyuan Zhang, Melissa A Proven, James C Swann, Kexuan Huang, William E Lowry, Emmanuelle Passegue.

Inflammation-driven emergency myelopoiesis (EM) contributes to the progression of many solid cancers and inflammatory diseases, yet therapeutic strategies to selectively suppress EM without compromising hematopoiesis remain lacking. Here, we use functional and single-cell transcriptomic analyses to determine metabolic programs organizing the hematopoietic hierarchy, myeloid lineage commitment, and myeloid differentiation. We identify de novo glutamine biosynthesis as a stem cell-specific survival mechanism allowing independence from exogenous glutamine. We show that myeloid differentiation is characterized by Myc-driven upregulation of mitochondrial respiration, which is hyperactivated during EM and renders myeloid progenitors dependent on glutaminolysis to fuel the TCA cycle. Both genetic and pharmacologic targeting of glutaminase suppresses EM and impairs breast tumor progression by reducing intratumoral neutrophil infiltration. Our study defines a central role for Myc-glutaminolysis in driving EM, identifies glutaminolysis as a therapeutic target to normalize maladaptive EM, and highlights myeloid overproduction as a systemic problem requiring HSPC targeting.

DOI: https://doi.org/10.64898/2026.03.26.714544
Anal Chem. 2026 Apr 06.

Single-Cell Metabolic Profiling in a Glioblastoma Coculture Model Using AP-MALDI-Based Mass Spectrometry Imaging.

Une Kontrimaite, Kei F Carver Wong, Sandra Martínez-Jarquín, Phoebe McCrorie, Ruman Rahman, Dong-Hyun Kim.

Mass spectrometry imaging enables spatially resolved, label-free detection of metabolites in tissue and culture systems, providing insight into their metabolic landscapes and spatial distribution. However, conventional approaches often lack the spatial resolution and specificity needed to investigate metabolic heterogeneity at the single-cell level, particularly in physiologically relevant models. Here, we present a single-cell ambient mass spectrometry imaging platform, enabling direct chemical mapping of metabolites at a 10 μm resolution. This method integrates cell labeling, high-resolution microscopy, and AP-MALDI Orbitrap mass spectrometry imaging to achieve cell-type-specific metabolite profiling. To demonstrate its application, we applied this approach to glioblastoma (GBM), an aggressive adult brain tumor characterized by cellular heterogeneity, metabolic adaptation, and infiltrative growth within the tumor microenvironment. A coculture model combining patient-derived glioblastoma invasive margin cells with human cortical astrocytes was used to recapitulate the invasive niche. Distinct metabolic signatures emerged upon glioblastoma-astrocyte interaction, involving pathways related to nucleotide metabolism, phospholipid turnover, and tyrosine metabolism. These findings suggest cell-type-specific metabolic activity and a potential intercellular metabolic interplay. Overall, this workflow offers a broadly accessible and robust approach for investigating metabolic heterogeneity at cellular resolution, enabling insights into metabolic interactions of heterogeneous cell types in both disease and nondisease settings.

DOI: https://doi.org/10.1021/acs.analchem.5c07924
bioRxiv. 2026 Mar 13. pii: 2026.03.12.711193. [Epub ahead of print]

Metabolites from plasma-like medium fuel nitrogen metabolism and influence proliferation in Leptospira interrogans.

Matthew H Ward, Nathan Scherer, Leah P Shriver, Gary J Patti.

Leptospirosis, caused by pathogenic Leptospira spp. such as L. interrogans , is a bacterial zoonosis of increasing prevalence with no consistently effective treatments in severe cases. We sought to characterize metabolic mechanisms that support L. interrogans infection in the host setting, with the ultimate goal of revealing unexplored therapeutic opportunities. We first established and validated a culture medium, which we refer to as supplemented Human Plasma-Like Medium (sHPLM). sHPLM more closely resembles the physiological environment of the human host than standard culture media, such as the EMJH (Ellinghausen-McCullough-Johnson-Harris) medium typically used for Leptospira culture. To better understand bacterial metabolism, we pioneered metabolomics in sHPLM-cultured Leptospira . Specifically, we developed a liquid chromatography mass spectrometry (LC/MS) metabolomics-based workflow for both medium analysis and stable isotope tracing with L. interrogans cultures. The application of these innovations revealed that the amino acid glutamine is a major nitrogen source for L. interrogans . A small-molecule inhibitor blocking glutamine utilization, JHU-083, effectively impaired the proliferation of sHPLM cultures. Further, adding glutamine to non-physiological EMJH medium rapidly induced a short-term proliferative boost in L. interrogans and increased biofilm formation. RNA-sequencing after glutamine exposure revealed transcriptional trends for increases in biosynthesis to support these phenotypes. Although ammonium has long been thought to be the sole nitrogen source for L. interrogans, our results demonstrate that glutamine provides a second source of nitrogen for biosynthesis and may act as a metabolite signal to alter L. interrogans physiology in ways that could influence infection. This work highlights that studying L. interrogans under physiological conditions is key to understanding mechanisms supporting infection and points to nitrogen assimilation as a potential target for therapies.
Author Summary: Leptospirosis is a potentially fatal disease transmitted through water and soil contaminated with pathogenic Leptospira bacteria. Much research is currently focused on the idea that an improved understanding of how Leptospira infects hosts and causes disease may inspire the development of improved therapeutics, which are urgently needed. Focusing on Leptospira interrogans , a clinically important pathogenic species, we determined that conventional growth media are inadequate for understanding how the bacterium behaves when inside hosts. Instead, we designed an optimized formulation to mimic human blood, and we applied an underutilized technique for measuring the biochemical reactions that enable pathogen survival. These two innovations revealed that L. interrogans uses glutamine, an abundant nutrient in host blood and tissues, as a source of nitrogen for the production of biomolecules that are required for replication and infection. This discovery is notable as nitrogen demands were previously thought to be met using ammonium. Treating L. interrogans with inhibitors of both glutamine and ammonium metabolism blocked bacterial replication. We also discovered that L. interrogans increases its growth rate, upregulates its expression of biosynthetic pathways when exposed to glutamine, and increases its formation of biofilm. Our results reveal the importance of glutamine in supporting the lifecycle of leptospirosis-causing bacteria.

DOI: https://doi.org/10.64898/2026.03.12.711193
EJC Suppl. 2026 Mar;17 1-10

Isocitrate dehydrogenase mutations as potential tumour agnostic targets.

Teresa Macarulla, Ghazaleh Tabatabai, Silvia Stacchiotti, John Bridgewater.

  The isocitrate dehydrogenase (IDH) family of proteins comprises three important metabolic enzymes that convert isocitrate to alpha ketoglutarate (α-KG) via oxidative decarboxylation. The IDH enzymes play important roles in epigenetic regulation, DNA repair, and cellular metabolism and biosynthesis. In mutant IDH (mIDH) cells, α-KG is converted into the functional oncometabolite 2-hydroxyglutarate (2-HG) in a process that consumes the reduced form of nicotinamide adenine dinucleotide phosphate to generate its oxidised form. 2-HG competitively inhibits α-KG from binding to the active site of histone and DNA demethylases, leading to hypermethylation, which inhibits cellular differentiation and induces tumour cell proliferation. Increased 2-HG also has other effects on cellular biology, including altered metabolism, dysregulation of gene expression, alterations in the DNA damage repair pathway, inflammation, and cell death, therefore supporting and promoting tumorigenesis. mIDH genes are associated with a variety of cancers, including but not limited to, cholangiocarcinoma, acute myeloid leukaemia, glioma, and chondrosarcoma, and the incidences of mIDH in these cancers varies and is approximately 13%, 33%, 73%, and 56%, respectively. The biological effects of mIDH are distinct in different cancers, but the reason that mIDH promotes tumour development in some tissues and not others is not clear. mIDH has no definitive prognostic impact in these cancers, except glioma, in which it is a disease-defining marker due to its distinct prognostic significance. mIDH1/2 are actionable mutations that represent therapeutic targets, however available targeted therapies to treat mIDH cancers are lacking. This article discusses mIDH genes and their importance in each of these cancers.

Keywords:  2-hydroxyglutarate; AML; Cholangiocarcinoma; Chondrosarcoma; Glioma; Isocitrate dehydrogenase mutation

DOI:  https://doi.org/10.1016/j.ejcsup.2025.12.002
STAR Protoc. 2026 Apr 06. pii: S2666-1667(26)00103-6. [Epub ahead of print]7(2): 104450

Protocol for stable isotope tracing of primary human peripheral blood mononuclear cells.

Samantha N Hart, Holden Williams, William B Inabnet, Joshua P Steiner, Varun Jain, Philip A Kern, Cecily R Wood, Barbara S Nikolajczyk, Lance A Johnson.

  Stable isotope tracing gives direct insight into the rate of metabolic reactions occurring in cells by analyzing the incorporation of labeled carbons into metabolic pathways. Here, we present a protocol for stable isotope tracing of primary human peripheral blood mononuclear cells (PBMCs). We describe the steps for culturing and exposing PBMCs to stable isotopes U13C glucose and U13C glutamine. We then detail procedures for derivatization, metabolite purification, and tracing analysis via single-quadrupole gas chromatography-mass spectrometry (GC-MS).

Keywords:  Immunology; Metabolism; Metabolomics

DOI:  https://doi.org/10.1016/j.xpro.2026.104450
Biochem Biophys Res Commun. 2026 Apr 06. pii: S0006-291X(26)00491-2. [Epub ahead of print]817 153727

Adapting high-resolution respirometry for adherent brain endothelial cells reveals stable and reproducible mitochondrial respiration.

Charul Jain, Akaljot Grewal, Helgi Kuzmychova, Revanti Mukherjee, Ujala Chawla, Versha Banerji, Emma Martell, Tanveer Sharif.

  High-resolution respirometry enables real-time assessment of mitochondrial respiration but remains challenging in human brain endothelial cells (BECs) due to their low basal respiration and high sensitivity to detachment, which can compromise mitochondrial integrity. We established a standardized and reproducible approach for applying Oroboros O2k respirometry to BECs. We optimized detachment and suspension conditions to preserve cell viability and enable stable oxygen consumption measurements and performed systematic titration of the uncoupler, carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), to define maximal respiratory capacity. Under optimized conditions, oxygen flux measurements were stable with low variability, allowing clear resolution of basal respiration, proton leak, and maximal respiratory capacity. FCCP titration demonstrated maximal respiration was achieved at 2 μM concentration indicating sensitive uncoupler response of BEC mitochondria. We validated the approach across independent experiments, obtaining highly consistent bioenergetic profiles with minimal variability, confirming the reliability of the optimized method. Compared with conventional extracellular flux assays, this approach enables continuous oxygen monitoring and flexible sequential titration, providing improved resolution of mitochondrial parameters. Together, this study establishes a validated and reproducible method for high-resolution Oroboros O2k respirometry in human BECs, providing a framework for investigating mitochondrial regulation and bioenergetic alterations in BECs in neurological and cerebrovascular disease.

Keywords:  Bioenergetics; Brain endothelial cells; Cell numbers; Oroboros; Oxygen consumption

DOI:  https://doi.org/10.1016/j.bbrc.2026.153727
Am J Physiol Cell Physiol. 2026 Apr 09.

Cardiometabolic effects of time-restricted eating (tentative).

Asger Maare Søndergaard, Mette Louise Gram Kjærulff, Lars Christian Gormsen, Esben Søndergaard.

  Time-restricted eating (TRE) confines daily caloric intake to 4-10 hours, thereby inducing recurrent fasting intervals of 14-20 hours. TRE alters meal timing without the need for calorie counting and has been proposed as a simple and sustainable dietary intervention with potential metabolic benefits mediated through circadian alignment and increased amount of time spent in the postabsorptive/fasted state. This mini-review summarizes evidence from randomized controlled trials and meta-analysis on cardiometabolic effects of TRE. Studies indicate a modest weight loss compared to ad libitum eating, but with no consistent benefit when compared to caloric restriction. Effects on glycemic control, insulin sensitivity, and lipid profiles are generally small, variable and context dependent. The most consistent finding is a lowering of blood pressure by about 4/2 mmHg. The effects of TRE on cardiac function and perfusion are still mostly unexplored, but a 3-week intervention with alternate-day fasting (~36 hours of fasting) improves myocardial flow reserve and reduces oxygen consumption. In summary, TRE appears to be a feasible dietary intervention, but robust evidence of beneficial effects remains limited. Larger and longer-term studies with clinically relevant cardiometabolic endpoints are needed to determine the clinical efficacy of TRE.

Keywords:  Blood pressure; Insulin sensitivity; Myocardial perfusion; Time-restricted eating; Weight loss

DOI:  https://doi.org/10.1152/ajpcell.00766.2025
Nature. 2026 Apr 08.

Tumour trap: engineered enhancer sequences enlisted to kill cancer cells.

Shi Wing Yeung, Ralf Jauch.



Keywords:  Cancer; Medical research

DOI:  https://doi.org/10.1038/d41586-026-00812-5
Nat Commun. 2026 Apr 06.

Quizartinib and omacetaxine mepesuccinate combination therapy in FLT3-ITD AML: a phase II trial.

Li-Chuan Zheng, Kelvin K W Wong, Stephen S Y Lam, Garret M K Leung, Chenqinyao Li, Kwui-Wa Tong, Wing Lam, Xiao-Yuan Zeng, Koon-Chuen Chan, Natalie Nok-Man Chan, Ka-Lam Ng, Chee-Chean Dang, Tsz-Ho Kwok, Sze-Pui Tsui, Rakesh Sharma, Jason W H Wong, Suet-Yi Leung, Anskar Y H Leung, Cheuk-Him Man.

FLT3-ITD inhibitors are approved for acute myeloid leukemia (AML) treatment but relapse is common. In this study, the combined inhibition of FLT3-ITD signal and protein translation by QUIZartinib and Omacetaxine Mepesuccinate (QUIZOM) synergistically suppressed the most critical FLT3-ITD survival signals including mitochondrial respiration and proteostasis, which induced apoptosis and pro-inflammatory response. In a Phase 2 trial (NCT03135054) involving 40 chemo-refractory/unfit FLT3-ITD AML patients, QUIZOM achieved a composite complete remission (CRc) of 83%, a median leukemia-free survival (LFS) of 10 months (Range: 0.7-68.2 months) and a median overall survival (OS) of 12.9 months (Range: 1.8-69.2 months). 13/33 (39%) received allogeneic HSCT after a median of 143 days (Range: 53-367 days). Higher CRc rates were observed in patients with NPM1 mutations, DNMT3A mutations, and wild-type WT1. Single-cell RNA-sequencing of QUIZOM cohort revealed positive correlation between pro-inflammatory response in blasts, CD8 + T activation and clinical responsiveness. Further, we identified a leukemic stem cell (LSC) subpopulation with activated JNK/JUN/HSPA1B axis via PLD1-driven phosphatidylcholine metabolism, which promoted proteostasis and drove QUIZOM resistance. PLD1-inhibitor remodeled phospholipid metabolism, induced ferroptosis and restored QUIZOM response in LSC. Our findings provided the therapeutic and resistant mechanisms of QUIZOM and paved the way for targeted interventions in this AML subtype.

DOI: https://doi.org/10.1038/s41467-026-71186-5
J Cereb Blood Flow Metab. 2026 Apr 07. 271678X261432989

Brain glucose extraction is fixed at 10% despite twofold variability in resting cerebral blood flow in healthy humans.

Jennifer S Duffy, Hannah G Caldwell, Philip N Ainslie, Travis D Gibbons.

  This commentary addresses the interpretation by Drs. Nybo and Rasmussen of our recent short report examining the interindividual variability in resting human cerebral blood flow (CBF) and metabolism in 75 otherwise healthy adult volunteers. We contend that the authors have mischaracterized the primary objective of the original short report. The objective was to quantify interindividual variability in resting CBF with oxygen and glucose extraction under resting, unstimulated conditions, rather than intraindividual regulatory responses to acute interventions. We highlight that their considerations raised do not invalidate the principal conclusion that lower resting CBF is associated with reduced aerobic glycolysis, possibly due to a greater compensatory capacity of oxygen relative to glucose extraction.

Keywords:  Aerobic glycolysis; arteriovenous; cerebral blood flow; cerebral metabolism; glucose extraction; oxygen extraction

DOI:  https://doi.org/10.1177/0271678X261432989
Nat Metab. 2026 Apr 07.

Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells.

Jennifer A Brain, Anna-Lena B G Vigil, Kristian Davidsen, Ayaha Itokawa, Abby C Jurasin, Hannah J Kerbyson, Maximilian Kobiesa, Madeleine L Hart, Sang Jun Yoon, Peter Bellotti, Juan Pablo Maianti, Gina M DeNicola, Lucas B Sullivan.

Cancer cells with constitutive NRF2 activation take up excess cystine beyond the cysteine demands of conventional pathways, implying unknown metabolic fates. Here, we develop an unbiased approach for the identification of cysteine metabolic fates and find that both known and previously uncharacterized cysteine-derived metabolites accumulate in NRF2-activated cancer cells. We identify many of these unknown metabolites as conjugates formed between cysteine and endogenous sugar metabolites, which can also be generated in vitro. We confirm the presence of these cysteine-derived conjugates in murine lung cancer models and primary human lung cancer samples, and their enrichment in NRF2-activated tumours in each context. Mechanistically, NRF2 promotes cystine uptake by driving SLC7A11 expression, which increases intracellular cysteine levels to promote these cysteine fates in a panel of cancer cell lines. Finally, we show that NRF2 activation creates a sensitivity to high environmental cystine, which impairs cell proliferation through excess free cysteine, and can be mitigated by sequestration into cysteine-derived conjugates. Overall, these findings reveal a cancer-associated metabolic vulnerability to excess cysteine stress, and reveal unrecognized routes of cysteine metabolism.

DOI: https://doi.org/10.1038/s42255-026-01499-8
EJC Suppl. 2026 Mar;17 11-19

Clinical advancement in the management of mutant isocitrate dehydrogenase (IDH) cancers.

John Bridgewater, Ghazaleh Tabatabai, Teresa Macarulla, Silvia Stacchiotti.

  The use of mutant isocitrate dehydrogenase (mIDH) inhibitors has been investigated and has shown significant improvement in survival outcomes in patients with a range of mIDH cancers, including acute myeloid leukaemia (AML), cholangiocarcinoma (CCA), glioma and conventional chondrosarcoma. In the phase 3 clinical trial ClarIDHy, patients with mIDH1 CCA treated with ivosidenib had improved overall survival (OS) compared to those treated with placebo (hazard ratio [HR]: 0.79 [95% confidence interval [CI]: 0.56-1.12]; P=0.09). In the phase 3 AGILE study, patients with mIDH1 AML treated with ivosidenib plus azacitidine showed improved OS compared to those treated with placebo plus azacitidine (HR: 0.42 [95% CI: 0.27-0.73]; P=0.001). In conventional chondrosarcoma, ivosidenib demonstrated efficacy in a phase 1 trial and the ongoing phase 3, placebo-controlled clinical trial CHONQUER will investigate the use of ivosidenib in patients with unresectable, progressive, conventional mIDH1 chondrosarcoma. The phase 3 clinical trial INDIGO explored the use of vorasidenib for the treatment of Central Nervous System World Health Organization grade 2 mIDH glioma and showed that vorasidenib had a progression-free survival benefit over placebo in previously untreated patients (HR: 0.39 [95% CI: 0.27-0.56]; P<0.0001). Across these studies, mIDH inhibitors were well-tolerated. Current efforts focus on further evaluating the efficacy and safety of mIDH inhibitors in different lines of therapy, in combination with other anti-neoplastic agents, and in other mIDH cancers.

Keywords:  Acute myeloid leukaemia; Cholangiocarcinoma; Chondrosarcoma; Glioma; Isocitrate dehydrogenase; Ivosidenib; Vorasidenib

DOI:  https://doi.org/10.1016/j.ejcsup.2025.12.001