bims-medica 2026-04-26 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–04–26
29 papers selected by
Brett Chrest, Wake Forest University

A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.
Mitochondrial respiration supports cancer growth independent of OXPHOS.
Benefits and adverse effects of ketogenic diet treatment in pediatric patients with inborn errors of metabolism.
Diet-Induced Hepatic and Mitochondrial Lipid Remodeling Engages One-Carbon Metabolism Under Preserved Mitochondrial Function.
Targeting nucleotide metabolism and epigenetic regulation to overcome the differentiation blockade in AML.
Patterns of mitochondrial ATP predict tissue folding.
A Flawed Conjecture Keeps Haunting Brain Energy Metabolism Research.
Efficacy and safety of ketogenic diet in glioblastoma: an updated systematic review and meta-analysis.
Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells.
D- and L-lactate dehydrogenase reactions increase pH to lactate production and decrease pH to pyruvate production.
Vitamin B12 improves skeletal muscle mitochondrial biology in aged mice.
Polyploid cancer cells surviving cisplatin reallocate central carbon sources to fuel antioxidant metabolism for survival.
Seven-day Venetoclax Combined With Dose-adjusted Intensive Chemotherapy as Induction Treatment in Newly Diagnosed Acute Myeloid Leukemia.
Fast & fuelious: the malate-aspartate shuttle in brown adipocyte lipid metabolism.
Not guilty by association: myelodysplasia-related mutations in AML.
Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.
Suppression of UCP2 alleviates leukemogenesis by enhancing branched-chain amino acids-induced oxidative stress via activating the PI3K/AKT/mTOR signaling pathway.
LDHA-driven ACAA2 lactylation at K270 reprograms fatty acid metabolism to promote clear cell renal cell carcinoma progression.
A cell-nonautonomous heme acquisition pathway enables erythroid hemoglobinization under stress.
SPC25 promotes gastric cancer cells G1/S cell cycle transition and tumorigenesis by enhancing SLC1A5-mediated glutamine metabolism.
Inhibiting muscle myosin super‑relaxation as a futile ATP cycle: a promising but narrow avenue for weight loss.
An optimized protocol for metabolic measurement in 3D tumor spheroids derived from primary and established glioblastoma cells.
Plasma serine and glycine in relation to clinical outcomes following neoadjuvant radiotherapy for rectal cancer.
Engineering of the glucose uptake system to increase 2,4-Dihydroxybutyric acid production in Escherichia coli.
Improving Knowledge and Care of Patients with AML: The Need to Get Out of Our Comfort Zone.
One size does not fit all: An in vitro evaluation of the effects of bezafibrate and medroxyprogesterone acetate on human SH-SY5Y and U-87 MG cancer cells.
Discovery of a Highly Potent and Selective ENL Degrader.
Phase 1 Trial of BCL-2 Inhibitor Lisaftoclax (APG-2575) in Chinese Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Other Non-Hodgkin Lymphomas.
Metabolic advances in 2025: from clinical breakthroughs to molecular reprogramming.

Cell Rep Med. 2026 Apr 23. pii: S2666-3791(26)00187-4. [Epub ahead of print] 102770

A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.

Omid Hajihassani, Asael Roichman, Jacob A Boyer, Michal MacArthur, Ricardo Cordova, Alexander Loftus, Christina S Boutros, Jonathan J Hue, Parnian Naji, Soubhi Tahhan, Peter Gallagher, William Beegan, Danyal Shah, James Choi, Nimat Manzoor, Shihong Lei, Christine Kim, Moeez Rathore, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Craig Hunter, Mehrdad Zarei, Sydney Alibeckoff, Karen Ji, Hallie Graor, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengraber, Rui Wang, Peder J Lund, Luke D Rothermel, Joshua D Rabinowitz, Jordan M Winter.

  Pancreatic cancer is the third leading cause of cancer-related death in the United States. Current chemotherapy options provide limited benefits. Emerging evidence suggests that a ketogenic diet (KD) exerts anti-tumor effects by reprogramming tumor metabolism and revealing therapeutic vulnerabilities. Efforts to target glutamine metabolism-an essential pathway in many cancers-have shown promise in preclinical models, but clinical efficacy has remained limited. Here, we show that a KD increases tricarboxylic acid (TCA) cycle activity and elevates reliance on glutamine-related metabolites in murine pancreatic cancer models and in vitro under KD-mimicking conditions. This metabolic adaptation occurs in response to reduced glucose availability. We demonstrate that combining glutamine metabolism inhibitors, such as CB-839 or 6-diazo-5-oxo-L-norleucine (DON), with a KD leads to robust anti-tumor effects in preclinical models of pancreatic cancer. Thus, metabolic vulnerability induced by dietary intervention provides a rationale for combining glutamine-targeted therapies with a ketogenic diet in future clinical studies.

Keywords:  PDAC nutrient flux; chemotherapy; combination therapy; glutamine metabolism; glutamine tracing; ketogenic diet; ketogenic diet media; pancreatic cancer; targeted therapy

DOI:  https://doi.org/10.1016/j.xcrm.2026.102770
Biochim Biophys Acta Rev Cancer. 2026 Apr 17. pii: S0304-419X(26)00065-X. [Epub ahead of print] 189593

Mitochondrial respiration supports cancer growth independent of OXPHOS.

Christos Chinopoulos.

  Oxidative phosphorylation is a coordinated process yielding ATP, yet its constituent modules can operate autonomously and support oxygen-dependent, non-OXPHOS reactions that serve cellular proliferation, including neoplasia. Furthermore, even with oxygen present and ETC active, ATP synthesis requires surpassing defined thresholds; thus, respiration is not equivalent to phosphorylation. This review surveys mitochondrial pathways that use the ETC with oxygen as the terminal electron acceptor yet decouple respiration from ATP synthesis. These pathways support tumor progression by sustaining mechanistically distinct respiration-supported currencies, states, and signals, including oxidized coenzyme Q, matrix NAD+, mitochondrial membrane potential, transhydrogenase-derived NADPH, the downstream oxidizing capacity of the CIII-cytochrome c-CIV segment, and ROS as context-dependent outputs. These determinants shape de novo purine and pyrimidine biosynthesis, one‑carbon metabolism, shuttling of reducing equivalents, heme and FeS biogenesis, and proline, choline, and sulfide metabolism, revealing targetable nodes in the respiratory redox network. Therapeutic progress is expected from interventions that collapse the underlying infrastructure - particularly at the coenzyme Q-junction and the CIII-cytochrome c-CIV segment - rather than from strategies aimed solely at ATP deprivation.

Keywords:  Metabolic rewiring; Nucleotide biosynthesis; Oncometabolism; One‑carbon metabolism; Redox homeostasis; Respiratory chain; Tumor metabolism; Ubiquinone; electron transport chain

DOI:  https://doi.org/10.1016/j.bbcan.2026.189593
Adv Clin Exp Med. 2026 Apr 21.

Benefits and adverse effects of ketogenic diet treatment in pediatric patients with inborn errors of metabolism.

Dorota Wesół-Kucharska, Magdalena Alicja Kaczor, Ewa Ehmke Vel Emczyńska-Seliga.

   BACKGROUND: The ketogenic diet (KD) is an established therapeutic option for epilepsy and selected inborn errors of metabolism (IEMs), particularly glucose transporter type 1 deficiency (GLUT1D) and pyruvate dehydrogenase complex deficiency (PDCD). Increasing evidence suggests broader applications of KD in pediatric metabolic disorders; however, data on its safety and efficacy in heterogeneous IEM populations remain limited.
OBJECTIVES: To evaluate the efficacy, clinical benefits, and adverse effects (AEs) of KD in pediatric patients with various IEMs.
MATERIAL AND METHODS: A retrospective analysis was conducted in pediatric patients with IEMs receiving KD treatment. Patients were categorized into 3 groups: 1) other IEMs (n = 7), 2) mitochondrial diseases (MD) (n = 17), and 3) GLUT1D and PDCD (n = 20). The median age at initiation of KD was 37, 53, and 53 months, respectively, and the median duration of KD treatment was 5, 11, and 55 months in groups 1, 2, and 3.
RESULTS: The KD was associated with clinical benefits in 84% of patients. Among children with epilepsy (n = 23), a seizure reduction of >50% was observed in 73.9% of patients, including complete seizure freedom in 4 individuals. Improvements were also noted in muscle tone (27.6%), exercise tolerance (51.2%), ataxia (83.3%), and involuntary movements (60%). Lactate levels decreased in 84.6% of patients with mitochondrial disease and in all patients with PDCD. The KD was discontinued in 12 patients due to insufficient efficacy (n = 5) or AEs (AEs; n = 7). The most common AEs included gastrointestinal (GI) symptoms, dyslipidemia, hyperuricemia, metabolic acidosis, and decreased free carnitine; most were transient. No significant association was found between median β-hydroxybutyrate (BHB) levels and clinical outcomes.
CONCLUSIONS: The KD is an effective and generally well-tolerated therapeutic option in pediatric IEMs, with benefits extending beyond seizure control. Adverse effects are typically manageable, although GI intolerance may limit long-term use. Ketogenic diet should be considered not only for refractory epilepsy but also for selected metabolic indications.

Keywords:  epilepsy; inborn errors of metabolism; ketogenic diet; mitochondrial diseases; pediatric metabolic disorders

DOI:  https://doi.org/10.17219/acem/219994
Free Radic Biol Med. 2026 Apr 21. pii: S0891-5849(26)00321-7. [Epub ahead of print]

Diet-Induced Hepatic and Mitochondrial Lipid Remodeling Engages One-Carbon Metabolism Under Preserved Mitochondrial Function.

Fabrizia Carli, Sara Guerra, Ines Mateus, Riccardo Ducoli, Silvia Sabatini, Samantha Pezzica, Egeria Scoditti, Caroline Dewalle, Véronique Lenoir, Carina Prip-Buus, Amalia Gastaldelli.

   BACKGROUND: Diets rich in saturated fat and sugar drive hepatic steatosis, yet their impact on mitochondrial lipid composition and function remains poorly understood. We investigated how steatotic diets reprogram phospholipid synthesis, remodel the hepatic mitochondrial lipidome, and affect mitochondrial energy metabolism.
METHODS: Mice were fed a high-fat/high-sucrose (HFHS) diet for 20 weeks alongside controls. Lipidomics, metabolomics and metabolic flux analysis using deuterated water (2H2O) were performed via high-resolution mass spectrometry in plasma, liver, and isolated hepatic mitochondria. Mitochondrial respiration was assessed via high-resolution respirometry (OROBOROS). A second cohort was fed a methionine choline-deficient (MCD) diet as a model of altered one-carbon metabolism.
RESULTS: HFHS feeding caused marked hepatic lipid accumulation and extensive remodeling of plasma, liver, and mitochondrial lipidomes, including reduced synthesis of select phosphatidylcholines (PCs). Mitochondrial PCs concentrations were tightly linked to dietary modulation of one-carbon metabolism, which governs PC biosynthesis via methylation. Despite these changes, the mitochondrial PC/PE ratio remained stable and mitochondrial respiration and energy metabolism were preserved. To further evaluate the role of one-carbon metabolism in mitochondrial PC, we evaluated changes during MCD feeding. MCD reduced total mitochondrial lipids, particularly PC and PE synthesis and the mitochondrial PC/PE ratio. Remarkably, mitochondrial function remained intact in both dietary conditions.
CONCLUSION: Steatotic and PC-depleting diets induce substantial remodeling of mitochondrial phospholipids without compromising mitochondrial respiratory capacity. These findings highlight the central role of one-carbon metabolism as a key regulator of mitochondrial membrane homeostasis and underscore the adaptive resilience of mitochondria under dietary and pro-fibrotic stress.

Keywords:  Fluxomics; Hepatic Lipid Remodeling; MASLD Models; Mitochondrial Function; One-Carbon Metabolism

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.031
Leuk Res Rep. 2026 ;25 100586

Targeting nucleotide metabolism and epigenetic regulation to overcome the differentiation blockade in AML.

Shinichiro Takahashi.

  Differentiation blockade is a central pathogenic hallmark of acute myeloid leukemia (AML). While all-trans retinoic acid (ATRA) achieves curative differentiation in acute promyelocytic leukemia (APL), this success has not extended to other AML subtypes. Recently, inhibitors targeting nucleotide metabolism-such as cytarabine, dihydroorotate dehydrogenase (DHODH) inhibitors, and DNA hypomethylating agents-have emerged as promising candidates to overcome this therapeutic barrier. These compounds promote myeloid maturation through mechanisms involving cell-cycle arrest, epigenetic reprogramming, and replication stress-activated signaling. Preclinical and early clinical evidence suggests that targeting nucleotide metabolism may induce partial differentiation of leukemic blasts, providing a metabolic and epigenetic avenue for therapy beyond APL. This mini-review summarizes current understanding of how metabolic inhibition restores differentiation in AML, focusing on representative agents and their mechanistic and translational implications. Targeting de novo nucleotide biosynthesis may offer a metabolic and epigenetic route to expand differentiation-based strategies beyond APL.

Keywords:  AML; DHODH inhibitors; De novo nucleotide biosynthesis; Differentiation therapy; Hypomethylating agents

DOI:  https://doi.org/10.1016/j.lrr.2026.100586
Sci Adv. 2026 Apr 24. 12(17): eaee6175

Patterns of mitochondrial ATP predict tissue folding.

Bezia Lemma, Megan Rothstein, Pengfei Zhang, Bridget Waas, Marcus Kilwein, Safiya Topiwala, Sherry X Zhang, Anvitha Sudhakar, Katharine Goodwin, Elizabeth R Gavis, Ricardo Mallarino, Andrej Kosmrlj, Celeste M Nelson.

The construction of tissue shapes during embryonic development results from patterns of gene expression and mechanical forces fueled by chemical energy from ATP hydrolysis. We find that chemical energy is similarly patterned during apical constriction, which is widely used across the animal kingdom to fold epithelial tissues. Time-lapse imaging, spatial transcriptomics, and measurements of oxygen consumption rate reveal that mitochondrial density, potential, and ATP increase at the apical side of epithelial cells before actomyosin contraction and tissue folding, which is prevented by inhibiting oxidative phosphorylation. Mitochondrial enrichment and apical bias are conserved during apical constriction in flies, chicks, and mice, and these patterns can be used to predict computationally patterns of tissue folding. These findings highlight a spatial dimension of bioenergetics in development.

DOI: https://doi.org/10.1126/sciadv.aee6175
NeuroSci. 2026 Apr 22. pii: 49. [Epub ahead of print]7(3):

A Flawed Conjecture Keeps Haunting Brain Energy Metabolism Research.

Avital Schurr.

  In 1988, two seminal studies were published almost simultaneously in the same scientific journal. Both spurred the field of brain energy metabolism research in new directions, culminating in a long-lasting debate that appeared to split its practitioners into two factions that seem unwilling to agree on what metabolic processes are fueling the active brain with adenosine triphosphate (ATP). The first study used rat hippocampal slices to demonstrate the ability of lactate to support neuronal function as the sole oxidative mitochondrial substrate. The second study demonstrated that upon brain stimulation, glucose consumption is not accompanied by respective oxygen consumption, but a non-oxidative glucose utilization or what has become known as "aerobic glycolysis". Consequently, for almost four decades, researchers in this field have been divided between those who profess that brain activity is supported by oxidative lactate metabolism and those who insist that non-oxidative glucose metabolism supports it. Hypotheses for both concepts were offered, "The Astrocyte Neuron Lactate Shuttle Hypothesis" and "The Efficiency Tradeoff Hypothesis," respectively. To bridge the gap between the two groups, a recent editorial, authored by over twenty leading investigators, was published. The editorial received two separate responses from investigators who supported the non-oxidative glucose consumption as the main process supporting neural activity, signaling that the gap between the two groups remained. The present perspective highlights the principal disagreements that divide this utmost important field of research. It argues that the main reason for these disagreements is rooted in the assumption that pyruvate is the end-product of aerobic glycolysis, even when many among those who adhere to this assumption accept that in the active brain glycolysis is the main provider of the necessary ATP and the end-product is lactate under aerobic conditions. The consideration of a paradigm shift, according to which lactate is the real end-product of glycolysis, independent of the presence or absence of oxygen, could bridge the great divide between those who separate glycolysis into two outcomes and those who profess that there is only one, prefix-less glycolytic pathway that always ends with the production of lactate.

Keywords:  TCA cycle; active brain; energy metabolism; glucose; glycolysis; lactate; oxidative phosphorylation; pyruvate

DOI:  https://doi.org/10.3390/neurosci7030049
Neurol Sci. 2026 Apr 25. pii: 461. [Epub ahead of print]47(5):

Efficacy and safety of ketogenic diet in glioblastoma: an updated systematic review and meta-analysis.

Jawaria Firdous, Abdul Eizad Asif, Hafiz Muhammad Haris, Uzair Iqbal, Muddassir Khalid, Hafiza Fatima Zahid, Moosa Mubarika, Iman Osman Abufatima, Mohammed Hammad Jaber Amin, Sadia Hafeez, Farha Jabeen, Muhammad Shahzaib, Noor Fatima, Nikil Kumar, Shuvendu Sen, Anid Hassan.



Keywords:  Fasting; Glioblastoma; Glioma; Ketogenic diet; Ketosis

DOI:  https://doi.org/10.1007/s10072-026-09035-y
Cell Death Discov. 2026 Apr 24.

Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells.

Alojzija Brcic, Hrvoje Lalic, Tomislav Smoljo, Klara Bardač, Vilma Dembitz, Romana Penker, Giovanny Rodriguez Blanco, Antonio Bedalov, Dora Visnjic.

Differentiation therapy offers a promising approach in acute myeloid leukemia (AML) by overcoming the developmental block that maintains leukemic blasts. Increasing evidence indicates that DNA replication stress can promote differentiation rather than cytotoxicity; however, the metabolic mechanisms linking replication stress to differentiation remain poorly defined. Here, we investigated how perturbations in nucleotide metabolism regulate replication stress-driven differentiation. Using metabolomic and functional analyses in AML cell lines, we show that agents inducing differentiation through replication stress, including 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), dihydroorotate dehydrogenase (DHODH) inhibition, and low-dose cytarabine, converge on disruption of nucleotide pool balance. Low-dose AICAr induced a pyrimidine-purine imbalance, S phase arrest, and enhanced differentiation, whereas high-dose reduced these effects. Although brequinar and cytarabine altered nucleotide metabolism through distinct mechanisms, differentiation induced by all agents was abolished by supplementation with high levels of ribo- and deoxyribonucleosides, confirming that nucleotide imbalance is a central driver. We further identify ribonucleotide reductase (RNR) as a critical modulator of this process. Replication stress induced context-dependent regulation of RNR subunits, with RRM2 upregulated in p53-mutant U937 cells and the p53-responsive RRM2B isoform predominating in p53-wild-type MOLM-13 cells. Consistent with these differences, RRM2 depletion enhanced differentiation in U937 cells without affecting viability but impaired differentiation and survival in MOLM-13 cells. These findings position nucleotide metabolism as a key regulator of AML differentiation and suggest that combining RNR-targeted and checkpoint-modulating strategies could optimize therapeutic responses.

DOI: https://doi.org/10.1038/s41420-026-03105-y
Front Mol Biosci. 2026 ;13 1715499

D- and L-lactate dehydrogenase reactions increase pH to lactate production and decrease pH to pyruvate production.

Robert Robergs, Marek Nalos, Petr Kelbich, Adela Jizerová, Ivana Mervartová, Michal Vostrý, Milan Štengl, Vaclav Babuška.

   Background: The traditional explanation of metabolic acidosis in extrahepatic tissues is the increased cellular production of lactic acid. We tested whether the LDH reaction produces lactate and pyruvate anions, or acids, and measured the pH changes that occur for either direction of the reaction.
Methods: In-vitro reagents (25-40 mL) of the D- and L-LDH reaction were prepared for lactate and pyruvate production at known substrate concentrations ([Substrate]), no added H+ buffers, at ∼25 °C. The pH of the reagent was measured using a glass polymer pH electrode. The initial reagent pH was adjusted to a target pH value by addition of HCl or KOH (0.02-0.1 N). The baseline pH was recorded for 2 min, followed by the addition of LDH. The pH response was recorded continuously at varied intervals for 20 min. Reagent samples (100-200 μL) were obtained intermittently for measurements of product.
Results: The H+ consumption of pyruvate reduction to lactate increased pH (6.3-10.5), and the H+ release of lactate oxidation to pyruvate decreased pH (8.8-6.9). The [Product] was small for all [Substrate] and LDH activity conditions (∼0.3 - 0.8 mmol·L-1), and lowest for pyruvate production. The pH and [Product] results were similar for both D- and L-LDH reactions. The pH to [Product] profiles for lactate vs. pyruvate equated to 9.215 vs. -9.074 pH units·mmol-1·L-1, respectively.
Conclusion: Scientists and clinicians are encouraged to use these results to further understand the function of the LDH reaction during perturbations of pH in biological systems.

Keywords:  acidosis; alkalosis; enzyme catalysis; metabolism; spectrophotometry

DOI:  https://doi.org/10.3389/fmolb.2026.1715499
Geroscience. 2026 Apr 24.

Vitamin B12 improves skeletal muscle mitochondrial biology in aged mice.

Abigail R Williamson, Angad Yadav, Wenxia Ma, Susan Schmitt, Shelby Rorrer, Lauren E Odom, Luisa F Castillo, Chloe T Purello, Olga V Malysheva, James Mobley, Martha Field, Anna E Thalacker-Mercer.

  Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced age, has not been examined. Thus, the impact of B12 supplementation on skeletal muscle mitochondrial biology was examined in aged female mice, given 12 weeks of B12 supplementation (SUPP) or vehicle control. In the mouse model, mitochondrial DNA and content were measured with PCR and citrate synthase activity, respectively; mitochondrial morphology was examined using transmission electron microscopy; mitochondrial function was examined using extracellular metabolic flux analysis; and proteins and pathway enrichment was identified with proteomics. The results demonstrated that SUPP in aged mice increased muscle mitochondrial content and improved morphology. Further, differentially expressed proteins were enriched in TCA cycle, OXPHOS, and oxidative stress pathways. This is the first study, to our knowledge, examining the impact of B12 supplementation on skeletal muscle mitochondrial biology in aged female mice. Results suggest that B12 supplementation improves mitochondrial biology in aged female mice.

Keywords:  Aging; Mitochondria; Sarcopenia; Skeletal muscle; Vitamin B12

DOI:  https://doi.org/10.1007/s11357-026-02264-1
Mol Metab. 2026 Apr 18. pii: S2212-8778(26)00054-2. [Epub ahead of print] 102370

Polyploid cancer cells surviving cisplatin reallocate central carbon sources to fuel antioxidant metabolism for survival.

Melvin Li, Bradley Priem, Luke V Loftus, Michael J Betenbaugh, Kenneth J Pienta, Sarah R Amend.

  Therapy resistance is the leading cause of cancer-related deaths. Polyploid cancer cells mediate resistance through adaptive cell states transitions that promote survival and tumor recurrence. Here, we investigate metabolic differences between cisplatin-surviving polyploid cells and parental cancer cells using integrated fluxomics. Transcriptomic and proteomic profiling and extracellular flux analyses revealed that surviving cells upregulate glycolysis and gluconeogenesis while reducing oxidative phosphorylation, indicating a shift in central carbon metabolism. Isotope tracing and metabolic modeling demonstrate that surviving cells utilize glucose to fuel the pentose phosphate pathway (PPP) for NADPH generation and metabolize glutamine to provide carbons for the PPP via gluconeogenesis. Integrating our multi-omic datasets into a genome-scale model identified that surviving cells sustain antioxidant metabolism by decreasing fluxes of other NADPH-consuming reactions upon in silico PPP knockout. In addition, pathway-centric transcriptomic analysis revealed that high PPP and antioxidant gene expression correlated with poor survival outcomes in patients across multiple cancer types, demonstrating the clinical prognostic value of PPP and antioxidant metabolism. These findings reveal a systems-level shift in metabolism that maintains antioxidant activity for cell survival, highlighting potential targets and treatment paradigms to overcome therapy resistance.

Keywords:  (13)C-metabolic flux analysis; Cancer metabolism; Chemotherapy resistance; Genome scale metabolic modeling; Integrated fluxomics

DOI:  https://doi.org/10.1016/j.molmet.2026.102370
Clin Lymphoma Myeloma Leuk. 2026 Mar 27. pii: S2152-2650(26)00094-7. [Epub ahead of print]

Seven-day Venetoclax Combined With Dose-adjusted Intensive Chemotherapy as Induction Treatment in Newly Diagnosed Acute Myeloid Leukemia.

Ting Liu, Xingli Zhao, Xiaohui Suo, Guanchen Bai, Yanliang Bai, Weihua Zhao, Hongling Peng, Fang Zheng, Dongmei Wang, Liyun Zhao, Jie Liu, Ling Li, Xinxiao Lu, Congcong Zhang, Sifeng Gao, Zeyan Shi, Yunya Luo, Xuemei Zhao, Yaxian Tan, Zeping Zhou, Pengxiang Guo, Yingchang Mi, Kaiqi Liu.

  While venetoclax (VEN) combined with intensive chemotherapy (IC) has demonstrated efficacy in newly diagnosed acute myeloid leukemia (AML), the optimal duration of VEN administration remains uncertain, leading to variability in its application during induction therapy. Herein, we reported the data of 259 ND AML patients who received 7-day VEN combined with dose-adjusted IC (DA, HAA, or HAD) as induction treatment, to further validate the efficacy and explore the safety of this combination. This study evaluated a truncated 7-day VEN regimen combined with dose-adjusted IC (DA, HAA, or HAD) as induction therapy. The patients included in this study were derived from 2 clinical trials (VEN+DA: ChiCTR2200061524; VEN+HAA: NCT05893472) and 1 retrospective study (VEN+HAD). All induction regimens include a 7-day oral administration of VEN, in combination with either DA, HAA, or HAD regimen. The composite complete remission rate was 90.3%, with a minimal residual disease (MRD) negativity rate of 92.2% as assessed by flow cytometry. After a median follow-up of 18 months, the median overall survival and event-free survival (EFS) were not reached. The estimated 24-month OS, EFS, and relapse-free survival (RFS) rates for the entire cohort were 72.9%, 69.3%, and 70.2%, respectively. No significant differences in survival outcomes were observed among the 3 treatment regimens (OS: P = .68; EFS: P = .73; RFS: P = .34). The median time of the absolute neutrophil count recovered to≥ 0.5 × 109/L and the platelet count to≥ 30 × 109/L after induction therapy was 14 (range: 5-52) days and 13 (range: 4-63) days, respectively. In conclusion, a 7-day VEN schedule maintains high efficacy while potentially reducing myelosuppressive risks of longer regimens.

Keywords:  AML; Induction Treatment; Intensive chemotherapy; Untreated; VEN

DOI:  https://doi.org/10.1016/j.clml.2026.03.017
FEBS J. 2026 Apr 24.

Fast & fuelious: the malate-aspartate shuttle in brown adipocyte lipid metabolism.

Lukas Blaas, Alexander Bartelt.

  Brown adipose tissue (BAT) produces heat in response to cold exposure, for which it relies on the coordination of aerobic and anaerobic metabolism. However, how reaction intermediates connect these two essential pathways is unclear. In this issue of The FEBS Journal, Veliova et al., report that the malate-aspartate shuttle (MAS) supports norepinephrine-induced lipolysis in brown adipocytes. Disruption of MAS during adrenergic activation impairs lipolysis without reducing respiration. These findings indicate that cytosolic redox balance influences thermogenic metabolism. By linking NAD+ regeneration to lipid metabolism, the study highlights the MAS as an important node coordinating metabolism, redox balance, and thermogenesis.

Keywords:  brown adipose tissue; lipid mobilization; malate–aspartate shuttle; metabolic redox balance; thermogenesis

DOI:  https://doi.org/10.1111/febs.70557
Leukemia. 2026 Apr 22.

Not guilty by association: myelodysplasia-related mutations in AML.

Sangeetha Venugopal, Mikkael A Sekeres.

DOI: https://doi.org/10.1038/s41375-026-02936-z
Redox Biol. 2026 Apr 14. pii: S2213-2317(26)00164-3. [Epub ahead of print]93 104166

Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.

Patrícia Coelho, Pedro Dionísio, Vilma Sardão Oliveira, Roberto A Dias, Matthias E Futschik, Robin Klemm, Ira Milosevic, Nuno Raimundo.

  Mitochondria and peroxisomes communicate to maintain lipid homeostasis, but how the latter adjust to mitochondrial dysfunction remains unclear. Here, we show that loss of complex I subunit NDUFS4 in mouse fibroblasts leads to impaired mitochondrial fatty acid oxidation, resulting in the accumulation of triacylglycerol and lipid droplet (LD) expansion. In this context, peroxisomal biogenesis is upregulated, but their β-oxidation capacity is impaired, suggesting an adaptive yet ineffective response. Additionally, lipid overload using a very-long-chain fatty acid (VLCFA) leads to peroxisomal proliferation but prevents LD expansion when peroxisomal β-oxidation is compromised. The data demonstrated that proper peroxisomal processing is necessary for lipid storage under mitochondrial stress conditions. Our findings reveal a peroxisomal maladaptive remodelling response that fails to compensate for mitochondrial dysfunction, leading to disruptions in LD homeostasis. We propose a critical axis involving peroxisomes-LD-mitochondria that buffers metabolic stress in mitochondrial diseases.

Keywords:  Complex I dysfunction; Lipid homeostasis; Mitochondria-peroxisome crosstalk; NDUFS4-KO; Peroxisomes

DOI:  https://doi.org/10.1016/j.redox.2026.104166
Genes Dis. 2026 Jul;13(4): 101794

Suppression of UCP2 alleviates leukemogenesis by enhancing branched-chain amino acids-induced oxidative stress via activating the PI3K/AKT/mTOR signaling pathway.

Agida Okohi Innocent, Yajie Shen, Yixuan Gao, Ruixin Sun, Kasimujiang Aximujiang, Zizhen Xu, Jinke Cheng, Jiao Ma.

  Although the cellular role of uncoupling protein 2 (UCP2) in tumorigenesis has been reported in various solid tumor models, its role in leukemogenesis remains elusive. Herein, we demonstrated that UCP2 was highly expressed in AML and significantly associated with poor prognosis and chemoresistance, suggesting that UCP2 can be used as a potential biomarker in acute myeloid leukemia. Mechanistically, in vitro and in vivo silencing of UCP2 significantly impairs acute myeloid leukemia cell growth and survival, accompanied by the disruption of mitochondrial homeostasis. Interestingly, RNA-sequencing analysis and metabolic mass spectrometry revealed that silencing UCP2 resulted in accumulated branched-chain amino acids (BCAAs), which induced oxidative stress through the PI3K/AKT/mTOR signaling pathway. Additionally, the lack of BCAAs restored leukemic cell growth and survival and decreased mitochondrial ROS production induced by inhibiting UCP2. More importantly, supplementation of BCAA enhanced the anti-tumor activity of genipin, a selective inhibitor that targets UCP2, resulting in significantly reduced acute myeloid leukemia blasts, increased mouse survival, and magnified oxidative stress. Taken together, our study elucidates the rationale of targeting the UCP2-BCAA-PI3K/AKT/mTOR signaling axis in leukemogenesis and provides a novel strategy for leveraging the metabolic dependencies of leukemic cells.

Keywords:  AML branched-chain amino acids; Leukemogenesis; Oxidative stress; PI3K/AKT/mTORsignaling; UCP2

DOI:  https://doi.org/10.1016/j.gendis.2025.101794
Sci Rep. 2026 Apr 20.

LDHA-driven ACAA2 lactylation at K270 reprograms fatty acid metabolism to promote clear cell renal cell carcinoma progression.

Yong Chen, Yaqian Wang, Xiaoyuan Ning, Jiayun Xu.



Keywords:  acetyl CoA acyltransferase 2; clear cell renal cell carcinoma; free fatty acid; lactate dehydrogenase A; lactylation

DOI:  https://doi.org/10.1038/s41598-026-46158-w
Science. 2026 Apr 23. 392(6796): 388-394

A cell-nonautonomous heme acquisition pathway enables erythroid hemoglobinization under stress.

Audrey Belot, Andrew Rock, Sohini Dutt, Gia Haemmerle, Amaury Maros, Xiaojing Yuan, Satoru Otsuru, David Bodine, Iqbal Hamza.

Heme, an iron-containing cofactor, is synthesized in mitochondria by an eight-enzyme pathway. Although cells were thought to manage heme autonomously, more than 1000 proteins contribute to its production, transport, and regulation. During terminal erythroid differentiation, mitochondria are discarded, yet hemoglobin production continues, which implies a cell-nonautonomous heme supply. We show that, under stress, erythroblasts import heme through the permease heme-responsive gene 1 (HRG1), which localizes to the plasma membrane and accumulates during stress erythropoiesis, the emergency program that expands red cell output. HRG1 loss impaired heme uptake, inhibited terminal erythroid differentiation, and caused anemia. In β-thalassemic mice, partial HRG1 loss reduces ineffective erythropoiesis, underscoring the importance of balanced heme import. These findings reveal intercellular heme sharing and identify HRG1 as a potential therapeutic target in hemoglobinopathies.

DOI: https://doi.org/10.1126/science.aea0552
J Bioenerg Biomembr. 2026 Apr 20. pii: 8. [Epub ahead of print]58(1):

SPC25 promotes gastric cancer cells G1/S cell cycle transition and tumorigenesis by enhancing SLC1A5-mediated glutamine metabolism.

Xinqi Yao, Jie Wu, Yu Song, Hao Shen.



Keywords:  IGF2BP2; SLC1A5; SPC25; gastric cancer; glutamine metabolism; m6A

DOI:  https://doi.org/10.1007/s10863-026-10108-y
J Physiol. 2026 Apr 22.

Inhibiting muscle myosin super‑relaxation as a futile ATP cycle: a promising but narrow avenue for weight loss.

Julien Ochala.



Keywords:  heart; myosin; obesity; skeletal muscle; weight loss

DOI:  https://doi.org/10.1113/JP291232
PLoS One. 2026 ;21(4): e0347569

An optimized protocol for metabolic measurement in 3D tumor spheroids derived from primary and established glioblastoma cells.

Samiya Al-Robaiy, Urszula Hohmann, Andreas Simm, Faramarz Dehghani, Julian Prell, Christian Strauss, Tim Hohmann.

Tumors are characterized by a multitude of genetic and epigenetic alterations, including a deregulation of the metabolism, driving migration and infiltration. To mimic the energetic landscape of in vivo tumors, 3D models surpass traditional 2D cultures, by introducing regions of different nutrient and oxygen supply. Yet, the analysis of metabolic processes in 3D cultures, including the mitochondrial answer and extracellular fluxes is more challenging. The extracellular flux analyzer is a powerful tool for investigating cellular metabolism, offering valuable insights that can drive advancements in biomedical research, but protocols for analysis of 3D cultures are sparse. Here, we present a protocol for optimized extracellular flux analysis, starting from the choice of the 3D culture model, dependencies on 3D culture size and testing multiple normalization approaches for two different glioblastoma and two primary cell lines. It was demonstrated that our approach was feasible for different glioblastoma cell lines, showing cell type and spheroid size dependent responses to metabolic challenges. In addition, normalization approaches using essentially 2D characteristics of spheroids were found insufficient to account for different spheroid sizes and cell lines. The data showed that using bio-printed spheroids with magnetic beads, combined with normalization to the median values of an experiment and the initially seeded cell number, delivered the most reliable results. Thus, we provided an approach that enables a straightforward and reproducible generation of 3D cell cultures and offer strategies to optimize metabolic measurements within these cultures.

DOI: https://doi.org/10.1371/journal.pone.0347569
Clin Transl Radiat Oncol. 2026 Jul;59 101159

Plasma serine and glycine in relation to clinical outcomes following neoadjuvant radiotherapy for rectal cancer.

Nienke R K Zwart, Per Magne Ueland, Adrian McCann, Jill A McKay, Heidi Rütten, Johannes A Bogers, Johannes H W de Wilt, Ellen Kampman, Dieuwertje E Kok.

   Introduction: There is substantial variation in radiotherapy response among patients with rectal cancer. The amino acids serine and glycine have been proposed as radiosensitizers in preclinical studies. Here, we explored associations between plasma serine, glycine, and their ratio and clinical outcomes following neoadjuvant treatment for rectal cancer, including tumour downstaging and cancer recurrence.
Methods: Based on a prospective cohort study, 288 patients with stage I-III rectal cancer were included. Blood was collected around diagnosis and plasma levels of serine and glycine were measured using GC-MS/MS. Tumour downstaging was defined as T-classification downstaging (pT < cT) after neoadjuvant treatment and recurrence included locoregional recurrences and distant metastases occurring in the 5-years after surgery. Regression models were used to calculate relative risks (RR) and hazard ratios (HR) and their 95% confidence intervals (CI) for tumour downstaging and recurrence, respectively.
Results: Tumour downstaging was observed in 41% (n = 117) of the patients and the 5-year recurrence rate was 23% (n = 67). Serine, glycine, and their ratio were not associated with tumour downstaging. A higher serine/glycine ratio was associated with a lower risk of cancer recurrence (HRperdoubling 0.47, 95%CI 0.22-0.99) and tumour downstaging was associated with lower risk of cancer recurrence (HR 0.40, 95%CI 0.22-0.70).
Conclusion: This is the first study demonstrating a potential association between the serine/glycine ratio, an indicator of SHMT enzyme activity, and rectal cancer recurrence. Further studies are warranted to confirm these findings, as well as investigate underlying biological mechanisms and potentially explore strategies to target SHMT enzyme activity in the context of cancer treatment.

Keywords:  Cancer recurrence; Glycine; Radiotherapy; Rectal cancer; Serine

DOI:  https://doi.org/10.1016/j.ctro.2026.101159
Metab Eng Commun. 2026 Jun;22 e00276

Engineering of the glucose uptake system to increase 2,4-Dihydroxybutyric acid production in Escherichia coli.

T A Stefanie Nguyen, Ceren Alkim, Nadine Ihle, Thomas Walther, Cláudio J R Frazão.

  2,4-Dihydroxybutyric acid (DHB) is a promising C4 platform compound for the synthesis of methionine analogues and biodegradable polymers. However, aerobic DHB production from glucose in Escherichia coli involves transient acetate overflow prior to product synthesis, which could be challenging for process scalability. Therefore, we engineered Escherichia coli K-12 MG1655 for optimized DHB production by replacing the phosphotransferase system mediated glucose uptake with the galactose permease GalP, coupled to ATP-dependent phosphorylation via endogenous glucokinase. In combination with targeted deletions of malate- and fumarate-consuming reactions, we obtained a strain with enhanced flux through the tricarboxylic acid (TCA) cycle and pentose phosphate pathway leading to improved NADPH availability and increased anaplerotic activity, as revealed by 13C metabolic flux analyses. Deletion of the mdh gene encoding for the cytosolic malate dehydrogenase further promoted DHB formation. The resulting strain achieved DHB yields up to 0.20 mol mol-1 (2.43 g L-1), a 4-fold increase compared to the wildtype background (0.05 mol mol-1, 0.60 g L-1), under aerobic conditions while suppressing acetate formation. Together, these results demonstrate that GalP-mediated glucose uptake and engineering of the TCA cycle provide a robust metabolic framework for efficient DHB biosynthesis and establish a foundation for further process and pathway development.

Keywords:  13C metabolic flux analysis; 2,4-Dihydroxybutyric acid; Escherichia coli; Galactose permease (GalP); Metabolic engineering; Phosphotransferase system (PTS)

DOI:  https://doi.org/10.1016/j.mec.2026.e00276
Blood Cancer Discov. 2026 Apr 20. OF1-OF3

Improving Knowledge and Care of Patients with AML: The Need to Get Out of Our Comfort Zone.

Ann-Kathrin Eisfeld, Elaine R Mardis.

Genetic ancestry as well as the lived experience of each patient shapes the landscape and effects of somatic alterations in acute myeloid leukemia (AML), determining outcomes. Expanding our knowledge of how these factors affect risk prognostication and care of a diverse patient population will help overcome existing survival disparities, thereby improving our knowledge and care of all patients with AML.

DOI: https://doi.org/10.1158/2643-3230.BCD-26-0053
FEBS Open Bio. 2026 Apr 21.

One size does not fit all: An in vitro evaluation of the effects of bezafibrate and medroxyprogesterone acetate on human SH-SY5Y and U-87 MG cancer cells.

Abhishek Kharawatkar, Francesco Michelangeli, Farhat Latif Khanim, Christopher Martin Bunce, William Eustace Basil Johnson.

  Here, we have examined the effects of the repurposed drugs bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) singly and in combination (BaP) on a neuroblastoma (SH-SY5Y) and a glioblastoma (U-87 MG) cell line. BaP was previously shown to inhibit the growth of blood and bone cancers through the generation of reactive oxygen species (ROS) and by targeting lipogenesis. Similarly, in our study, BaP inhibited cell proliferation and induced cell death in both neuroblastoma and glioblastoma cells more effectively than single BEZ or MPA drug treatments, albeit less effectively than in blood cancers. Furthermore, we observed significant increases in ROS levels in both cancer cell lines and reductions in the levels of the lipogenic enzyme, stearoyl-CoA-desaturase 1 (SCD1). Supplementation with the SCD1 product, oleic acid (OA), moderately abrogated the inhibitory effects of BaP on neuroblastoma proliferation. However, this effect was not seen in glioblastoma cultures, where OA supplementation of BaP-treated cells was associated with further decreases in cell proliferation. Lastly, we show that a clinically achievable BaP concentration enhanced the antiproliferative effects of temozolomide on glioblastoma cells. These findings show that drugs that have been successfully repurposed to potentially treat some types of cancers may have use in other cancers, but that their efficacy and mechanisms of action do not necessarily translate from one cancer type to another. Thus, successful drug repurposing requires investigation and optimisation on a case-by-case basis.

Keywords:  SH‐SY5Y neuroblastoma; Stearoyl‐CoA‐desaturase 1; U87‐MG glioblastoma; cancer cell growth; drug repurposing; reactive oxygen species

DOI:  https://doi.org/10.1002/2211-5463.70259
J Med Chem. 2026 Apr 23.

Discovery of a Highly Potent and Selective ENL Degrader.

Kaixiu Luo, Zhaoyu Xue, Lihuai Qin, Zhefan Wang, Pengcheng Gao, Ling Xie, Yangzhou Su, Xian Chen, H Ümit Kaniskan, Hong Wen, Jian Jin.

The eleven-nineteen leukemia protein (ENL), a YEATS domain-containing acyl-lysine reader, represents a critical dependency in acute myeloid leukemia (AML). We previously reported our first-generation ENL proteolysis-targeting chimera (PROTAC) degrader, MS41. Here, via a comprehensive structure-activity relationship (SAR) study, we discovered MS108 (compound 124), the most potent ENL degrader to date, which recruits the von Hippel-Lindau (VHL) E3 ligase and achieved 5.8-fold higher ENL degradation potency (DC50 = 0.6 ± 0.05 nM) and 18-fold stronger antiproliferation potency (GI50 = 1.19 ± 0.03 nM) over MS41 in MV4;11 cells. Compound 124 induced robust and highly selective degradation of ENL in a concentration-, time-, VHL-, and ubiquitin-proteasome system (UPS)-dependent manner while displaying improved pharmacokinetic properties. Collectively, we discovered a highly potent and selective ENL degrader, providing a useful chemical tool for the research community and a compelling lead for further development of ENL degraders into therapeutics to treat AML.

DOI: https://doi.org/10.1021/acs.jmedchem.6c00386
Clin Lymphoma Myeloma Leuk. 2026 Mar 17. pii: S2152-2650(26)00075-3. [Epub ahead of print]

Phase 1 Trial of BCL-2 Inhibitor Lisaftoclax (APG-2575) in Chinese Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Other Non-Hodgkin Lymphomas.

Mingyuan Sun, Keshu Zhou, Junyuan Qi, Huilan Liu, Aizong Shen, Liangquan Geng, Fuling Zhou, Jianying Huang, Zi Chen, Ke Zhang, Lichuang Men, Danhua Cong, Fang Lu, Dajun Yang, Yifan Zhai, Jianxiang Wang.

   BACKGROUND: Lisaftoclax is a novel BCL-2 inhibitor. This phase 1 trial (NCT03913949) evaluated the safety and preliminary efficacy of lisaftoclax in Chinese patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and other non-Hodgkin lymphomas (NHL).
PATIENTS AND METHODS: Lisaftoclax was administered orally in 28-day cycles, targeting daily doses of 20-800 mg for up to 24 cycles, using a daily ramp-up to minimize tumor lysis syndrome (TLS) risk. Patients with previous resistance to a BCL-2 inhibitor or exposure to a BCL-2 inhibitor in the most recent treatment line were excluded. Among 51 enrolled patients, 14 had CLL/SLL, 13 mantle cell lymphoma (MCL), and 4 marginal zone lymphoma (MZL).
RESULTS: The maximum tolerated dose of lisaftoclax was not reached; neither dose-limiting toxicity nor TLS was observed. Common adverse events included anemia, neutropenia, and thrombocytopenia. Significant antitumor activity was observed in CLL/SLL (overall response rate [ORR] 71.4%, complete response [CR] 28.6%); MCL (ORR 50.0%, CR 20.0%); and MZL (ORR 50.0%, CR 0). Median progression-free survival was 7.9 (95% CI, 4.9-14.1) months for all patients and 18.6 (95% CI, 8.4-not reached [NR]) and 7.9 (95% CI, 2.0-NR) months for those with CLL/SLL and MCL, respectively. The median overall survival was NR (95% CI, 26.2-NR) for all patients.
CONCLUSION: Lisaftoclax has a manageable safety profile and induces durable responses in R/R CLL/SLL and NHL.

Keywords:  BCL-2 inhibitor; CLL/SLL; Relapsed/refractory; non-Hodgkin lymphoma

DOI:  https://doi.org/10.1016/j.clml.2026.03.010
Metabol Open. 2026 Mar;29 100442

Metabolic advances in 2025: from clinical breakthroughs to molecular reprogramming.

Maria Dalamaga, Junli Liu.

  The year 2025 represented a turning point in metabolic research, marked by advances that combined unprecedented clinical efficacy with deep mechanistic insight. Landmark obesity trials redefined therapeutic expectations, with head-to-head and combination studies showing that the depth and distribution of weight loss are critical determinants of metabolic benefit across obesity and type 2 diabetes. In parallel, gene-editing studies crossed a translational threshold, showing that durable modification of metabolic pathways in humans is feasible, from bespoke correction of inborn errors to population-scale lipid lowering. Mechanistic investigations challenged long-standing assumptions about metabolic regulation. Experimental work revealed that mitochondrial electron transport functions as a dynamic redox regulator rather than a passive energy conduit, linking coenzyme Q imbalance and reverse electron transport to hepatic steatosis and metabolic dysfunction. Other studies reframed nutrient exposure and endogenous metabolites, demonstrating that non-nutritive sweeteners and cyanide exert context-dependent metabolic effects through regulated endocrine and redox pathways. At the systems level, multi-omics analyses defined reproducible microbiome-metabolome signatures associated with impaired glucose regulation, while artificial intelligence and continuous glucose monitoring exposed dynamic glycemic phenotypes invisible to conventional biomarkers. Precision-nutrition studies further showed that selective manipulation of sulfur amino acid availability can program thermogenic and metabolic responses. Collectively, these studies illustrate how metabolism in 2025 was approached as a modifiable, programmable system, shaped by clinical intervention, molecular control, and data-driven phenotyping, and point toward an era of increasingly precise and integrated metabolic medicine.

Keywords:  Artificial intelligence; GLP-1; Gene editing; Metabolism; Microbiome–metabolome; Obesity; Obesity pharmacotherapy; Precision nutrition; Redox metabolism; Tirzepatide; Type 2 diabetes; gene editing

DOI:  https://doi.org/10.1016/j.metop.2026.100442