bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2026–08–16
seventeen papers selected by
Brett Chrest, Wake Forest University
  1. A mitochondrial antioxidant axis fuels iron addiction in colorectal cancer.
  2. Ketogenic Diet Extinguishes Firing at the Synapses.
  3. Beyond BCL-2: What drives venetoclax resistance in acute myeloid leukemia?
  4. GLUD1 Inhibition Disrupts Glutamate Homeostasis and Induces Metabolic and Redox Stress in Gliomas.
  5. Metabolic Therapy in Glioblastoma-Mapping the Evidence for Ketogenic Diet as an Adjunctive Strategy.
  6. The mitochondrial swelling channel.
  7. Metabolism of fructose in the heart favors glycerate production and is linked to cardiac dysfunction in diabetes.
  8. Blocking L-carnitine synthesis by meldonium prolongs the survival in mice with pancreatic cancer.
  9. Excess folate elevates formaldehyde genotoxicity in cell lines but not in mice or humans.
  10. Metformin Attenuates Sepsis-Induced Cardiomyopathy via Inhibition of Reverse Electron Transfer at Mitochondrial Complex I.
  11. The emerging metabolic role and treatment target of CPT1A in CRC.
  12. MCART1 (SLC25A51) deficiency exacerbates mitochondrial dysfunction during MPP+-induced complex I stress.
  13. Acute AKT signaling increases glucose phosphorylation and contribution to glycogen in hepatocytes.
  14. Quizartinib Resistance Mutations and Treatment Outcomes in Relapsed or Refractory FLT3-ITD-Positive AML.
  15. A bedside-to-outside model of human nutrition research.
  16. RNA terminal uridylyl transferases are druggable vulnerabilities in AML but are dispensable for normal hematopoiesis.
  17. Beyond acetylation: Evaluating the emerging biology of lysine acylation.
  1. Cell Metab. 2026 Aug 04. pii: S1550-4131(26)00237-8. [Epub ahead of print]38(8): 1521-1523
    A mitochondrial antioxidant axis fuels iron addiction in colorectal cancer.
    Le Jin Sun, Gina M DeNicola.
      Colorectal cancer (CRC) cells accumulate iron to fuel proliferation yet paradoxically resist its toxicity. Jain et al. reveal that heme stabilizes succinate dehydrogenase subunit C, sustaining complex II-dependent coenzyme Q reduction and its redistribution to the plasma membrane, enabling CRC cells to buffer oxidative stress and iron-induced cell death.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.011
  2. Epilepsy Curr. 2026 Aug 10. 15357597261468567
    Ketogenic Diet Extinguishes Firing at the Synapses.
    Bin Gu.
      
    DOI:  https://doi.org/10.1177/15357597261468567
  3. Cancer Cell. 2026 Aug 10. pii: S1535-6108(26)00313-2. [Epub ahead of print]44(8): 1525-1532
    Beyond BCL-2: What drives venetoclax resistance in acute myeloid leukemia?
    Anna Skwarska, Marina Konopleva.
      The BCL-2 inhibitor venetoclax has transformed outcomes for older or frail patients with acute myeloid leukemia (AML), and its resistance mechanisms are becoming better defined, including compensatory and lineage-associated switches toward MCL-1 or BCL-xL dependence, oncogenic signaling activation, blast phenotype, and differentiation stage. Additional putative mechanisms-such as emerging BAX mutations, mitochondrial structure remodeling, integrated stress response, and metabolic adaptations, including enhanced amino acid uptake and fatty acid oxidation to sustain oxidative phosphorylation-require further validation.
    DOI:  https://doi.org/10.1016/j.ccell.2026.07.004
  4. Cells. 2026 Aug 03. pii: 1401. [Epub ahead of print]15(15):
    GLUD1 Inhibition Disrupts Glutamate Homeostasis and Induces Metabolic and Redox Stress in Gliomas.
    Malgorzata Trybula, Małgorzata Łysiak, Emilia Wiechec, Annika Malmström, Peter Söderkvist.
      Glutamate dehydrogenase (GLUD1) links glutamine metabolism and redox regulation, yet its prognostic and functional relevance across different glioma subtypes warrants further study. Here, we show that GLUD1 expression was inversely associated with tumor grade and positively associated with survival across glioma subtypes, a relationship not fully recapitulated by broader glutaminolysis-related gene signatures. To investigate the consequences of GLUD1 inhibition, we treated endogenous IDH-mutant and IDH-wildtype glioma cell lines with the reported GLUD1 inhibitor R162. GLUD1 inhibition reduced viability in all cell lines tested. This effect was not rescued by α-ketoglutarate (α-KG) supplementation, indicating that impaired tricarboxylic acid (TCA) cycle anaplerosis was not the primary mechanism underlying GLUD1 dependency. Instead, GLUD1 inhibition caused intracellular glutamate accumulation, increased reactive oxygen species (ROS), γ-H2AX induction, and elevated intracellular calcium, while complementary in silico analyses predicted disruption of mitochondrial membrane potential following R162 exposure. Together, these findings indicate that GLUD1 inhibition induces metabolic and redox stress associated with disrupted glutamate and calcium homeostasis and DNA damage. Our findings distinguish the favorable prognostic value of GLUD1 expression from the cellular vulnerability revealed by its inhibition, supporting further investigations of GLUD1 as both a prognostic biomarker and potential therapeutic target in glioma.
    Keywords:  GLUD1; cancer metabolism; glioma; glutamate dysregulation; redox
    DOI:  https://doi.org/10.3390/cells15151401
  5. Nutrients. 2026 Aug 03. pii: 2498. [Epub ahead of print]18(15):
    Metabolic Therapy in Glioblastoma-Mapping the Evidence for Ketogenic Diet as an Adjunctive Strategy.
    Dominika Wiśniewska, Martyna Winiarska, Sabina Krupa-Nurcek.
      Background/Objectives: Glioblastoma multiforme (GB) is an extremely aggressive tumor of the central nervous system, characterized by rapid growth, high invasiveness, and significant resistance to treatment. A growing body of data indicates that metabolic reprogramming of GB cells may be a therapeutic target, and that the ketogenic diet (KD)-by limiting glucose and inducing ketosis-may modulate tumor metabolism. The aim of this review was to provide a synthetic presentation of the current state of knowledge regarding the use of KD as an adjunctive therapy in the treatment of GB, with a particular focus on the mechanisms of action, safety, feasibility and results of clinical trials. Methods: The review was conducted in accordance with the Joanna Briggs Institute methodology and the PRISMA-ScR guidelines. A systematic search of PubMed, Scopus, EBSCO, Web of Science, Google Scholar, and Cochrane Library (1-10 April 2026) included studies on the use of KD in patients with GB. Full-text observational studies, randomised trials and reviews were included in the analysis. Data extraction was carried out according to the Population-Concept-Context (PCC) model. Results: Of the 26 publications identified, 12 met the inclusion criteria. Preclinical data consistently indicate that KD may reduce glycolysis, lower insulin and IGF-1 levels, increase oxidative stress in cancer cells, and modulate the inflammatory microenvironment. Clinical trials confirm the safety and feasibility of KD, as well as the ability to maintain stable ketosis. Preliminary data suggest potential metabolic benefits and improved quality of life, however, clinical efficacy remains inconclusive due to small trials, heterogeneous dietary protocols, and a lack of randomized trials. The variety of interventions used (classic KD; MCT-KD-Medium-chain triglyceride KD; KD-IF-KD and intermittent fasting) makes it difficult to compare the results. Conclusions: The KD represents a promising, low-toxic strategy to support the treatment of GB, based on biological basis. Available data indicate its safety and feasibility, but there is insufficient evidence to recommend its routine use in clinical practice. Large, multicenter, randomized trials with standardized dietary protocols and objective monitoring of metabolic parameters are needed to unambiguously assess the impact of KD on disease survival and progression.
    Keywords:  KD; adjunctive therapy; glioblastoma; glucose-ketone index; ketosis; neuroinflammation; tumor metabolism
    DOI:  https://doi.org/10.3390/nu18152498
  6. J Gen Physiol. 2026 Sep 07. pii: e202614066. [Epub ahead of print]158(5):
    The mitochondrial swelling channel.
    Elizabeth A Jonas, Eleanora Margulis, Ava Yu, Nelli Mnatsakanyan.
      Early bioenergeticists who described the principles of chemiosmosis were aware that swelling of mitochondria was a likely and even frequent event, based on the large electrochemical gradient of K+ ions across the mitochondrial inner membrane. Swelling could be measured as a change in electron density by electron microscopy or by spectrophotometry in isolated mitochondria. The mitochondrial permeability transition (mPT) was originally described as an acute swelling change in mitochondria, later determined to be caused by the rapid opening of a pore (mPTP) defined biophysically and pharmacologically as a Ca2+- and voltage-dependent, cyclosporine A-sensitive large-conductance channel. The identity of the pore is controversial, but the ATP synthase c-subunit is a major candidate. In their breakthrough study (Akosah et al. https://doi.org/10.1085/jgp.202613979), they establish a novel dark-field imaging approach, allowing detection of mitochondrial swelling in living cells. Swollen mitochondria exhibit decreased light scattering and, therefore, microscopically "disappear." The cell-based imaging technique enables dissection of two separate processes, mitochondrial swelling, and depolarization. The authors demonstrate that K+ influx causes swelling but not immediate mitochondrial depolarization in wild-type cells, whereas in ATP synthase c-subunit knockout cells, Ca2+-dependent mitochondrial depolarization occurs without swelling, suggesting a lack of K+ influx. The results suggest that the ATP synthase c-subunit channel is the key member of a channel complex constituting the "swelling channel" of the mPTP.
    DOI:  https://doi.org/10.1085/jgp.202614066
  7. J Mol Cell Cardiol. 2026 Aug 13. pii: S0022-2828(26)00121-5. [Epub ahead of print]218 121-129
    Metabolism of fructose in the heart favors glycerate production and is linked to cardiac dysfunction in diabetes.
    Marco Annandale, Dominic Lachance, Isabelle F Robillard, George Guo, Xun Li, Parisa Koutsifeli, Lorna J Daniels, Erica Zarate, Angus C Grey, Lea M D Delbridge, Matthieu Ruiz, Christine Des Rosiers, Kimberley M Mellor.
      Increased cardiac risk in diabetes has been linked to disturbances in myocardial metabolism. Circulating and cardiac fructose levels are elevated in diabetes but the relationship between fructose and cardiac pathology is unclear. The goal of this study was to assess myocardial capacity for fructose metabolism and evaluate the time-course of cardiac fructose accumulation relative to the emergence of cardiac functional impairment in diabetic rats. Cardiac capability for fructose metabolism to support function was demonstrated in ex vivo working mouse hearts perfused with 11 mM fructose. Using isotope-labeled fructose [U13C], we observed 13C enrichment into downstream metabolites glyceraldehyde, glycerate, pyruvate, lactate, and mitochondrial acetyl-CoA in perfused working mouse hearts. Metabolite profiling demonstrated that relative to glucose, myocardial fructose metabolism favored glycerate production. In diabetic rats (streptozotocin, 55 mg/kg), cardiac fructose elevation was evident prior to the onset of cardiac dysfunction. This study provides proof-of-principle evidence that fructose metabolism is operational in the working heart and identifies key fructose-derived metabolites. The finding that cardiac fructose elevation precedes functional impairment supports the contention that fructose may be an early instigator of diabetic cardiomyopathy and further investigation is now warranted. NEW AND NOTEWORTHY (<75 WORDS): Circulating and cardiac fructose levels are elevated in diabetes but the relationship between fructose and cardiac pathology is unclear. This study provides proof-of-principle evidence that fructose metabolism is operational in the working heart and identifies that cardiac fructose metabolism favors production of glycerate. In diabetes, cardiac fructose elevation precedes functional impairment supporting the contention that fructose may be an early instigator of diabetic cardiomyopathy.
    Keywords:  Cardiac metabolism; Diabetic cardiomyopathy; Isotope tracing; Metabolomics
    DOI:  https://doi.org/10.1016/j.yjmcc.2026.08.003
  8. iScience. 2026 Aug 21. 29(8): 117071
    Blocking L-carnitine synthesis by meldonium prolongs the survival in mice with pancreatic cancer.
    Makoto Sano, Hideaki Ijichi, Sho Tabata, Akiyoshi Hirayama, Shuichi Shimma, Yohei Masugi, Yoshimi Ichimaru, Jinsuk Kim, Gen Kimura, Koji Miyabayashi, Ryota Takahashi, Hiroto Hatakeyama, Takahiro Suzuki, Atsushi Masamune, Tomoyoshi Soga, Mitsuhiro Fujishiro.
      Pancreatic ductal adenocarcinoma (PDAC) is the cancer with poorest prognosis, with metabolic reprogramming reported. We investigated metabolic alterations in mice with PDAC using capillary electrophoresis-mass spectrometry (CE-MS) and mass spectrometry imaging (MSI). o-Acetylcarnitine, a metabolite of carnitine, and acetyl-CoA increased during cancer progression in a PDAC mouse model by CE-MS, while MSI revealed that o-acetylcarnitine was mainly localized in PDAC cells. Also, immunohistochemistry showed overexpression of γ-butyrobetaine 2-oxoglutarate dioxygenase 1 (BBOX1), which synthesizes carnitine from γ-butyrobetaine, mainly in PDAC cells. Meldonium, an inhibitor of BBOX1, inhibited PDAC proliferation and cytokine secretion, thereby prolonging the survival of PDAC-bearing mice, accompanied by improved skeletal muscle atrophy. In patients undergoing PDAC resection, BBOX1 expression was determined as an independent poor prognostic factor for overall survival. Therefore, these results suggest that blocking L-carnitine synthesis would improve the prognosis of patients with PDAC.
    Keywords:  BBOX1; CE-MS; MSI; PDAC; cachexia; capillary electrophoresis-mass spectrometry; mass spectrometry imaging; meldonium; metabolome; o-acetylcarnitine; overall survival; pancreatic cancer; pancreatic ductal adenocarcinoma; γ-butyrobetaine 2-oxoglutarate dioxygenase 1
    DOI:  https://doi.org/10.1016/j.isci.2026.117071
  9. EMBO Mol Med. 2026 Aug 12.
    Excess folate elevates formaldehyde genotoxicity in cell lines but not in mice or humans.
    Christopher Mellor, Brandon T James, Saeideh Azad, Emma P Kosmeder, Chloe T Purello, Monika Singh, Victoria Simon, Nicholas W Cheng, Jessica Niedermaier, Guillermo Burgos-Barragan, John O Blenis, Anthony R Mato, Martha S Field, Meng Wang.
      Folate metabolites are chemically unstable: spontaneous decomposition releases formaldehyde, a genotoxin in blood stem cells and a human carcinogen. Despite this, folic acid consumption frequently exceeds the Recommended Dietary Allowance and is prescribed at high doses for patients with blood disorders. However, the impact of excess folate on endogenous formaldehyde genotoxicity in vivo has not been studied. We find that excess tetrahydrofolate (THF) treatment of cell lines elevates formaldehyde-DNA adducts and genotoxicity. To test this in vivo, we fed a high-folic acid diet (10-fold above standard) to mice with heightened sensitivity to formaldehyde: detoxification-impaired Adh5-/- mice, and Fanconi anemia DNA repair mutants Fanca-/- and Fancj-/-. In contrast to cell lines, elevated tissue THF was not associated with increased formaldehyde-DNA adducts nor blood stem cell attrition. Finally, in cancer patients, high-dose folic acid therapy elevated plasma folic acid but did not increase formaldehyde-DNA adducts in peripheral blood mononuclear cells. In conclusion, increased folate in vivo does not elevate endogenous formaldehyde genotoxicity in sensitized mouse models or humans.
    DOI:  https://doi.org/10.1038/s44321-026-00504-7
  10. Biology (Basel). 2026 Aug 02. pii: 1267. [Epub ahead of print]15(15):
    Metformin Attenuates Sepsis-Induced Cardiomyopathy via Inhibition of Reverse Electron Transfer at Mitochondrial Complex I.
    Nannan He, Wen Cao, Yannian Luo, Chao Sun, Ting Zhao, Xiongxiong Liu, Meiling Li, Lin Wei, Bing Wang, Jian Liu.
      Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication of sepsis; however, its molecular mechanisms remain incompletely understood, which has hindered the development of targeted therapies. We hypothesized that excessive mitochondrial reactive oxygen species (mtROS) production through reverse electron transfer (RET) at mitochondrial complex I contributes to septic myocardial injury and that metformin, a clinically used inhibitor of mitochondrial complex I, protects the myocardium by inhibiting this process. In lipopolysaccharide-stimulated H9C2 cardiomyocytes and cecal ligation and puncture-induced septic rats, sepsis was characterized by an elevated mitochondrial membrane potential, accompanied by succinate accumulation, an increased NADH/NAD+ ratio, and impaired downstream electron transport. These metabolic changes established favorable conditions for RET-mediated mtROS generation. Metformin inhibited complex I activity and selectively suppressed RET-mediated mtROS generation without increasing ROS production associated with forward electron transport (FET). This effect was accompanied by attenuated inflammatory responses and apoptosis. In septic rats, metformin preserved cardiac function and alleviated myocardial oxidative stress and injury. Overall, these results suggest that RET at mitochondrial complex I represents a potential therapeutic target in SICM and support the use of metformin as a promising strategy for preventing and treating septic myocardial dysfunction.
    Keywords:  complex I; metformin; mitochondrial ROS; reverse electron transfer; sepsis-induced cardiomyopathy
    DOI:  https://doi.org/10.3390/biology15151267
  11. Front Cell Dev Biol. 2026 ;14 1881073
    The emerging metabolic role and treatment target of CPT1A in CRC.
    Xinyu Zhu, Ting Sun, Jintao Yuan, Fei Mao, Tao Jin, Chengxue Yi.
      Fatty acid oxidation is a major metabolic pathway responsible for fatty acid breakdown and energy production. Carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme in this process, catalyzes the conversion of acyl-coenzyme A into acyl-carnitine, enabling mitochondrial transport for oxidative metabolism. Emerging evidence indicates that dysregulated CPT1A contributes to metabolic disorders and cancer progression by driving metabolic reprogramming, modulating oxidative stress, and regulating protein modifications, including histone acetylation and lysine succinylation. Colorectal cancer (CRC), one of the leading causes of cancer-related mortality worldwide, has recently been linked to aberrant CPT1A activity. Studies demonstrate that CPT1A promotes CRC progression by regulating oncogenic signaling pathways, enhancing cancer stemness, supporting tumor proliferation and metastasis, and shaping the tumor microenvironment. Increasing evidence suggests that targeting CPT1A may be a promising therapeutic strategy for CRC. In this review, we summarize the biological functions of CPT1A, discuss its mechanistic role in CRC progression, and highlight its emerging potential as a metabolic and therapeutic target in CRC.
    Keywords:  cancer metabolic reprogramming; carnitine palmitoyltransferase 1a; colorectal cancer; fatty acid oxidation; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2026.1881073
  12. Free Radic Biol Med. 2026 Aug 10. pii: S0891-5849(26)01024-5. [Epub ahead of print]255 763-773
    MCART1 (SLC25A51) deficiency exacerbates mitochondrial dysfunction during MPP+-induced complex I stress.
    Shiliang Wang, Peixin Sun, Yue Zhang, Jinlun Kylian Zhang, Xurui Shen, Hanting Yang.
      Mitochondrial NAD+ homeostasis, sustained by the inner membrane transporter MCART1, is critical for oxidative metabolism and stress resilience. Inhibition of complex I by 1-methyl-4-phenylpyridinium (MPP+) triggers metabolic collapse and mitochondrial dysfunction, yet whether MCART1 provides a protective gatekeeping function against the MPP+ toxin remains unclear. Here, we show that loss of MCART1 exacerbates mitochondrial dysfunction under physiological conditions, and that MCART1 contributes to maintaining membrane potential, preventing ATP depletion, and suppressing ROS accumulation in MPP+-treated neuronal cells. We identify key NAD+-binding residues within the predicted substrate-binding pocket. Mutation of these residues uncouples MPP+ resistance from constitutive NAD+ transport, defining a structural determinant required for the stress-responsive gatekeeping function of MCART1. These findings establish that MCART1 acts as a conditionally indispensable protector of mitochondrial integrity during complex I poisoning, and reveal that failure of this NAD+ influx pathway drives metabolic collapse in the MPP+ toxin model relevant to Parkinson's disease.
    Keywords:  MCART1 / SLC25A51; Mitochondrial NAD(+) homeostasis; Mitochondrial dysfunction; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.022
  13. iScience. 2026 Aug 21. 29(8): 116956
    Acute AKT signaling increases glucose phosphorylation and contribution to glycogen in hepatocytes.
    Megan Stefkovich, Won Dong Lee, Talia Coopersmith, Joseph A Baur, Joshua D Rabinowitz, Paul M Titchenell.
      Insulin's regulation of hepatic glucose production and glycogen is critical for postprandial glucose disposal. AKT, a serine-threonine kinase and insulin signaling intermediate, regulates liver glucose metabolism through transcriptional and posttranslational mechanisms. However, current knowledge largely stems from genetic loss-of-function models, precluding observation of AKT's non-transcriptional effects. To measure rapid changes to glucose and glycogen metabolism, isotope tracing using [U-13C]-glucose and [U-14C]-glucose was coupled with the AKT inhibitor MK-2206 in primary rat hepatocytes. MK-2206 treatment decreased AKT phosphorylation and glucose contribution to glucose 6-phosphate and uridine diphosphate glucose within minutes without affecting metabolite pool sizes or protein levels of glucokinase, glucose 6-phosphatase, or phosphoenolpyruvate carboxykinase. MK-2206 also decreased glucose contribution to glycogen, independent of glycogen breakdown or glycogen synthase phosphorylation. These results demonstrate that AKT acutely regulates glucose contribution to glycogen and upstream precursors, suggesting a transcription-independent mechanism that is proximal to glucose 6-phosphate generation for glycogen synthesis.
    Keywords:  glucokinase; gluconeogenesis; glucose 6-phosphate; glucose homeostasis; glycogen; glycolysis
    DOI:  https://doi.org/10.1016/j.isci.2026.116956
  14. Cancer Sci. 2026 Aug 12.
    Quizartinib Resistance Mutations and Treatment Outcomes in Relapsed or Refractory FLT3-ITD-Positive AML.
    Yuichiro Semba, Toshihiro Miyamoto, Senji Kasahara, Yoshikane Kikushige, Takahiro Maeda, Goichi Yoshimoto, Shuichi Ota, Akio Saito, Yuho Najima, Hiroki Hosoi, Daigo Niiya, Koji Kato, Koji Nagafuji, Takashi Akasaka, Tomohiko Kamimura, Atsushi Takita, Maiko Narahara, Tadashi Toki, Koichi Iwanaga, Koji Yonemoto, Mine Harada, Koichi Akashi.
      Quizartinib is a FMS-like tyrosine kinase 3 (FLT3) inhibitor indicated for FLT3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukemia (AML). We aimed to evaluate quizartinib resistance mechanisms, in addition to efficacy and safety outcomes, in patients with relapsed or refractory FLT3-ITD-positive AML. This multicenter, single-arm study in Japan (jRCTs071200015) enrolled 18 patients between May 2020 and December 2022. Of these, 15 patients received oral quizartinib (up to 53 mg once daily) for up to 12 cycles of 28 days each, then were followed for 12 months. The primary endpoint was to evaluate the type and rate of quizartinib resistance mutations; secondary endpoints included composite complete remission (CRc) rate, overall response rate (ORR), hematopoietic stem cell transplantation (HSCT) rate, relapse-free survival (RFS), overall survival (OS), and adverse events (AEs). Among seven evaluable patients, acquired mutations were detected in four patients (NF1 [R2616X], CSF3R [Q754X], NRAS [G13R], and FLT3 [D835Y] in one patient each), while loss of FLT3-ITD was observed in two patients. In efficacy analyses (n = 15), CRc rate was 66.7% (95% confidence interval [CI], 38.4-88.2), ORR was 73.3% (44.9-92.2), and median OS was 13.6 months (5.4-not evaluable). Three patients (20.0%) received HSCT directly after quizartinib; in these patients, median RFS was 8.5 months (95% CI, 6.2-not evaluable). Grade ≥ 3 non-hematologic AEs and grade 1 QT prolongation were each reported in three patients (20.0%). These data offer additional information on potential resistance mechanisms in patients with relapsed or refractory FLT3-ITD-positive AML. Trial Registration: Japan Registry of Clinical Trials (jRCTs071200015).
    Keywords:  FMS‐like tyrosine kinase 3; acute myeloid leukemia; drug resistance; next‐generation sequencing; quizartinib
    DOI:  https://doi.org/10.1111/cas.70485
  15. Cell Metab. 2026 Aug 11. pii: S1550-4131(26)00283-4. [Epub ahead of print]
    A bedside-to-outside model of human nutrition research.
    Aaron Hengist, Stephanie T Chung, Valerie L Darcey, Kong Chen, Juen Guo, Gary Frost, Javier T Gonzalez, Kevin D Hall.
      One of the fundamental challenges with human nutrition research is the difficulty of knowing what people actually eat. Asking people to live in the laboratory enables precise control and measurement of food intake, but the environment does not reflect real-world conditions. Here, we present a bedside-to-outside model, which aims to address this gap by combining controlled feeding studies (prioritizing efficacy) with free-living intervention studies (incorporating effectiveness) within the same cohort. This approach will enable translation of the efficacy and effectiveness of dietary interventions with causal inference within the same cohort, offering novel insights into the real-world impact of controlled dietary interventions.
    Keywords:  clinical trials; diet; effectiveness; efficacy; intervention; nutrition; randomization
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.010
  16. Sci Adv. 2026 Aug 14. 12(33): eaec3399
    RNA terminal uridylyl transferases are druggable vulnerabilities in AML but are dispensable for normal hematopoiesis.
    Christopher Mapperley, Elise Georges, Ali A Azar, Yuka Kabayama, Hannah Lawson, Iwo Kucinski, Derek George, Joana Campos, Corey Fyfe, Jozef Durko, Wei Y Chan, Lewis Allen, Babak Jazayeri, Edward Blacker, Louie N van de Lagemaat, Aurelien Tripp, Theodoros I Roumeliotis, Giulia Guiducci, Eleanor Herbert, Jasmin Paris, Jyoti Choudhary, George Poulogiannis, Robert M Campbell, Marcos Morgan, Lovorka Stojic, Folkert J Van Werven, Douglas Vernimmen, Berthold Göttgens, Dónal O'Carroll, Kamil R Kranc.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from hematopoietic stem and progenitor cells (HSPCs). Current treatments often fail to eradicate AML; therefore, new therapeutic strategies are essential. Here, we reveal that RNA terminal uridylyl transferase enzymes 4 and 7 (TUT4/7) are druggable therapeutic targets, whose genetic deletion suppresses AML growth, induces apoptosis, and improves the survival in leukemic mouse models. Notably, a preclinical TUT4/7 inhibitor promotes cell death in samples from patients with AML and synergizes with venetoclax. Mechanistically, TUT4/7 inactivation suppresses mevalonate pathway gene expression, compromising the cholesterol synthesis pathway. Current AML therapies often cause severe hematopoietic toxicity. Although Tut4/7 deletion results in inflammatory activation throughout the hematopoietic system, this is permissive to a normal life span and Tut4/7 deficiency does not compromise HSPC function. Together, these findings identify TUT4/7 as druggable targets, whose inactivation suppresses AML while sparing normal hematopoiesis. In combination with venetoclax, this represents a promising therapeutic strategy.
    DOI:  https://doi.org/10.1126/sciadv.aec3399
  17. Cell Chem Biol. 2026 Aug 12. pii: S2451-9456(26)00282-5. [Epub ahead of print]
    Beyond acetylation: Evaluating the emerging biology of lysine acylation.
    Jordi C J Hintzen, George M Burslem.
      Lysine acylation has emerged as a rapidly expanding family of post-translational modifications that directly links cellular metabolism to protein regulation. Beyond lysine acetylation, advances in mass spectrometry and chemical biology have uncovered a diverse repertoire of acyl modifications spanning short-chain, branched, unsaturated, aromatic, and dicarboxylic groups. Together these modifications establish lysine acylation as a molecular interface through which metabolic state can shape protein function, chromatin regulation, and cell signaling. Yet fundamental questions remain regarding their biological significance, enzymatic regulation, site specificity, and whether many acylations function as bona fide regulatory signals or reflect metabolite-driven mechanisms. Here, we synthesize the current understanding of the metabolic origins, structural and biochemical properties, and their writer, reader, and eraser systems that govern lysine acylations. We further highlight emerging chemical biology approaches for detecting, manipulating, and functionally interrogating acyl marks and discuss the conceptual and technological advances needed to distinguish closely related modifications and establish their causal biological roles.
    Keywords:  PTMs; acylation; epigenetics; lysine post-translational modifications; mass spectrometry; metabolism
    DOI:  https://doi.org/10.1016/j.chembiol.2026.07.009
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