bims-medica 2026-07-26 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2026–07–26
eleven papers selected by
Brett Chrest, Wake Forest University

Short-term ketogenic diet induces systemic lipidomic remodeling associated with metabolic adaptation in humans.
Competitive catabolism drives hyperglycemia and hyperinsulinemia in obesity.
SLC25A51 and mitochondrial NAD⁺ transport in acute myeloid leukemia: mechanisms, therapeutic potential, and translational perspectives.
BCAA metabolic reprogramming identifies BCKDK as a therapeutic target in cancer.
Targeting chordoma via an isocitrate dehydrogenase-1-dependent susceptibility to redox metabolism.
Effects of aging in combination with high-fat or ketogenic diet on skeletal muscle hypertrophy after functional overloading in C57BL/6J mice.
Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.
Real-world clinical outcomes of newly diagnosed AML unfit for intensive chemotherapy treated with venetoclax and azacitidine: does it depend on the number of days of venetoclax administration?
Targeting ATP-citrate lyase across cardiometabolic and oncologic disease.
LY3410738, a Covalent Inhibitor of Mutant IDH1/2, is Effective in Acute Myeloid Leukemia Preclinical Models.
Recent advances in the bioanalysis of acylcarnitines: Methodologies, challenges, and clinical perspectives.

Front Nutr. 2026 ;13 1884256

Short-term ketogenic diet induces systemic lipidomic remodeling associated with metabolic adaptation in humans.

Minkuk Park, Jae Sik Yu, Justin Y Jeon, Hyun-A Oh, Yong-Ho Lee, Sang-Guk Lee, Gakyung Lee.

  The ketogenic diet (KD) induces a shift in systemic energy metabolism toward fatty acid oxidation and ketone body production, but its impact on lipid species-level remodeling and insulin sensitivity in humans remains incompletely characterized. We aimed to characterize short-term KD-induced changes in circulating metabolites and lipid profiles and their relationships with insulin sensitivity in healthy adults. Fifteen participants (24-38 years) underwent a 3-day isocaloric KD (75% fat, 20% protein, 5% carbohydrate) under controlled conditions. Serum samples collected before and after the intervention were profiled using metabolomics and lipidomics. KD was associated with increased circulating acylcarnitines, acetyl-L-carnitine, and β-hydroxybutyrate, along with reduced lactate, consistent with enhanced fatty acid oxidation and ketogenesis. Lipidomics showed widespread changes across multiple classes, including lower total triglycerides and shifts toward species with longer acyl chains and higher unsaturation. Ether-linked phospholipids, including plasmalogens, tended to increase, whereas lysophospholipid-to-phospholipid ratios decreased, suggesting altered membrane turnover. Sphingolipid metabolism also appeared to be modulated, with higher sphingomyelin and hexosylceramide levels. Notably, specific lipid species, including phosphatidylethanolamine (16:0/20:5), were correlated with changes in insulin sensitivity indices (QUICKI, HOMA-IR, fasting insulin). Although these associations require validation in larger cohorts, they suggest that lipid species-level remodeling may be linked to short-term metabolic adaptation to KD. These findings highlight lipid species-level remodeling as a key feature of human KD responses and provide a basis for future mechanistic and validation studies.

Keywords:  ether-linked phospholipid; insulin sensitivity; ketogenic diet; lipidomics; metabolomics

DOI:  https://doi.org/10.3389/fnut.2026.1884256
Cell Metab. 2026 Jul 21. pii: S1550-4131(26)00274-3. [Epub ahead of print]

Competitive catabolism drives hyperglycemia and hyperinsulinemia in obesity.

Daniel R Weilandt, Won Dong Lee, Michael R MacArthur, Lingfan Liang, Corey D Holman, Qingwei Chu, Alexis J Cowan, Joseph A Baur, Ned S Wingreen, Joshua D Rabinowitz.

  Systemic metabolic homeostasis maintains circulating nutrient concentrations within physiological ranges. Insulin is central to this process, lowering circulating levels of glucose, lactate, free fatty acids, and ketones. Yet how the simultaneous homeostasis of these nutrients is achieved remains unclear. Here, we develop a differential equation model of fasting metabolic homeostasis. Grounded in mass action kinetics, this multi-nutrient model reveals how a fixed energy demand naturally leads to competition between major circulating nutrients for oxidation ("competitive catabolism"). Perturbative nutrient infusions confirm this emergent behavior. The multi-nutrient model predicts that insulin promotes fasting glucose homeostasis primarily indirectly by slowing lipolysis. It further identifies a physiological circuit by which obesity causes insulin resistance: increased fat mass promotes lipolysis, releasing fatty acids into circulation that compete with glucose for oxidation, elevating glucose and thus insulin, which acts to restore proper lipid catabolic flux. Thus, quantitative modeling reveals a physiological homeostatic circuit through which obesity causes type 2 diabetes.

Keywords:  competitive catabolism; differential equation modeling; hyperinsulinemia; insulin regulation; insulin resistance; mass action kinetics; metabolic homeostasis; nutrient competition; obesity; type 2 diabetes

DOI:  https://doi.org/10.1016/j.cmet.2026.07.001
Hum Cell. 2026 Jul 19. pii: 111. [Epub ahead of print]39(8):

SLC25A51 and mitochondrial NAD⁺ transport in acute myeloid leukemia: mechanisms, therapeutic potential, and translational perspectives.

Chunmeng Rong, Ruixiu Chen, Hanqi Lou, Yongming Xia, Shiwei Duan.

  Acute myeloid leukemia (AML) remains a highly lethal hematologic malignancy characterized by metabolic reprogramming, therapeutic resistance, and poor survival, particularly in older patients. Nicotinamide adenine dinucleotide (NAD⁺) metabolism has emerged as a central driver of AML progression, and recent studies have identified solute carrier family 25 member 51 (SLC25A51) as the primary mitochondrial NAD⁺ transporter in mammalian cells. SLC25A51 regulates mitochondrial redox balance, oxidative phosphorylation, and tricarboxylic acid (TCA) cycle activity, thereby sustaining leukemic proliferation and survival. Structural studies have elucidated its six-transmembrane helix architecture, salt-bridge-mediated transport mechanism, and stabilization by cardiolipin binding. Functional investigations demonstrate that SLC25A51 overexpression correlates with poor prognosis, while its depletion disrupts mitochondrial metabolism, induces apoptosis, and suppresses AML progression in vivo. Therapeutically, pharmacologic inhibition of SLC25A51 with fludarabine, or its combination with hypomethylating agents, such as 5-azacytidine, enhances antileukemic efficacy by perturbing metabolic and epigenetic regulation. Moreover, SLC25A51 expression may serve as a predictive biomarker for mitochondrial-targeted therapies, such as complex I inhibitors. Future translational research should focus on developing selective inhibitors, optimizing combination strategies with demethylating agents and BCL-2 inhibitors, and validating its prognostic significance in clinical cohorts. Collectively, SLC25A51 represents a promising metabolic target with potential to overcome therapeutic resistance and improve patient outcomes in AML. Furthermore, this review discusses its potential implications across distinct genetic subtypes of AML (e.g., mutations in TP53, NPM1, and RAS), thereby highlighting key directions for future translational research.

Keywords:  Acute myeloid leukemia (AML); Metabolic reprogramming; Mitochondrial NAD⁺ transport; SLC25A51; Targeted therapy

DOI:  https://doi.org/10.1007/s13577-026-01428-7
Expert Opin Ther Targets. 2026 Jul 24.

BCAA metabolic reprogramming identifies BCKDK as a therapeutic target in cancer.

Zhihan Li, Yuxuan Zhou, Li Zhang, Quanjun Yang.

   INTRODUCTION: Branched-chain keto acid dehydrogenase kinase (BCKDK) is a mitochondrial kinase that suppresses branched-chain amino acid (BCAA) oxidative catabolism by phosphorylating and inhibiting the branched-chain α-keto acid dehydrogenase complex. Beyond this canonical metabolic function, accumulating evidence indicates that aberrant BCKDK activation contributes to tumor metabolic rewiring, signaling adaptation, malignant progression and therapy resistance.
AREAS COVERED: This review summarizes the regulatory position of BCKDK in BCAA catabolism, its context-dependent functions across tumor types, and recent progress in BCKDK inhibitor development. Although selected non-oncological studies are discussed to inform inhibitor mechanism, pharmacology and safety, this review focuses on the oncology relevance of BCKDK. Particular attention is given to the transition from early proof-of-concept inhibitors to BT2-derived allosteric compounds, Pfizer-developed clinical candidates, and emerging non-BT2 scaffolds or alternative binding regions. A PubMed search was conducted to identify relevant studies on BCKDK, BCAA metabolism, cancer progression and BCKDK-targeted inhibitors.
EXPERT OPINION: BCKDK is unlikely to function as a universal pan-cancer target. Its therapeutic value will depend on identifying tumor contexts with true BCKDK dependency, especially those relying on BCKDK-driven metabolic adaptation or downstream signaling. For BCKDK inhibitors, future development should integrate biochemical potency with mechanism-aligned conformational effects, long-term pharmacological consequences and biomarker-supported patient stratification.

Keywords:  Allosteric inhibitor; BCAA metabolism; BCKDK; cancer metabolism; precision oncology; therapeutic target

DOI:  https://doi.org/10.1080/14728222.2026.2709804
Acta Neuropathol. 2026 Jul 23. pii: 10. [Epub ahead of print]152(1):

Targeting chordoma via an isocitrate dehydrogenase-1-dependent susceptibility to redox metabolism.

Matthew Pun, Akash Deogharkar, Siva Kumar Natarajan, Nicholas Nuechterlein, Wentao Tian, Sunjong Ji, Eleanor Young, Fusheng Yang, Debra Hawes, Anthony C Andren, John Henry Owen, Sagar Rau, Fengyun Su, Xuhong Cao, Abhijit Parolia, Mark Prince, Joshua Fry, Paul A Gardner, Rendong Yang, Alexander R Judkins, Carl J Koschmann, Andrew S Venteicher, Costas A Lyssiotis, Arul M Chinnaiyan, Sriram Venneti.

  Chordomas are rare cancers that arise along the axial skeleton. Alterations in metabolism are a hallmark of cancer, and we sought to identify metabolic vulnerabilities in chordoma. We discovered that the tricarboxylic acid (TCA)-related enzyme isocitrate dehydrogenase-1 (IDH1) was expressed highly in bulk and single-cell patient-derived chordomas and was associated with worse survival outcomes. IDH1 catalyzes the conversion of isocitrate and nicotinamide adenine dinucleotide phosphate (NADP+) to alpha-ketoglutarate (⍺-KG) and NADPH. This critical reaction influences TCA cycle metabolism, regulates epigenetic pathways, and affects redox balance. Both IDH1 knockdown and treatment with an inhibitor targeting IDH1 were toxic to chordoma cells. An integrated analysis of the transcriptomic, chromatin, and metabolomic responses on IDH1 inhibition converged on deregulated glutathione metabolism. IDH1 inhibition was associated with increased expression and enrichment of activating H3K27ac at NRF2 (nuclear factor erythroid 2-related factor 2) signature genes including those in the glutathione biosynthetic pathway. This was accompanied by reduction of both NADPH/NADP+ and reduced/oxidized glutathione (GSH/GSSG) ratios. Importantly, IDH1 inhibitor-driven toxicity was rescued via media supplementation with the antioxidant N-acetylcysteine, suggesting that IDH1 inhibition in chordomas creates a redox-dependent metabolic vulnerability. Finally, IDH1 inhibitor treatment reduced tumor growth in two independent chordoma mouse xenograft models. Our findings suggest a potential therapeutic avenue for further exploration in chordoma.

Keywords:  Chordoma; IDH1; Metabolism; NRF2; Redox

DOI:  https://doi.org/10.1007/s00401-026-03048-9
Growth Factors. 2026 Jul 19. 1-13

Effects of aging in combination with high-fat or ketogenic diet on skeletal muscle hypertrophy after functional overloading in C57BL/6J mice.

Mantas Dirmontas, Petras Minderis, Aivaras Ratkevicius.

  We investigated how aging interacts with high-fat (HFD) and ketogenic (KD) diets to influence functional overload (FO)-induced muscle hypertrophy in C57BL/6J mice. Male mice aged 3, 16, and 24 months were fed regular chow (RD), HFD, or KD for 12 weeks, with FO of the plantaris muscle induced by denervation of the soleus and gastrocnemius during the final 6 weeks (n = 8-10 per group). Muscle hypertrophy was unaffected by diet (p = 0.897) but declined with age (p < 0.001), with a marked reduction already in mature mice. Plasma IGF-1 was higher in adult than mature (p < 0.05) and old (p < 0.001) mice and correlated positively with hypertrophy (r = 0.29, p = 0.01). The weak correlation of hypertrophy with plasma IGF-I levels suggests that IGF-I is only one among many factors playing a role in muscle hypertrophy.

Keywords:  High-fat diet; IGF-1; aging; ketogenic diet; muscle hypertrophy

DOI:  https://doi.org/10.1080/08977194.2026.2704554
Nat Metab. 2026 Jul 23.

Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.

Deborah Y Moss, Connor N Brown, Andrew M Shaw, Christopher McCann, Nikita Lewis, Matilda Downs, Rebecca Wurelly, Ciara Cunningham, Aaron Philips, Niamh Doherty, Sarah Gallagher, William J McDaid, Andrew Roe, Aisling Y Coughlan, Brenton Cavanagh, Callum Ormsby, Fiammetta Falcone, Rachel McCole, Scott Monteith, Emily Rogan, Sudhir B Malla, Alexandra J Emerson, Letitia Mohammed-Smith, Shaun Sharkey, Aoife Leonard, Peter F Gallagher, Arindam Banerjee, Sandra Van Schaeybroeck, Sufyan Pandor, Brian Quinn, Brett Greer, Christopher Elliott, Sarah Maguire, Aideen E Ryan, Philip D Dunne, Mary Mallon, Stephanie Craig, Omar Aftab, Laura C Greaves, Bryan P Marzullo, Daniel A Tennant, Vicky Coyle, Ian G Mills, Owen Sansom, Tríona Ní Chonghaile, Daniel B Longley, Simon S McDade, Melissa J LaBonte, Emma M Kerr.

Therapy resistance is attributed to over 80% of cancer deaths per year, emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. As an antimetabolite, 5FU imposes substantial metabolic stress, forcing cells that survive treatment to rapidly adapt. We explored acute 5FU-driven changes in mitochondria, the organelle critical for coordinating metabolic stress responses. Here we demonstrate in a range of CRC models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Furthermore, we show that targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.

DOI: https://doi.org/10.1038/s42255-026-01578-w
Neoplasma. 2026 Jul 22. pii: 260404N105. [Epub ahead of print]

Real-world clinical outcomes of newly diagnosed AML unfit for intensive chemotherapy treated with venetoclax and azacitidine: does it depend on the number of days of venetoclax administration?

Jozef Lukáš, Balázs Gálffy, Stanislava Fliegová, Zuzana Sninská, Ľubica Harvanová, Katarína Slezáková, Ladislav Sopko.

Until 2020, patients with acute myeloid leukemia (AML) who were not suitable for intensive treatment were mostly limited to symptomatic and palliative care, or to low-intensity regimens including low-dose cytosine-arabinoside (ARA-C) and azacitidine (AZA) monotherapy, which didn't bring much benefit. The situation changed with the arrival of venetoclax, a Bcl-2 inhibitor that causes leukemic cells to rapidly undergo apoptosis. The aim of our retrospective study was to summarize the treatment outcomes of all newly diagnosed patients with AML, unsuitable for intensive chemotherapy, treated with a combination of venetoclax and AZA at the Department of Hematology and Transfusion Medicine, University Hospital in Bratislava from January 1, 2021, to December 31, 2025. A total of 108 patients underwent treatment with a median follow-up of 35.9 months; median age was 69.5 years (47-84 years) and median number of cycles 3 (1-34). Induction mortality rate was 7.4%, and tumor lysis syndrome occurred in 4.5%. The overall response rate, which included the number of complete remissions, complete remissions with incomplete hematopoietic recovery, and morphologically leukemia-free status (CR/CRi/MLFS), was 64%, the median overall survival was 9 months, and disease-free survival was 8 months. As of December 31, 2025, 23 patients are alive and 85 have died. The main cause of death was the progression of the disease. The main contribution of our study is the finding that shortening the duration of venetoclax treatment maintains efficacy. There was no significant difference in remission rate achieved or in overall survival based on the number of days of venetoclax administration (< 14 vs. 14 vs. 21 vs. 28 days). The combination of AZA and venetoclax in AML has proven to be highly effective in inducing complete remission, usually immediately after the first cycle. Unfortunately, remission is not long-lasting, relapses are frequent, and the median overall survival in real-world data is 7.9 to 13.6 months.

DOI: https://doi.org/10.4149/neo_2026_260404N105
Pharmacol Res. 2026 Jul 20. pii: S1043-6618(26)00263-X. [Epub ahead of print]231 108348

Targeting ATP-citrate lyase across cardiometabolic and oncologic disease.

Chiara Macchi, Silvia Pedretti, Serena Ghisletti, Alberto Corsini, Nico Mitro, Cesare R Sirtori, Massimiliano Ruscica.

  ATP-citrate lyase (ACLY) is a key metabolic enzyme that links mitochondrial citrate export to the generation of cytosolic acetyl-CoA, thereby supporting de novo lipogenesis, cholesterol biosynthesis, protein acetylation, chromatin remodelling, and transcriptional control. Interest in ACLY inhibition initially arose from its lipid-lowering properties and led to the clinical development of bempedoic acid, whose ability to reduce low-density lipoprotein cholesterol and improve cardiovascular outcomes now provides the strongest clinical proof of concept for targeting this pathway. Beyond dyslipidaemia, preclinical evidence suggests that targeting the ACLY pathway and related bempedoic acid-responsive metabolic programs may ameliorate metabolic dysfunction-associated steatotic liver disease (MASLD). ACLY inhibition is expected to reduce de novo fatty-acid and cholesterol synthesis by limiting cytosolic acetyl-CoA availability, whereas parent bempedoic acid can directly activate PPARα, and thereby enhance fatty-acid oxidation. However, unlike the cardiovascular setting, robust clinical data supporting ACLY inhibition in MASLD are still lacking. More recently, the identification of nuclear ACLY functions has substantially expanded its biological significance, establishing ACLY as a metabolic-epigenetic integrator that couples nutrient availability to chromatin remodelling, transcriptional programs and immune responses. In cancer, dysregulated ACLY activity contributes to tumour growth, metabolic plasticity, therapy resistance and immune evasion, and its inhibition has shown promising antitumour effects in preclinical models. This review summarizes ACLY biology and pharmacology, emphasizing established cardiovascular applications, emerging MASLD opportunities and exploratory oncologic indications, while highlighting unresolved translational questions.

Keywords:  ATP-citrate lyase; Bempedoic acid; Cancer; Epigenetic regulation; Lipid lowering drugs; Metabolic dysfunction-associated steatotic liver disease

DOI:  https://doi.org/10.1016/j.phrs.2026.108348
Blood Cancer Discov. 2026 Jul 23.

LY3410738, a Covalent Inhibitor of Mutant IDH1/2, is Effective in Acute Myeloid Leukemia Preclinical Models.

Nathan A Brooks, Anna Skwarska, Vivian Salama, Mark H Bender, Lisa Kays, Robin I DeWalt, Bryan Perria, Deepti Thete, Jason R Manro, Rachel Cavitt, Rebecca Leon, Sandra Gomez, Raquel Torres, John M Strelow, Paul Milligan, Kate Newell, Kenneth D Roth, Jean-Emmanuel Sarry, Steven M Chan, Danalyn Manglicmot Lagutan, Richard Romero, Stephen Antonysamy, Robert L Johnson, Xueqian Gong, Renato A Bauer, Timothy P Burkholder, Patric J Hahn, Zoran Rankovic, Serge L Boulet, Courtney D DiNardo, Marina Konopleva, Raymond Gilmour.

Acute myeloid leukemia (AML) is an aggressive blood disorder characterized by rapid growth of poorly differentiated myeloid cells. Gain-of-function mutations in isocitrate dehydrogenases (IDHs) are detected in ~20% of AML and ~80% of secondary gliomas. Mutant IDH1/2 isoenzymes acquire neomorphic activity to produce 2-hydroxyglutarate (2-HG) oncometabolite, resulting in hypermethylated DNA and histones, altered gene expression, and blocked differentiation of hematopoietic progenitors. Here, we presented preclinical development of LY3410738, an oral, dual IDH1/2 inhibitor with potential to penetrate the blood-brain barrier. LY3410738 covalently inhibited mutated-IDH1/2, reduced 2-HG levels at low nanomolar concentrations in human AML and glioma models, and demonstrated efficacy in AML patient-derived xenografts (PDXs) in vivo, inducing myeloid differentiation. LY3410738 retained in vitro activity in cancer models with acquired secondary IDH1/2 mutations conferring resistance to ivosidenib and enasidenib. LY3410738 synergized and was well tolerated with standard-of-care regimens such as cytarabine, azacitidine, venetoclax, or midostaurin in IDH1/2-mutated AML PDXs.

DOI: https://doi.org/10.1158/2643-3230.BCD-25-0379
Pharm Sci Adv. 2026 Dec;4 100130

Recent advances in the bioanalysis of acylcarnitines: Methodologies, challenges, and clinical perspectives.

Jiaxin Zheng, Wanting Chen, Fengxia Qin, Pei Zhang, Fengguo Xu.

  Acylcarnitines (ACs) are a diverse class of fatty acid esters of L-carnitine that serve as critical mediators in energy homeostasis and mitochondrial function. Beyond their classical role in newborn screening for inborn errors of metabolism, ACs have emerged as promising biomarkers for complex pathologies, including cardiovascular diseases, diabetes, and drug-induced toxicities. However, the accurate quantification and comprehensive profiling of ACs in biological matrices remain analytically challenging due to their broad polarity range, vast concentration disparities, and the presence of isomers. This review provides a comprehensive overview of the current bioanalytical strategies for ACs, covering sample preparation techniques and detection platforms, with a focus on liquid chromatography-mass spectrometry. Special attention is given to the differentiation of isomers. Finally, we discuss the clinical applications of ACs profiling and highlight future perspectives, including the integration of ion mobility spectrometry, automated high-throughput workflows, spatial and single-cell metabolomics, and AI-driven analytics, to pave the way for precision medicine.

Keywords:  Acylcarnitines; Clinical diagnosis; Mass spectrometry; Metabolic disease; Sample pretreatment

DOI:  https://doi.org/10.1016/j.pscia.2026.100130