bims-medica 2025-08-03 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–08–03
25 papers selected by
Brett Chrest, Wake Forest University

Conservation and divergence of metabolic phenotypes between patient tumours and matched xenografts.
Metabolic Adaptations in Cancer Progression: Optimization Strategies and Therapeutic Targets.
Bioenergetic profiles and respiratory control in mitochondrial physiology: Precision analysis of oxidative phosphorylation.
Chronic stress inhibits weight gain and decreases beta-hydroxybutyrate levels and glucose tolerance in female BALB/c fed a high-fat ketogenic diet.
Impact of Metastatic Microenvironment on Physiology and Metabolism of Small Cell Neuroendocrine Prostate Cancer Patient-Derived Xenografts.
Towards Precision Nutrition: A Novel Smartphone-Connected Biosensor for Point-of-Care Detection of β-Hydroxybutyrate in Human Blood and Saliva.
Enzymatic synthesis of 3-hydroxyacyl-CoAs of branched-chain amino acid catabolism.
Mitochondrial pyruvate dehydrogenase phosphatase metabolism disorder in malignant tumors.
Targeting iNAMPT and NAD Biosynthesis to Break the Obesity-Associated Liver Cancer Link.
Hypoxia-Induced Creatine Uptake Reprograms Metabolism to Antagonize PARP1-Mediated Cell Death and Facilitate Tumor Progression in Hepatocellular Carcinoma.
Engineering Escherichia coli Pyruvate Metabolism to Generate Noncanonical Reducing Power.
Monocarboxylate Transporter-1 Is Dispensable for Hepatocellular Carcinoma Development.
Isocitrate Dehydrogenase-Wildtype Glioma Adapts Toward Mutant Phenotypes and Enhanced Therapy Sensitivity Under D-2-Hydroxyglutarate Exposure.
Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.
Nutrient sensing in intestinal stem cell: Linking dietary nutrients to cellular metabolic regulation.
Revisiting the biological role of the Warburg effect: Evolving perspectives on cancer metabolism.
Mitochondrial Calcium Uniporter Links Acetyl-CoA Metabolism and H3K27 Acetylation to Maintain Glioblastoma Stem Cells.
De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer.
Germline and Somatic Changes Associated with the Development of Inherited and De Novo Pediatric Acute Myeloid Leukemia.
Unraveling the causal nexus between serum lactate levels and cancer risk: A Mendelian randomization study.
Linking mitochondria, fatty acids and HSC expansion during infection: implications for aging and metabolic diseases.
The metabolic advantage of being young and male in obesity treatment outcomes in mice.
Research advances on amino acid starvation interventions for hepatocellular carcinoma.
The source of dietary fat influences anti-tumour immunity in obese mice.
AFG2A-related encephalopathy: Effectiveness of ketogenic diet in epilepsy and mitochondrial dynamics modulation.

Nat Metab. 2025 Jul 29.

Conservation and divergence of metabolic phenotypes between patient tumours and matched xenografts.

Aparna D Rao, Ling Cai, Marelize Snyman, Rachel E Walsdorf, Xiangyi Li, Sophia N Wix, Gabrielle Gard, Ariel B Brown, Juliana Kim, Joao Santos Patricio, Sarah Muh, Misty Martin Sandoval, Lauren G Zacharias, Kristen A Heimdal, Wen Gu, Jade Homsi, Brittny Tillman, Rohit Sharma, Travis W Vandergriff, Ashley Solmonson, Brandon Faubert, Thomas P Mathews, Sean J Morrison, Ralph J DeBerardinis, Jennifer G Gill.

Patient-derived xenografts (PDXs) are frequently used as preclinical models, but their recapitulation of tumour metabolism in patients has not been closely examined. We developed a parallel workflow to analyse [U-13C]glucose tracing and metabolomics data from patient melanomas and matched PDXs. Melanomas from patients have substantial TCA cycle labelling, similar to levels in human brain tumours. Although levels of TCA cycle labelling in PDXs were similar to those in the original patient tumours, PDXs had higher labelling in glycolytic metabolites. Through metabolomics, we observed consistent alterations of 100 metabolites among PDXs and patient tumours that reflected species-specific differences in diet, host physiology and microbiota. Despite these differences, most of nearly 200 PDXs retained a 'metabolic fingerprint' largely durable over six passages and often traceable back to the patient tumour of origin. This study identifies both high- and low-fidelity metabolites in the PDX model system, providing a resource for cancer metabolism researchers.

DOI: https://doi.org/10.1038/s42255-025-01338-2
Cancers (Basel). 2025 Jul 15. pii: 2341. [Epub ahead of print]17(14):

Metabolic Adaptations in Cancer Progression: Optimization Strategies and Therapeutic Targets.

Agnieszka Dominiak, Beata Chełstowska, Grażyna Nowicka.

  As tumor research has deepened, the deregulation of cellular metabolism has emerged as yet another recognized hallmark of cancer. Tumor cells adapt different biochemical pathways to support their rapid growth, proliferation, and invasion, resulting in distinct anabolic and catabolic activities compared with healthy tissues. Certain metabolic shifts, such as altered glucose and glutamine utilization and increased de novo fatty acid synthesis, are critical early on, while others may become essential only during metastasis. These metabolic adaptations are closely shaped by, and in turn remodel, the tumor microenvironment, creating favorable conditions for their spread. Anticancer metabolic strategies should integrate pharmacological approaches aimed at inhibiting specific biochemical pathways with well-defined dietary interventions as adjunctive therapies, considering also the role of gut microbiota in modulating diet and treatment responses. Given the established link between the consumption of foods rich in saturated fatty acids and sugars and an increased cancer risk, the effects of diet cannot be ignored. However, current evidence from controlled and multicenter clinical trials remains insufficient to provide definitive clinical recommendations. Further research using modern omics methods, such as metabolomics, proteomics, and lipidomics, is necessary to understand the changes in the metabolic profiles of various cancers at different stages of their development and to determine the potential for modifying these profiles through pharmacological agents and dietary modifications. Therefore, clinical trials should combine standard treatments with novel approaches targeting metabolic reprogramming, such as inhibition of specific enzymes and transporters or binding proteins, alongside the implementation of dietary restrictions that limit nutrient availability for tumor growth. However, to optimize therapeutic efficacy, a precision medicine approach should be adopted that balances the destruction of cancer cells with the protection of healthy ones. This approach, among others, should be based on cell type-specific metabolic profiling, which is crucial for personalizing oncology treatment.

Keywords:  amino acids utilization; anticancer metabolic strategies; dietary interventions; fatty acid synthesis; glucose metabolism; gut microbiota; metabolic reprogramming; precision oncology; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers17142341
Exp Physiol. 2025 Aug 01.

Bioenergetic profiles and respiratory control in mitochondrial physiology: Precision analysis of oxidative phosphorylation.

Alba Timón-Gómez, Carolina Doerrier, Zuzana Sumbalová, Luiz F Garcia-Souza, Eleonora Baglivo, Luiza H D Cardoso, Erich Gnaiger.

  Oxidative phosphorylation (OXPHOS) is fundamental to mitochondrial function. Respirometry with living cells provides limited information compared to precision OXPHOS analysis with mitochondrial preparations, including isolated mitochondria, tissue homogenates, permeabilized tissues, and permeabilized cells. We studied mouse mitochondria from brain, a glucose-dependent tissue, and from heart, which relies highly on fatty acid oxidation (FAO). HEK 293T cells were analysed as a widely used experimental model. Human peripheral blood mononuclear cells (PBMCs) and platelets were obtained from non-invasive liquid biopsies, considering their potential as mitochondrial biomarkers. Twenty respiratory states were interrogated applying two substrate-uncoupler-inhibitor titration (SUIT) reference protocols in parallel. Convergent electron transfer (ET) into the coenzyme Q junction increased OXPHOS and ET capacities compared to separately stimulated pathways. In mouse heart and human PBMCs, OXPHOS capacities were identical to ET capacities in every pathway state. While this equivalence applied to the NADH-linked pathway in platelets, ET capacity exceeded OXPHOS capacity supported by NADH-linked substrates plus succinate. Surprisingly, mouse brain exhibited the highest excess ET capacity in the NADH-linked pathway. In contrast, ET capacity of different batches of HEK 293T cells varied at constant OXPHOS capacity. Precision OXPHOS analysis enables attribution of respiratory performance to nutrient-specific pathways. In studies ranging from exercise physiology to mitochondrial diseases, metabolic adjustments must be distinguished from functional defects. Bioenergetic profiles obtained by precision OXPHOS analysis gain perspective in the context of comparative mitochondrial physiology.

Keywords:  OXPHOS; coupling control; electron transfer system (ETS); high‐resolution respirometry (HRR); pathway control; substrate‐uncoupler‐inhibitor‐titration (SUIT) protocol

DOI:  https://doi.org/10.1113/EP092792
BMC Nutr. 2025 Jul 25. 11(1): 146

Chronic stress inhibits weight gain and decreases beta-hydroxybutyrate levels and glucose tolerance in female BALB/c fed a high-fat ketogenic diet.

Ana L Cantú-Ruiz, Diana Caballero-Hernández, Isaias Gutierrez-Leal, Ana C Martínez-Torres, Ricardo Gomez-Flores, Patricia Tamez-Guerra, Reyes Tamez-Guerra, Cristina Rodríguez-Padilla.

   INTRODUCTION: Known for its neuroprotective properties, the ketogenic diet (KD) recently has been shown to prevent weight loss induced by chronic stress in rats, although the mechanisms remain to be elucidated. The obesity-resistant BALB/c mouse is susceptible to chronic stress-induced weight loss, providing a useful model to study the interactions between diet and stress.
OBJECTIVE: This study aimed to evaluate the potential of a ketogenic diet to prevent chronic stress-induced weight loss in the obesity-resistant BALB/c mouse strain.
METHOD: BALB/c mice of both sexes, were divided into groups: (1) standard chow, (2) KD, (3) standard chow + stress, and (4) KD + stress. The stress groups were subjected to a restraint stress protocol for 23 d, 4 h a day. Morphometric changes, glucose tolerance, plasmatic corticosterone levels, and circulating ketone bodies were evaluated.
RESULTS: Levels of β-hydroxybutyrate increased in the KD group in both sexes. However, under stress, the increase in ketone bodies was lower in female mice. Compared with standard chow-fed groups, females on a KD gained significant body weight, an effect lost in females under stress, with decreasing fat tissue deposits. In male mice, although no changes in body weight were observed in the KD group, the mass of adipose tissue depots increased and remained unchanged under stress. Under chronic stress both standard chow and KD-fed mice lost weight. Under KD, female and male BALB/c mice exhibited decreased water and food intake, as well as reduced glucose tolerance, under resting and chronic stress conditions.
CONCLUSIONS: There is an interplay between chronic stress and ketogenic metabolism in BALB/c mice. In female mice, chronic stress interferes with ketogenesis, lowering beta-hydroxybutyrate levels and preventing weight gain whereas the KD inhibits chronic stress-induced glucose tolerance, this in a sex-dependent manner.

Keywords:  Chronic stress; Glucose tolerance; Ketogenic diet; Obesity-resistance; Sex-dependent; Β-hydroxybutyrate

DOI:  https://doi.org/10.1186/s40795-025-01129-8
Cancers (Basel). 2025 Jul 18. pii: 2385. [Epub ahead of print]17(14):

Impact of Metastatic Microenvironment on Physiology and Metabolism of Small Cell Neuroendocrine Prostate Cancer Patient-Derived Xenografts.

Shubhangi Agarwal, Deepti Upadhyay, Jinny Sun, Emilie Decavel-Bueff, Robert A Bok, Romelyn Delos Santos, Said Al Muzhahimi, Rosalie Nolley, Jason Crane, John Kurhanewicz, Donna M Peehl, Renuka Sriram.

  Background: Potent androgen receptor pathway inhibitors induce small cell neuroendocrine prostate cancer (SCNC), a highly aggressive subtype of metastatic androgen deprivation-resistant prostate cancer (ARPC) with limited treatment options and poor survival rates. Patients with metastases in the liver have a poor prognosis relative to those with bone metastases alone. The mechanisms that underlie the different behavior of ARPC in bone vs. liver may involve factors intrinsic to the tumor cell, tumor microenvironment, and/or systemic factors, and identifying these factors is critical to improved diagnosis and treatment of SCNC. Metabolic reprogramming is a fundamental strategy of tumor cells to colonize and proliferate in microenvironments distinct from the primary site. Understanding the metabolic plasticity of cancer cells may reveal novel approaches to imaging and treating metastases more effectively. Methods: Using magnetic resonance (MR) imaging and spectroscopy, we interrogated the physiological and metabolic characteristics of SCNC patient-derived xenografts (PDXs) propagated in the bone and liver, and used correlative biochemical, immunohistochemical, and transcriptomic measures to understand the biological underpinnings of the observed imaging metrics. Results: We found that the influence of the microenvironment on physiologic measures using MRI was variable among PDXs. However, the MR measure of glycolytic capacity in the liver using hyperpolarized 13C pyruvic acid recapitulated the enzyme activity (lactate dehydrogenase), cofactor (nicotinamide adenine dinucleotide), and stable isotope measures of fractional enrichment of lactate. While in the bone, the congruence of the glycolytic components was lost and potentially weighted by the interaction of cancer cells with osteoclasts/osteoblasts. Conclusion: While there was little impact of microenvironmental factors on metabolism, the physiological measures (cellularity and perfusion) are highly variable and necessitate the use of combined hyperpolarized 13C MRI and multiparametric (anatomic, diffusion-, and perfusion- weighted) 1H MRI to better characterize pre-treatment tumor characteristics, which will be crucial to evaluate treatment response.

Keywords:  glycolysis; hyperpolarized carbon-13 magnetic resonance imaging; metabolism; metastases; microenvironment; perfusion; physiology; small cell neuroendocrine cancer

DOI:  https://doi.org/10.3390/cancers17142385
Sensors (Basel). 2025 Jul 11. pii: 4336. [Epub ahead of print]25(14):

Towards Precision Nutrition: A Novel Smartphone-Connected Biosensor for Point-of-Care Detection of β-Hydroxybutyrate in Human Blood and Saliva.

Cristina Tortolini, Massimiliano Caprio, Daniele Gianfrilli, Andrea Lenzi, Riccarda Antiochia.

  Precision nutrition is an emerging approach that tailors dietary recommendations based on an individual's unique genetic, metabolic, microbiome, and lifestyle factors. β-hydroxybutyrate (β-HB) is a key ketone body produced during fat metabolism, especially in states of fasting, low-carbohydrate intake, or prolonged exercise. Therefore, monitoring β-HB levels provides valuable insights into an individual's metabolic state, making it an essential biomarker for precision and personalized nutrition. A smartphone-connected electrochemical biosensor for single-use, rapid, low-cost, accurate, and selective detection of β-HB in whole blood and saliva at the Point-of-Care (POC) is reported. A graphite screen-printed carbon electrode modified with potassium ferricyanide (Fe(III)GSPE) was used as an electrode platform for the deposition of β-hydroxybutyrate dehydrogenase (HBDH), nicotinamide adenine dinucleotide oxidized form (NAD+), and chitosan nanoparticles (ChitNPs). An outer poly(vinyl) chloride (PVC) diffusion-limiting membrane was used to protect the modified electrode. The biosensor showed a linear range in the clinically relevant range, between 0.4 and 8 mM, with a detection limit (LOD) of 0.1 mM. The biosensor was tested on human blood and saliva samples, and the results were compared to those obtained with a commercial ketone meter, showing excellent agreement.

Keywords:  chitosan nanoparticles; ferricyanide carbon screen printed electrode; precision nutrition; smartphone connected biosensor; β-hydroxybutyrate

DOI:  https://doi.org/10.3390/s25144336
Mol Genet Metab. 2025 Jul 19. pii: S1096-7192(25)00183-0. [Epub ahead of print]146(1-2): 109192

Enzymatic synthesis of 3-hydroxyacyl-CoAs of branched-chain amino acid catabolism.

Shupei Wang, Karine Gilbert, Hao Yang, Youlin Wang, Marie-Christine Tang, Alexandra Furtos, Grant A Mitchell.

  Acyl-coenzyme A (CoA) thioesters occupy key positions in normal metabolism and are directly related to many inborn errors of metabolism. The degradation pathways of the branched-chain amino acids (BCAAs) are rich in acyl-CoA intermediates, many of which give rise to diagnostically important organic acids and acylcarnitines. Because several such acyl-CoAs are not routinely commercially available, they cannot be identified and quantified in biological samples. This leaves a gap in the characterization of BCAA-related inborn errors of metabolism. We attempted the enzymatic synthesis of BCAA-related 3-hydroxyacyl-CoAs, starting with the corresponding 2,3-enoyl free acids. First the 2,3-enoyl free acid is linked to CoA by purified recombinant glutaconate coenzyme A-transferase (GctAB), a bacterial CoA transferase active toward short chain acids. Then, hydration of the resulting 2,3-enoyl-acyl-CoA is catalyzed by recombinant human short-chain enoyl-CoA hydratase (ECHS1, gene ECHS1), producing a 3-hydroxyacyl-CoA. In this fashion, we synthesized 3-hydroxyisovaleryl-CoA, 3-hydroxyisobutyryl-CoA, 2-methyl-3-hydroxybutyryl-CoA and 3-hydroxypropionyl-CoA. All of these are detectable in normal mouse liver. We also found an unexpected peak with the same mass/charge ratio as 2-methyl-3-hydroxybutyryl-CoA. This proved to be 3-hydroxyvaleryl-CoA, an intermediate of odd chain fatty acid oxidation. All 3-hydroxyacyl-CoA intermediates of BCAA degradation are either commercially available or can be synthesized by the methods described.

Keywords:  Acyl-CoAs; Coenzyme A; Diagnosis; Inborn errors of metabolism; Pathophysiology; Synthesis

DOI:  https://doi.org/10.1016/j.ymgme.2025.109192
Oncol Res. 2025 ;33(8): 1861-1874

Mitochondrial pyruvate dehydrogenase phosphatase metabolism disorder in malignant tumors.

Yufeng Wang, Huifeng Dang, Qianqian Wang, Shuxiao Wu, Lei Han, X U Luo, Yingxia Tian, Hailin Tang.

  This review focuses on the metabolic issues related to mitochondrial pyruvate dehydrogenase phosphatase (PDP) in malignant tumors and its potential mechanisms. Recent research on tumor metabolic mechanisms has shown that PDP dysregulation is closely linked to metabolic reprogramming in tumor cells, and potentially promotes tumor. Research has comprehensively explored the structural-functional characteristics of PDP, its metabolic regulatory mechanisms, and its role in various types of malignant tumors. Nevertheless, several questions still exist regarding its potential mechanisms within acetylation, phosphorylation, hypoxia, immune infiltration, mitochondrial metabolism, drug resistance, oxidative phosphorylation, and tumor prognosis. This article intends to summarize the latest research, examine PDP's potential as a therapeutic target, and propose future research directions to enhance cancer treatment strategies.

Keywords:  Malignant tumors; Metabolism; Mitochondria; Pyruvate dehydrogenase phosphatase (PDP)

DOI:  https://doi.org/10.32604/or.2025.063716
Biomedicines. 2025 Jun 24. pii: 1533. [Epub ahead of print]13(7):

Targeting iNAMPT and NAD Biosynthesis to Break the Obesity-Associated Liver Cancer Link.

Kelly Thornton, Linda Torres, Elisa L Pedone, Jessica S Waltenbaugh, Cassandra M Swanson, Emily Gonzalez, Ramona S Price.

  Background and Objectives: Obesity is linked to liver cancer through metabolic mechanisms and can promote tumor growth through metabolic impairment, decreased lipid metabolism, and interference of the energy balance in the liver. NAMPT is an enzyme expressed in the liver and is involved in the progression of tumors in obesogenic environments, while iNAMPT is known to be the rate-limiting enzyme in the synthesis of NAD, an essential coenzyme involved in ATP synthesis which promotes a pro-growth environment in the context of obesity. Because iNAMPT and cellular energetics, a hallmark of cancer, play an important role in liver cancer progression, it has become a target for cancer therapies focused on inhibiting its functions. The objective of this study was to determine the contribution of NAD biosynthesis in obesity-associated liver cancer progression. Methods: Cell culture studies were conducted with serum from male mice randomized to diet-induced obesity (OB) or control (CR) ± FK866 (iNAMPT inhibitor) in SNU, HepG2 human liver cancer cells, and Hepa 1-6 liver murine cells. Protein analysis of pAkt and pErk was performed via immunoblot. Cytotoxicity, reactive oxygen species (ROS), cell viability, and invasion were also measured in the cells. For the mouse model, the C57BL/6J male mice were randomized to the DIO or CR group. At 21 weeks of age, the mice were injected subcutaneously with Hepa 1-6 liver cancer cells. At 23 weeks, the mice received an I.P. injection of FK866 (30 mg/kg) for 2 weeks. The tumor and mouse weights were measured. Results: The cells exposed to OB sera showed increased proliferation, lactate dehydrogenase (LDH) secretion, ROS, and invasion. FK866 decreased proliferation, LDH secretion, ROS, and invasion for all liver cancer cells. The cells exposed to CR sera and OB + FK866 resulted in more LDH, suggesting increased apoptosis compared with OB sera. The OB sera increased phosphorylation of Akt, which was suppressed by FK866 compared with the OB group. In liver cancer cells, physiological and cellular signaling is affected differently when inhibiting NAD biosynthesis in an in vitro model of obesity and liver cancer. In vivo, the diet-induced obese (DIO) mice weighed significantly more than the mice fed a control diet. In addition, 70% of the DIO mice developed tumors, compared with 20% of the CR mice, and had tumors with greater volumes and weights. NAD inhibition blocked obesity-induced tumor growth. Conclusions: In this study, we demonstrate that inhibition of iNAMPT resulted in suppression of tumor growth in the context of obesity. Identifying pre-clinical strategies to reverse the impact of obesity on liver cancer progression is important due to the strong increased risk of liver cancer and its poor prognosis. Future translational research studies can be built from this pre-clinical foundational research.

Keywords:  NAMPT; adipokine; liver cancer; obesity; visfatin

DOI:  https://doi.org/10.3390/biomedicines13071533
Cancer Res. 2025 Jul 31.

Hypoxia-Induced Creatine Uptake Reprograms Metabolism to Antagonize PARP1-Mediated Cell Death and Facilitate Tumor Progression in Hepatocellular Carcinoma.

Rui-Zhe Li, Guo-Qiang Pan, Chen Xiong, Zi-Niu Ding, Tuan-Song Zhang, Lun-Jie Yan, Dongxu Wang, Xiaolu Zhang, Xiao-Feng Dong, Yu-Chuan Yan, Yu Zhou, Rui Dong, Zhao-Ru Dong, Tao Li.

Recently, a PARP1-dependent cell-death process termed "parthanatos" that is driven by DNA damage has emerged as a crucial regulator of tissue homeostasis and tumorigenesis. Hypoxia is a hallmark of solid tumors and profoundly affects the malignant phenotypes of cancer cells. Here, we investigated the crosstalk between parthanatos and hypoxia. Despite causing DNA damage, hypoxia failed to induce parthanatos in hepatocellular carcinoma (HCC). The creatine transporter SLC6A8 promoted parthanatos antagonism and malignant phenotypes in hypoxic HCC cells. Hypoxia-induced creatine accumulation drove metabolic reprogramming and antagonized parthanatos. Mechanistically, creatine elevated SERPINE1 expression through MPS1-mediated Smad2/3 phosphorylation and formed a creatine/SERPINE1/HIF-1α positive feedback loop. SERPINE1 facilitated USP10-mediated deubiquitination and stabilization of PKLR by forming a SERPINE1-USP10-PKLR complex. USP10 contained a strong PAR-binding motif, and SERPINE1 reversed the attenuated deubiquitination activity of USP10 caused by the direct binding of PAR under hypoxia. The SLC6A8 inhibitor RGX-202 exerted potent antitumor activity alone and in combination with lenvatinib in patient-derived xenografts and primary HCC mouse models. Overall, this study identified intracellular creatine accumulation as a mechanism that allows hypoxic cancer cells to circumvent parthanatos and as a therapeutic target in HCC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0301
ACS Catal. 2024 Jul 05. 14(13): 9776-9784

Engineering Escherichia coli Pyruvate Metabolism to Generate Noncanonical Reducing Power.

Derek Aspacio, Emma Luu, Suphanida Worakaensai, Youtian Cui, Sarah Maxel, Edward King, Raine Hagerty, Alexander Chu, Derek Minn, Justin B Siegel, Han Li.

  The future of biomanufacturing is dependent on rewiring biological systems to establish an alternative approach to our current chemical industries. However, a key limitation in biomanufacturing is that desired processes must rely on the same two redox cofactors as natural metabolism, nicotinamide adenine dinucleotide (phosphate) NAD(P)+, to shuttle electrons energy. Thus, competition of resources with natural reactions within host cells is nearly unavoidable. One strategy to overcome redox cofactor resource competition is the implementation of a third, noncanonical redox cofactor, such as nicotinamide mononucleotide (NMN+), which supports specific electron delivery to desired reactions. Here, we redesign the Escherichia coli pyruvate dehydrogenase multienzyme complex (PDHc) to specially utilize NMN+ by engineering its E3 subunit (Lpd). Through rational design, we discover a cofactor promiscuous variant Lpd Penta (G182R-I186T-M206E-E205W-I271L) with an ~2500-fold improvement in NMN+ apparent turnover number. We tailor the enzyme to exclusively use NMN+ through computational design and construct Lpd Ortho (Penta-R292E-Q317L) with a 2.4 × 105-fold cofactor specificity improvement toward NMN+ compared to the wild type. Molecular simulation allowed tracking of the cofactor's alternative binding poses that emerge as the enzyme evolves, which was crucial to precisely guide engineering. We demonstrate that the engineered NMN+-specific PDHc functions in E. coli cells to sustain the life-essential pyruvate metabolism, in an NMN+-dependent manner. These results expand the available NMN+ toolkit to include the high flux and nearly irreversible reaction of PDHc as an insulated electron source.

Keywords:  biomimetic cofactor; dihydrolipoamide dehydrogenase; nicotinamide mononucleotide; noncanonical redox cofactor; orthogonal pathway engineering; pyruvate dehydrogenase complex; rational protein design

DOI:  https://doi.org/10.1021/acscatal.4c02131
Mol Carcinog. 2025 Jul 31.

Monocarboxylate Transporter-1 Is Dispensable for Hepatocellular Carcinoma Development.

Shaimaa A Gad, Bryan Bridgeman, Kyle Boedeker, Xianzhong Ding, Wei Qiu.

  Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer and the deadliest liver disease. It is imperative to understand the underlying molecular mechanisms involved in the development of HCC. Monocarboxylate transporter-1 (MCT1) is a proton-coupled protein that facilitates the bidirectional transport of monocarboxylates, such as lactate and pyruvate, across the plasma membrane to maintain the cellular metabolism and energy supply. MCT1 was found to be upregulated in human HCC specimens, and its inhibition reduced xenograft tumor growth. However, the role of MCT1 in HCC remains to be further investigated using immune-competent in vivo models. To better understand the role of MCT1 in HCC, we established liver-specific MCT1 knockout mice. We found that deletion of MCT1 in liver cells did not affect morphology, proliferation, or apoptosis. DEN/CCl4 model, where a single injection of DEN is followed by repeated injections of CCl4, was used to induce HCC in mice. Intriguingly, we found that liver-specific knockout of MCT1 was not sufficient to reduce the size or count of DEN/CCl4-induced liver tumors. In addition, we used immunohistochemical staining to evaluate the expression of Ki67, collagen A1, and myeloperoxidase, and we found that MCT1 knockout was not able to hinder the proliferation, fibrosis, and inflammation in the DEN/CCl4-induced HCC tumors. In conclusion, MCT1 is dispensable for HCC development, and its deletion was insufficient to alleviate the phenotypic repercussions of HCC tumors in the DEN/CCl4-induced HCC model.

Keywords:  dispensable; hepatocellular carcinoma; metabolism; monocarboxylate transporter 1

DOI:  https://doi.org/10.1002/mc.70021
Biomedicines. 2025 Jun 28. pii: 1584. [Epub ahead of print]13(7):

Isocitrate Dehydrogenase-Wildtype Glioma Adapts Toward Mutant Phenotypes and Enhanced Therapy Sensitivity Under D-2-Hydroxyglutarate Exposure.

Geraldine Rocha, Clara Francés-Gómez, Javier Megías, Lisandra Muñoz-Hidalgo, Pilar Casanova, Jose F Haro-Estevez, Vicent Teruel-Martí, Daniel Monleón, Teresa San-Miguel.

  Background/Objectives: Isocitrate dehydrogenase (IDH) mutations are hallmark features in subsets of gliomas, producing the oncometabolite D-2-hydroxyglutarate (2HG). Although IDH mutations are associated with better clinical outcomes, their relationship with tumor progression is complex. This study aimed to investigate, in vitro and in vivo, the phenotypic consequences of IDH mutation and 2HG exposure in glioblastoma (GBM) under normoxic and hypoxic conditions and under temozolomide (TMZ) and radiation exposure. Methods: Experiments were conducted using IDH-wildtype (IDH-wt) and IDH-mutant (IDH-mut) glioma cell lines under controlled oxygen conditions. Functional assays included cell viability, cell cycle analysis, apoptosis profiling, migration, and surface marker expression via flow cytometry. Orthotopic xenografts were established in immunocompromised mice to assess in vivo tumor growth and morphology, followed by MRI and histological analysis. Treatments included TMZ, radiation, and 2HG at varying concentrations. Statistical analyses were performed using SPSS and RStudio. Results:IDH-wt cells exhibited faster proliferation and greater adaptability under hypoxia, while IDH-mut cells showed cell cycle arrest and limited growth. 2HG recapitulated IDH-mut features in IDH-wt cells, including increased apoptosis under TMZ, reduced proliferation, and altered CD24/CD44 expression. In vivo, IDH-wt tumors were larger and more infiltrative, while 2HG administration reduced tumor volume and promoted compact morphology. Notably, migration was initially similar across genotypes but increased in IDH-mut and 2HG-treated IDH-wt cells over time, though suppressed under therapeutic stress. Conclusions:IDH mutation and 2HG modulate glioma cell biology, including cell cycle dynamics, proliferation rates, migration, and apoptosis. While the IDH mutation and its metabolic product confer initial growth advantages, they enhance treatment sensitivity and reduce invasiveness, highlighting potential vulnerabilities for targeted therapy.

Keywords:  2-hydroxyglutarate; IDH; adjuvant radiotherapy; astrocytoma; drug resistance in neoplasms; glioblastoma; glioma; isocitrate dehydrogenase mutation; orthotopic xenograft models

DOI:  https://doi.org/10.3390/biomedicines13071584
Blood. 2025 Aug 01. pii: blood.2024027822. [Epub ahead of print]

Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.

Cornelius Pauli, Michael Kienhöfer, Maximilian Felix Blank, Oguzhan Begik, Christian Rohde, Sarah Mn Zimmermann, Laura Werner, Daniel Heid, Fu Xu, Katharina Weidenauer, Sylvain Delaunay, Nadja Krall, Katrin Trunk, Duoduo Zhao, Fengbiao Zhou, Laia Llovera, Ollivier Alexane, Anke Heit-Mondrzyk, Uwe Platzbecker, Claudia D Baldus, Hubert Serve, Martin Bornhäuser, Cathrine B Vågbø, Salvador Aznar Benitah, Jeroen Krijgsveld, Eva Maria Novoa, Carsten Müller-Tidow, Michaela Frye.

Dysregulated RNA modifications contribute to cancer progression and therapy resistance, yet the underlying mechanism often remains unknown. Here, we perform CRISPR-based synthetic lethality screens to systematically explore the role of RNA modifications in mediating resistance to anti-leukaemic drugs. We identify the TRMT5-mediated formation of N1-methylguanosine (m1G) in the tRNA anticodon loop as essential for mediating drug tolerance to cytarabine and venetoclax in acute myeloid leukemia (AML). TRMT5 methylates nearly all mitochondrial and nuclear tRNAs with a guanosine at position 37, but its role in promoting drug tolerance specifically depends on its mitochondrial function. TRMT5 is essential for the dynamic upregulation of mitochondrial mRNA translation and oxidative phosphorylation (OXPHOS), which are critical for sustaining drug tolerance in leukemia cells. This mitochondrial dependency correlates with therapy outcomes in leukemia patients: lower expression of electron transport chain genes is linked to poorer outcomes in a cohort of nearly 100 AML patients undergoing first induction therapy. Finally, we demonstrate that targeted depletion of TRMT5 protein using a conditional degron, in conjunction with cytarabine and venetoclax treatment, synergistically induces cell death in drug-tolerant AML cells. Thus, our study reveals TRMT5 as promising drug target for therapy-resistant leukemia.

DOI: https://doi.org/10.1182/blood.2024027822
World J Stem Cells. 2025 Jul 26. 17(7): 107770

Nutrient sensing in intestinal stem cell: Linking dietary nutrients to cellular metabolic regulation.

Wen-Hao Li, Xin-Yi Yuan, Zhe Wang, Rong Lin.

  Diet and nutrition significantly influence health, largely by regulating intestinal nutrient absorption. The intestinal epithelium, as the primary site for nutrient uptake, undergoes continuous renewal driven by precise regulation of intestinal stem cells (ISCs). Nutrient sensing and metabolism are key determinants of ISC fate, making ISCs a central link between nutrient metabolism and the regulation of intestinal tissue renewal and homeostasis. Understanding how ISCs respond or make adaptations to nutritional signals is therefore vital for maintaining intestinal homeostasis. Recent studies have spotlighted the origin and identity of ISCs and broadened our insight into the plasticity and function of ISCs under different conditions. Mitochondria, the central hubs of energy production and metabolic signals provided by dietary components and metabolic substrates, such as glucose, amino acids, and lipids, govern the intricate balance between self-renewal and differentiation of ISCs. This review highlights the importance of nutrient sensing, metabolic regulation, and mitochondrial function in the specification of ISC fate. A thorough understanding of these mechanisms paves the way for the development of stem cell-based therapy for the mucosal healing of gastrointestinal diseases and diet intervention to foster body health.

Keywords:  Intestinal organoids; Intestinal stem cell; Metabolic regulation; Mitochondria; Nutrient sensing

DOI:  https://doi.org/10.4252/wjsc.v17.i7.107770
Pathol Res Pract. 2025 Jul 28. pii: S0344-0338(25)00344-9. [Epub ahead of print]273 156151

Revisiting the biological role of the Warburg effect: Evolving perspectives on cancer metabolism.

Diego De Leon-Oliva, Paula González-Prieto, Patricia De Castro-Martinez, Diego Liviu Boaru, Pilar Laguna-Hernández, Oscar Fraile-Martinez, Cielo García-Montero, Luis G Guijarro, Laura López-González, Raul Díaz-Pedrero, Melchor Álvarez-Mon, Miguel A Saez, Miguel A Ortega.

  Cancer cells exhibit metabolic reprogramming towards a glycolysis-dominant profile. This shift, known as the Warburg effect, enhances cancer cell survival, growth, and metastasis by increasing glucose uptake and lactate production. It also meets the high anabolic demands of proliferation by providing important biosynthetic precursors. Despite its long-standing discovery, the origins and roles of the Warburg effect in cancer remain unclear. Recent research has provided deeper insights into its cellular origins and involvement in cancer progression and metastasis. Therefore, this review aims to provide a comprehensive and updated understanding of the significance of glycolysis in cancer. Initially, a brief overview of the glycolytic pathway will be presented, followed by an in-depth discussion of how this pathway is altered in cancer, its biological significance, and its regulatory mechanisms. We highlight that lactate production in cancer cells may not solely reflect a metabolic inefficiency, but rather a compensatory mechanism to regenerate cytosolic NAD⁺ when mitochondrial NADH shuttles become saturated, thereby sustaining glycolytic flux under rapid proliferative demands. Finally, the review will explore the translational implications of glycolysis research in the clinical context.

Keywords:  Cancer; Cancer therapy; Glucose; Glycolysis; Warburg effect

DOI:  https://doi.org/10.1016/j.prp.2025.156151
Cancer Res. 2025 Jul 25.

Mitochondrial Calcium Uniporter Links Acetyl-CoA Metabolism and H3K27 Acetylation to Maintain Glioblastoma Stem Cells.

Guangqin Liu, Haoqian Zhang, Siqi Chen, Jun Gao, Haixin Zhao, Yan Dong, Changwei Liu, Xuechen Wei, Ting Li, Chang Lu, Haizhen Zhu, Dingyi Lu, Shiyu Feng, Teng Li, Weina Zhang, Qing Xia, Jianghong Man, Tao Zhou, Jiayi Chen, Ailing Li, Xin Pan.

Glioblastoma stem cells (GSCs) exhibit remarkable metabolic and epigenetic adaptability, contributing to therapeutic resistance and tumor recurrence. The mechanisms underlying this plasticity represent potential targetable vulnerabilities to improve glioblastoma treatment. Here, we identified a critical metabolic-epigenetic axis centered on the mitochondrial calcium uniporter (MCU) that governs GSC survival and tumor initiation. MCU was preferentially expressed in GSCs, and loss of MCU significantly impaired GSC self-renewal and viability. Mechanistically, MCU enhanced mitochondrial calcium uptake, promoting acetyl-CoA production via pyruvate dehydrogenase activation. Elevated acetyl-CoA levels drove histone H3K27 acetylation at the TRIB3 locus to maintain GSC growth. In glioblastoma patients, higher MCU expression was correlated with increased acetyl-CoA levels, elevated H3K27 acetylation, enhanced TRIB3 expression, higher tumor grade, and poorer survival. Pharmacological inhibition of MCU with berberine suppressed GSC growth and extended survival in mouse GBM models. These findings establish MCU as a critical link between mitochondrial metabolism and epigenetic regulation, highlighting its potential as a therapeutic target for glioblastoma.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0419
Nat Commun. 2025 Jul 30. 16(1): 6987

De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer.

Huan Zhang, Naiara Santana-Codina, Qijia Yu, Clara Poupault, Claudia Campos, Xingping Qin, Nicole Sindoni, Marina Ciscar, Aparna Padhye, Miljan Kuljanin, Junning Wang, Matthew J Dorman, Peter Bross, Andrew J Aguirre, Stephanie K Dougan, Kristopher A Sarosiek, Joseph D Mancias.

Oncogenic KRAS induces metabolic rewiring in pancreatic ductal adenocarcinoma (PDAC) characterized, in part, by dependency on de novo pyrimidine biosynthesis. Pharmacologic inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, delays pancreatic tumor growth; however, limited monotherapy efficacy suggests that compensatory pathways may drive resistance. Here, we use an integrated metabolomic, proteomic and in vitro and in vivo DHODH inhibitor-anchored genetic screening approach to identify compensatory pathways to DHODH inhibition (DHODHi) and targets for combination therapy strategies. We demonstrate that DHODHi alters the apoptotic regulatory proteome thereby enhancing sensitivity to inhibitors of the anti-apoptotic BCL2L1 (BCL-XL) protein. Co-targeting DHODH and BCL-XL synergistically induces apoptosis in PDAC cells and patient-derived organoids. The combination of DHODH inhibition with Brequinar and BCL-XL degradation by DT2216, a proteolysis targeting chimera (PROTAC), significantly inhibits PDAC tumor growth. These data define mechanisms of adaptation to DHODHi and support combination therapy targeting BCL-XL in PDAC.

DOI: https://doi.org/10.1038/s41467-025-61242-x
Genes (Basel). 2025 Jul 01. pii: 798. [Epub ahead of print]16(7):

Germline and Somatic Changes Associated with the Development of Inherited and De Novo Pediatric Acute Myeloid Leukemia.

Scott C Smith, Lei Zhang.

  Acute myeloid leukemia (AML) accounts for only about 15-20% of pediatric leukemia and an overall incidence of 1.4 cases per 200,000 children under the age of 15 years. The majority of pediatric AML occurs de novo, often as the result of somatic first hits in utero. A minority of pediatric AML occurs in response to a predisposition syndrome, such as a bone marrow failure syndrome, or other inherited mutations and copy number changes. While the overall survival of pediatric patients with AML is approximately 70%, survival at the individual level is dependent on the abnormality detected either through cytogenomic analyses or sequencing for mutations in responsible genes. Indeed, de novo infant AML carries a more sobering prognosis than that of pediatric AML. This review describes many of the common genomic abnormalities associated with pediatric AML and characterizes their detection from a laboratory assessment perspective. Pediatric AML is primarily a disease of gene rearrangements rather than of gene mutations, and, as such, clinical cytogenetics takes a primary role.

Keywords:  cytogenetics; cytogenomics; de novo AML; genetic abnormalities; inherited AML; pediatric AML

DOI:  https://doi.org/10.3390/genes16070798
Medicine (Baltimore). 2025 Jul 25. 104(30): e43388

Unraveling the causal nexus between serum lactate levels and cancer risk: A Mendelian randomization study.

Lei Yang, Yan Zheng, Faping Li, Jinyu Yu.

  Lactate, traditionally regarded as a metabolic byproduct, has emerged as a potential signaling molecule involved in tumorigenesis. Although numerous observational studies have linked serum lactate levels to various tumors, establishing a direct causal relationship remains challenging. We conducted a 2-sample Mendelian randomization (MR) analysis using genetic instrumental variables to assess the causal effects of serum lactate levels on the risk of various cancer types. The primary analytical method used in this investigation was the random inverse-variance weighted (IVW) method, supported by auxiliary methods such as MR-Egger, weighted median, simple mode, and weighted mode, with the IVW method enabling the meta-analysis of their combined effects. To obtain exposure data, we extracted genome-wide association studies (GWAS) data on metabolite levels from the Canadian Longitudinal Study on Aging and the UK Biobank cohorts. Concurrently, GWAS data for 17 types of cancer were obtained from the IEU Open GWAS project and the GWAS Catalog project. Sensitivity analyses were performed using the Cochran Q test, MR-Egger intercept test, MR-PRESSO, and the leave-one-out method. Our MR analysis identified a causal relationship between serum lactate and endometrial cancer (odds ratio [OR]IVW = 1.1217, 95% confidence interval [CI] = 1.0264-1.2258, P = .0112), melanoma (ORIVW = 1.0015, 95% CI = 1.0006-1.0024, P = .0010), and prostate cancer (ORIVW = 0.9578, 95% CI = 0.9319-0.9844, P = .0020). Notably, elevated lactate levels were identified as a risk factor for endometrial cancer and melanoma, while having a protective effect against prostate cancer. However, this observed relationship was not replicated in other cancer types. Our study, using GWAS data, establishes a causal link between circulating lactate and the risk of endometrial cancer, melanoma, and prostate cancer. The identification of these associations suggests the potential utility of lactate as a biomarker for these cancers or as a target for cancer prevention strategies.

Keywords:  Mendelian randomization; cancers; causality; lactate

DOI:  https://doi.org/10.1097/MD.0000000000043388
Stem Cells. 2025 Jul 29. pii: sxaf053. [Epub ahead of print]

Linking mitochondria, fatty acids and HSC expansion during infection: implications for aging and metabolic diseases.

Katherine Hampton, Alyssa Polski-Delve, Charlotte Hellmich, Stuart A Rushworth.

  In steady state, hematopoietic stem cells (HSCs) reside quiescently in their hypoxic niche with minimal mitochondrial activity, maintaining characteristically low levels of reactive oxygen species (ROS) and instead favoring glycolysis to meet their low energy requirements. However, stress, such as acute infection, triggers a state of emergency hematopoiesis during which HSCs expand more rapidly to produce up to ten-fold more downstream differentiated immune cells. To cope with this demand, HSCs increase their energy production by switching from low ATP-yielding glycolysis to high ATP-yielding mitochondrial oxidative phosphorylation. It is this metabolic switch that enables rapid HSC expansion and differentiation into downstream progeny to increase the immune cell pool and effectively clear the infection. This metabolic switch relies on the sufficient availability of healthy mitochondria as well as fuel in the form of free fatty acids to drive the necessary production of cellular components. This concise review aims to focus on how HSCs increase their mitochondrial content and fuel ATP production via fatty acid oxidation and the impact of HSC dysfunction during aging and other metabolic diseases.

Keywords:  Acute myelogenous leukemia (AML); Adult haematopoietic stem cells; Bone marrow; Stem cell expansion; adipose

DOI:  https://doi.org/10.1093/stmcls/sxaf053
NPJ Metab Health Dis. 2025 Aug 01. 3(1): 32

The metabolic advantage of being young and male in obesity treatment outcomes in mice.

Amanda S Dirnberger, Elen Yanina Aguirre-Rodriguez, Elias Carlos Aguirre-Rodriguez, John O Degraft Hanson, Yanping Sun, Dave Delima, Benjamin F Bykov, Aneirson Francisco da Silva, Marko Kraljević, Fernando Augusto Silva Marins, Ana Bf Emiliano.

Although diversity in clinical trials is important to test the efficacy of a treatment, weight loss trials rarely account for age and sex. To highlight this deficiency, we set out to test whether age and sex affect WAT mobilization after weight loss surgery or intermittent fasting, in an obese mouse model. Here we show that male sex, youth, and WAT transcriptomic plasticity are characteristics associated with improved weight loss outcomes. Conversely, aging impairs WAT mobilization and transcriptomic plasticity. Greater surgical weight loss is associated with changes in the expression of genes relevant to the IL17 inflammatory signaling pathway, angiotensin converting enzyme 2 (ACE2) signaling, lipolysis, carbohydrate metabolism and adipocyte differentiation. In conclusion, female sex and older age appear to hinder molecular processes necessary for the reversal of WAT expansion. Future studies should examine the relevance of these findings to human obesity therapeutics.

DOI: https://doi.org/10.1038/s44324-025-00065-2
Biochim Biophys Acta Rev Cancer. 2025 Jul 24. pii: S0304-419X(25)00142-8. [Epub ahead of print]1880(5): 189400

Research advances on amino acid starvation interventions for hepatocellular carcinoma.

Yanqi Li, Lin Li, Yongyong Hou, Xueqiang Peng, Hangyu Li.

  Hepatocellular carcinoma (HCC) is an aggressive malignancy associated with high mortality. Numerous endeavors have been undertaken to develop more effective pharmaceutical interventions. Metabolic reprogramming is recognized as a hallmark of cancer for adapting to heightened bioenergetic and biosynthetic demands. Amino acid (AA) metabolism dysregulation plays a crucial role in the tumor initiation and progression of HCC, resulting in high reliance on AA availability. This makes HCC cells vulnerable to AA starvation, implying that restricting AA supply and utilization may offer a promising nutritional strategy in HCC therapy. We delineate the pivotal physiological functions and aberrant alterations of various AA metabolisms in HCC. We systematically summarize the recent advances in agents, targets, antineoplastic effects, and mechanisms of various AA starvation strategies in HCC, including dietary restriction, circulating depletion, transporter blockade, and metabolic enzyme inhibition. We further discussed a suite of adaptive responses that enable HCC cells to survive with AA shortage. Targeting these adaptive pathways in combination with AA starvation may enhance the efficacy of HCC treatment. This review aims to provide a comprehensive overview of progress in the field of AA starvation for HCC therapy and to explore novel therapeutic opportunities and strategies through nutritional intervention for HCC therapy.

Keywords:  Amino acid metabolism; Amino acid starvation; Cancer nutrition; Hepatocellular carcinoma

DOI:  https://doi.org/10.1016/j.bbcan.2025.189400
Nat Metab. 2025 Jul 25.

The source of dietary fat influences anti-tumour immunity in obese mice.

Britta Kunkemoeller, Hannah Prendeville, Claire McIntyre, Ayantu Temesgen, Rόisín M Loftus, Conghui Yao, Lydia Dyck, Linda V Sinclair, Christina Rollings, Aaron Douglas, Gerard Pernes, Kathleen A J Mitchelson, Cathal Harmon, Mathilde Raverdeau, Ross Ward, Harry Kane, Jaclyn Kline, Katie L O'Brien, Martin Brennan, Frances Smith, Brenneth Stevens, Helen M Roche, Ed C Lavelle, David K Finlay, Doreen A Cantrell, Edward T Chouchani, Susan Kaech, Evanna L Mills, Marcia Haigis, Lydia Lynch.

Obesity increases the risk of many cancers and impairs the anti-tumour immune response. However, little is known about whether the source or composition of dietary fat affects tumour growth or anti-tumour immunity in obesity. Here, we show that high-fat diets (HFDs) derived from lard, beef tallow or butter accelerate tumour growth in a syngeneic model of melanoma, but HFDs based on coconut oil, palm oil or olive oil do not, despite equivalent obesity. Using butter-based and palm oil-based HFDs as examples, we find that these dietary fat sources differentially regulate natural killer and CD8 T cell infiltration and function within the tumour microenvironment, governed by distinct effects on the plasma metabolome and intracellular metabolism. We identify diet-related lipid intermediates, namely long-chain acylcarnitine species, as immunosuppressive metabolites enriched in mice fed butter compared to palm oil HFD. Together, these results highlight the significance of diet in maintaining a healthy immune system and suggest that modifying dietary fat may improve cancer outcomes in obesity.

DOI: https://doi.org/10.1038/s42255-025-01330-w
Eur J Paediatr Neurol. 2025 Jul 19. pii: S1090-3798(25)00116-3. [Epub ahead of print]58 20-26

AFG2A-related encephalopathy: Effectiveness of ketogenic diet in epilepsy and mitochondrial dynamics modulation.

Laia Nou-Fontanet, Uliana Musokhranova, Alia Ramírez Camacho, Verónica Delgadillo Chilavert, Víctor Soto Insuga, Luisa Arrabal Fernández, Itziar Alonso-Colmenero, Alexis Arzimanoglou, Ángeles García Cazorla, Alfonso Oyarzabal, Carmen Fons.

AFG2A-related encephalopathy (AFG2A-RE) is a neurodevelopmental disorder that may present with drug-resistant epilepsy (DRE). Our aims were: to evaluate the clinical response to a ketogenic diet (KD) in a series of patients with AFG2A-RE and DRE, and to describe the mitochondrial effects in patient's fibroblasts cultured in a KD mimicking medium (KD-MM). This was a collaborative, descriptive, and experimental study involving a total of five patients. The primary outcomes assessed following ketogenic diet (KD) treatment were the percentage of seizure reduction and the parents' global impression of change. Additionally, patient-derived fibroblasts (n = 3) were cultured in a KD-MM to evaluate effects on mitochondrial dynamics and metabolism. The mean age of the patients was 7.9 years, and four were males. All patients presented with developmental and epileptic encephalopathy with DRE, motor impairment, severe intellectual disability, deafness, and microcephaly. In all but one case, the initial epilepsy presentation was infantile epileptic spasms syndrome (IESS), with a mean age at onset of 13.6 months. Four patients received KD treatment for DRE, with seizure reduction rates of 0 %, 30 %, 70 % and 100 %, respectively. Improvement in social interaction improvement was observed in one patient, while improvements in attentional and motor function were noted in two. In vitro studies demonstrated that AFG2A-deficient fibroblasts exhibited altered mitochondrial morphology and dynamics, as well as reduced ATP production and ROS levels. These abnormalities were significantly reversed when the fibroblasts were cultured in KD-MM. In conclusion, this small series of patients with AFG2A-RE showed beneficial effects from KD treatment. Greater seizure control was achieved when the ketogenic diet was initiated during early childhood. These findings are preliminary and validation in multicenter prospective study is required.

DOI: https://doi.org/10.1016/j.ejpn.2025.07.007