bims-medica 2025-05-25 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–05–25
24 papers selected by
Brett Chrest, Wake Forest University

Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.
Hepatic glutamic-oxaloacetic transaminase (GOT2) promotes mitochondrial respiration energized at complex II and alters whole body metabolism.
De novo serine biosynthesis is protective in mitochondrial disease.
The effects of ketone bodies and ketogenesis on the PI3K/AKT/mTOR signaling pathway: A systematic review.
Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of 13C-labelled glucose metabolism.
Microbiome metabolism of dietary phytochemicals controls the anticancer activity of PI3K inhibitors.
NDUFS3 promotes proliferation via glucose metabolism reprogramming inducing AMPK phosphorylating PRPS1 to increase the purine nucleotide synthesis in melanoma.
Crosstalk of glutamine metabolism between cancer-associated fibroblasts and cancer cells.
Excessive dietary saturated fat or fructose and their combination (found in ultra-processed foods) impair mitochondrial dynamics markers and cause brown adipocyte whitening in adult mice.
Image-guided targeting of mitochondrial metabolism sensitizes pediatric malignant rhabdoid tumors to low-dose radiotherapy.
GPT2 mediates metabolic alterations in platinum-resistant ovarian cancer cells.
Mathematical modelling of carbohydrate and protein metabolism in muscle.
Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia.
Targeting lipid metabolism in acute myeloid leukemia: biological insights and therapeutic opportunities.
Adenine nucleotide translocase 2 silencing promotes metabolic reprogramming in P19 embryonal carcinoma stem cells.
Mapping of Functional Metabolic Phenotypes in Acute Myeloid Leukemia.
Antiproliferative effect of ketogenic diet on hormone independent mammary gland carcinoma via harnessing glucose metabolism: In-vitro and In-vivo investigations.
Ketogenic diet and β-hydroxybutyrate inhibit HDAC1 to preserve vascular smooth muscle cell function in thoracic aortic aneurysm.
Subjective Experiences and Blood Parameter Changes in Individuals From Germany Following a Self-Conceived "Carnivore Diet": An Explorative Study.
β-hydroxybutyrate inhibits Plasmodium falciparum development and confers protection against malaria in mice.
Dietary lipids are largely deposited in skin and rapidly affect insulating properties.
ABHD18 degrades cardiolipin by stepwise hydrolysis of fatty acids.
Glutamine catabolism supports amino acid biosynthesis and suppresses the integrated stress response to promote photoreceptor survival.
Venetoclax and hypomethylating agents versus induction chemotherapy for newly diagnosed acute myeloid leukemia patients: a systematic review and meta-analysis.

Cancer Metab. 2025 May 19. 13(1): 22

Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.

Ayşegül Erdem, Séléna Kaye, Francesco Caligiore, Manuel Johanns, Fleur Leguay, Jan Jacob Schuringa, Keisuke Ito, Guido Bommer, Nick van Gastel.

   BACKGROUND: Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD+.
METHODS: We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry.
RESULTS: Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD+ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD+/NADH ratio in AML cells. Continuous intracellular NAD+ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition.
CONCLUSIONS: Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD+/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD+ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells.

Keywords:  Acute myeloid leukemia; Cancer metabolism; Glycolysis; Lactate dehydrogenase A; NAD+ ; Redox balance

DOI:  https://doi.org/10.1186/s40170-025-00392-4
J Biol Chem. 2025 May 21. pii: S0021-9258(25)02111-8. [Epub ahead of print] 110261

Hepatic glutamic-oxaloacetic transaminase (GOT2) promotes mitochondrial respiration energized at complex II and alters whole body metabolism.

Brian D Fink, Ritu Som, Adam J Rauckhorst, Eric B Taylor, Liping Yu, William I Sivitz.

  The mitochondrial enzyme, glutamic-oxaloacetic transaminase (GOT2), catalyzes the reaction between oxaloacetate and glutamate generating aspartate and alpha-ketoglutarate (α-KG). Glutamate can also be directly converted to α-KG by glutamate dehydrogenase. We investigated mitochondrial and systemic effects of an inducible liver specific-mouse GOT2 knockout (KO). We observed no differences in body mass or percent fat mass in KO mice, however, KO mice had lower fasting glucose and liver tissue contained more fat. Respiration by liver mitochondria energized at complex II by succinate + glutamate was decreased in KO compared to wildtype (WT) mice at low inner membrane potential (ΔΨ) as induced by titration with ADP. Metabolite studies by NMR showed that at low versus high ΔΨ, GOT2KO mitochondria energized by succinate + glutamate generated more oxaloacetate (a potent inhibitor of succinate dehydrogenase, SDH) and less aspartate. Respiration and mitochondrial metabolites energized by pyruvate + malate or palmitoyl-carnitine + malate did not differ between KO and WT mice. Respiration by GOT2KO mitochondria energized by glutamate + malate was decreased at all levels of ΔΨ. Pathway analysis of LC-MS profile data in liver tissue of KO versus WT mice revealed differential enrichment of the malate aspartate shuttle, TCA cycle, aspartate metabolism, glutamate metabolism, and gluconeogenesis. In summary, GOT2KO impaired potential-dependent complex II energized O2 flux likely due at least in part to oxaloacetate inhibition of SDH.

Keywords:  Mitochondria; glutamic-oxaloacetic transaminase-2; liver; mitochondrial complex II; mitochondrial inner membrane potential; oxaloacetate; respiration; succinate dehydrogenase

DOI:  https://doi.org/10.1016/j.jbc.2025.110261
Cell Rep. 2025 May 15. pii: S2211-1247(25)00481-4. [Epub ahead of print]44(5): 115710

De novo serine biosynthesis is protective in mitochondrial disease.

Christopher B Jackson, Anastasiia Marmyleva, Geoffray Monteuuis, Ryan Awadhpersad, Takayuki Mito, Nicola Zamboni, Takashi Tatsuta, Amy E Vincent, Liya Wang, Nahid A Khan, Thomas Langer, Christopher J Carroll, Anu Suomalainen.

  The importance of serine as a metabolic regulator is well known for tumors and is also gaining attention in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of the metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-driven de novo serine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles, and enhanced the mitochondrial integrated stress response (ISRmt) in vivo in skeletal muscle and in cultured cells. Our evidence indicates that de novo serine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activating de novo serine synthesis may protect against mitochondrial failure in skeletal muscle.

Keywords:  CP: Metabolism; de novo serine synthesis; mitochondrial disease; mitochondrial integrated stress response; mitochondrial translation; tissue specificity; treatment

DOI:  https://doi.org/10.1016/j.celrep.2025.115710
Nutr Res. 2025 Apr 22. pii: S0271-5317(25)00062-4. [Epub ahead of print]139 16-49

The effects of ketone bodies and ketogenesis on the PI3K/AKT/mTOR signaling pathway: A systematic review.

Azlinah Matawali, Jia Wen Yeap, Shaida Fariza Sulaiman, Mei Lan Tan.

  Ketogenesis and the PI3K/AKT/mTOR pathway are linked to metabolic imbalance and disease progression. While ketone metabolism and mTOR inhibition are mechanistically connected, their functional relationship across disease models remains unclear. Although ketogenesis can be induced by ketone ingestion, ketogenic diet, or fasting, their individual effects on this pathway require further clarification. This study systematically reviews the relationship between ketogenesis and PI3K/AKT/mTOR signaling, following PRISMA guidelines across 3 databases. Eligible studies that met the selection criteria were evaluated using the risk of bias tools. In most studies involving the ketogenic diet or ketone bodies, suppression of the signaling pathway may lead to positive outcomes in terms of survival rate, lifespan, improved metabolic homeostasis, enhanced neurovascular function and suppressed progression of tumors. By contrast, β-hydroxybutyrate supplementation is associated with the up-regulation of AKT and downstream markers. It may exert an anabolic activity by activating the mTOR signaling pathway in muscle atrophy models and is associated with muscle recovery. Although fasting increases p-AKT expression, this may not necessarily indicate activation of the downstream mTOR signaling cascade, as it could result from an insulin response or regulatory feedback mechanisms. Regulation of the mTOR signaling by ketogenesis may be tissue-specific. Inhibition of PI3K/AKT/mTOR in ketogenesis-induced circumstances may justify the importance of a ketogenic-based diet regimen in combating metabolic diseases. However, future studies should consider standardizing factors such as the duration of fasting, timing, composition of the ketogenic diet and target tissues as these factors may affect study outcomes.

Keywords:  Ketogenesis; Ketogenic diet; Ketone bodies; PI3K/AKT/mTOR

DOI:  https://doi.org/10.1016/j.nutres.2025.04.010
Nat Metab. 2025 May 19.

Cell-intrinsic metabolic phenotypes identified in patients with glioblastoma, using mass spectrometry imaging of 13C-labelled glucose metabolism.

CRUK Rosetta Grand Challenge Consortium

Transcriptomic studies have attempted to classify glioblastoma (GB) into subtypes that predict survival and have different therapeutic vulnerabilities1-3. Here we identified three metabolic subtypes: glycolytic, oxidative and a mix of glycolytic and oxidative, using mass spectrometry imaging of rapidly excised tumour sections from two patients with GB who were infused with [U-13C]glucose and from spatial transcriptomic analysis of contiguous sections. The phenotypes are not correlated with microenvironmental features, including proliferation rate, immune cell infiltration and vascularization, are retained when patient-derived cells are grown in vitro or as orthotopically implanted xenografts and are robust to changes in oxygen concentration, demonstrating their cell-intrinsic nature. The spatial extent of the regions occupied by cells displaying these distinct metabolic phenotypes is large enough to be detected using clinically applicable metabolic imaging techniques. A limitation of the study is that it is based on only two patient tumours, albeit on multiple sections, and therefore represents a proof-of-concept study.

DOI: https://doi.org/10.1038/s42255-025-01293-y
Cell. 2025 May 15. pii: S0092-8674(25)00511-2. [Epub ahead of print]

Microbiome metabolism of dietary phytochemicals controls the anticancer activity of PI3K inhibitors.

Asael Roichman, Qianying Zuo, Sunghoon Hwang, Wenyun Lu, Ricardo A Cordova, Michael R MacArthur, Jacob A Boyer, Sarah J Mitchell, Jesse Powers, Sophia A Koval, Craig J Hunter, Jamie Rijmers, Rolf-Peter Ryseck, Jenna E AbuSalim, Seema Chatterjee, Won Dong Lee, Xincheng Xu, Xi Xing, Zihong Chen, Xianfeng Zeng, Siddharth Marwaha, Matthew J McBride, Jessie Y Guo, Yibin Kang, Mohamed S Donia, Joshua D Rabinowitz.

  Phosphatidylinositol 3-kinase (PI3K) signaling is both the effector pathway of insulin and among the most frequently activated pathways in human cancer. In murine cancer models, the efficacy of PI3K inhibitors is dramatically enhanced by a ketogenic diet, with a proposed mechanism involving dietary suppression of insulin. Here, we confirm profound diet-PI3K anticancer synergy but show that it is, surprisingly, unrelated to diet macronutrient composition. Instead, the diet-PI3K interaction involves microbiome metabolism of ingested phytochemicals. Specifically, murine ketogenic diet lacks the complex spectrum of phytochemicals found in standard chow, including the soy phytochemicals soyasaponins. We find that soyasaponins are converted by the microbiome into inducers of hepatic cytochrome P450 enzymes, and thereby lower PI3K inhibitor blood levels and anticancer activity. A high-carbohydrate, low-phytochemical diet synergizes with PI3K inhibition to treat cancer in mice, as do antibiotics that curtail the gut microbiome. Thus, diet impacts anticancer drug activity through phytochemical-microbiome-liver interactions.

Keywords:  PI3Ki; breast cancer; cytochrome P450; diet and cancer treatment; gut-liver axis; microbiome metabolites; pancreatic cancer; pharmacokinetics; phytochemicals; soyasaponins

DOI:  https://doi.org/10.1016/j.cell.2025.04.041
Cell Death Differ. 2025 May 22.

NDUFS3 promotes proliferation via glucose metabolism reprogramming inducing AMPK phosphorylating PRPS1 to increase the purine nucleotide synthesis in melanoma.

Guohang Xiong, Fang Yun, Lu Jiang, Zihan Yi, Xiaojia Yi, Lijuan Yang, Xuedan Zhang, Xiaoyu Li, Zhe Yang, Qiao Zhang, Buqing Sai, Yingmin Kuang, Yuechun Zhu.

NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) is the core subunit of the respiratory chain complex I (CI). We found NDUFS3 were abnormally elevated in human melanoma and promoted melanoma proliferation. Furthermore, NDUFS3 could promote the oxidative phosphorylation (OXPHOS) and the pentose phosphate pathway (PPP), as well as attenuated glycolysis. As NDUFS3-mediated the metabolic changes of OXPHOS and glucose metabolism, melanoma cells produced more ATP, resulting in the inhibition of AMP kinase (AMPK). AMPK induced phosphoribosyl pyrophosphate synthetase1 (PRPS1) phosphorylation, which resulted in suppressed PRPS1 activity. Briefly, the NDUFS3-AMPK-PRPS1 signaling axis coupled OXPHOS, glucose metabolism, and purine nucleotide biosynthesis to regulate melanoma proliferation. Our study highlighted an unrecognized role for NDUFS3 in melanoma, which might be used as a potential therapeutic target for the treatment of this type of cancer. NDUFS3 regulating PRPS1 activity through AMPK to affect melanoma proliferation.

DOI: https://doi.org/10.1038/s41418-025-01525-4
Cell Signal. 2025 May 15. pii: S0898-6568(25)00289-X. [Epub ahead of print]133 111874

Crosstalk of glutamine metabolism between cancer-associated fibroblasts and cancer cells.

Tingyu Chen, Yiming Xu, Fan Yang, Yanxin Pan, Ning Ji, Jing Li, Xin Zeng, Qianming Chen, Lu Jiang, Ying-Qiang Shen.

  Glutamine (Gln), a critical metabolic substrate, fuels the uncontrolled proliferation of cancer cells. Cancer-associated fibroblasts (CAFs), essential components of the tumor microenvironment, facilitate tumor progression by supplying Gln to cancer cells and driving drug resistance through metabolic reprogramming. This review highlights the key processes of Gln uptake, transport, and catabolism and explores the metabolic crosstalk between CAFs and cancer cells. It also examines the roles of major oncogenic regulators-c-Myc, mTORC, KRAS, p53, and HIF-in controlling Gln metabolism and shaping therapeutic resistance. Current pharmacological approaches targeting Gln metabolism, including enzyme inhibitors and transporter blockers, are discussed alongside emerging therapeutic strategies and ongoing clinical trials. Lastly, we underscore the importance of integrating advanced technologies like artificial intelligence and spatial omics to refine treatment targeting and develop more effective, personalized therapeutic interventions.

Keywords:  Cancer cells; Cancer-associated fibroblasts; Glutamine; Metabolism

DOI:  https://doi.org/10.1016/j.cellsig.2025.111874
Nutrition. 2025 Apr 11. pii: S0899-9007(25)00123-6. [Epub ahead of print]137 112805

Excessive dietary saturated fat or fructose and their combination (found in ultra-processed foods) impair mitochondrial dynamics markers and cause brown adipocyte whitening in adult mice.

Jade Sancha de Oliveira Glauser, Daiana Araujo Santana-Oliveira, Flávia Maria Silva-Veiga, Aline Fernandes-da-Silva, Marcia Barbosa Aguila, Vanessa Souza-Mello.

   OBJECTIVE: To investigate the effects of comparable dietary excess of fat or fructose and the combination of these two insults (mimicking ultra-processed foods) on interscapular brown adipose tissue (iBAT) whitening and markers of mitochondrial dynamics in adult male mice.
METHODS: Male C57BL/6 mice were randomly assigned into four groups according to the diet: control diet (C, following AIN-93M), high-fat diet (HF, 32% energy as lard), high-fructose diet (HFRU, 32% energy as fructose) or for high-fat/high-fructose diet (HF-HFRU, 32% as lard and 32% as fructose) for 12 weeks. Data were tested with one-way ANOVA and Dunnet T3 post-test (n=5 per analysis, significance level P < 0.05).
RESULTS: All diets caused insulin resistance and iBAT whitening, albeit with overweight only in the HF and HF-HFRU groups. Principal component analysis indicated that the HFRU scores loaded next to inflammation (Nlrp3) and adipogenesis markers (Pparg), and the HF diet influenced more a mitochondrial gene (Tomm20). However, iBAT whitening in all groups was associated with deficits in mitochondrial dynamics (Ppargc1a, Dnml1, and Pink1), vascularization (Vegfa), and thermogenic markers (Bmp8b, and Ucp1).
CONCLUSION: Similar increases in dietary saturated fat or fructose (32% as energy) and the combination of these two insults (32% / 32%) caused insulin resistance and brown adipocyte dysfunction (whitening) in adult mice after 12 weeks independent of being overweight. In comparison, the PC scores of the HFRU groups were closer to the HF-HFRU group than the HF group, implying a worse outcome and highlighting the importance of limiting saturated fat and fructose intake from ultra-processed foods.

Keywords:  Brown adipose tissue; Fructose; Mitochondria; Saturated fat; Whitening

DOI:  https://doi.org/10.1016/j.nut.2025.112805
Sci Adv. 2025 May 23. 11(21): eadv2930

Image-guided targeting of mitochondrial metabolism sensitizes pediatric malignant rhabdoid tumors to low-dose radiotherapy.

Wenxi Xia, Esther Need, Carmine Schiavone, Neetu Singh, Jiemin Huang, Matthew Goff, Joseph Cave, David L Gillespie, Randy L Jensen, Mark D Pagel, Prashant Dogra, Sixiang Shi, Shreya Goel.

Tumor hypoxia leads to radioresistance and markedly worse clinical outcomes for pediatric malignant rhabdoid tumors (MRTs). Our transcriptomics and bioenergetic profiling data reveal that mitochondrial oxidative phosphorylation is a metabolic vulnerability of MRT and can be exploited to overcome consumptive hypoxia by repurposing an FDA-approved antimalarial drug, atovaquone (AVO). We then establish the utility of oxygen-enhanced-multispectral optoacoustic tomography, a label-free, ionizing radiation-free imaging modality, to visualize and quantify spatiotemporal changes in tumor hypoxia in response to AVO. We show a potent but transient increase in tumor oxygenation upon AVO treatment that results in complete elimination of tumors in all tested mice when combined with 10-gray radiotherapy, a dose several times lower than the current clinic standard. Last, we use translational mathematical modeling for systematic evaluation of dosing regimens, administration timing, and therapeutic synergy in a virtual patient cohort. Together, our work establishes a framework for safe and pediatric patient-friendly image-guided metabolic radiosensitization of rhabdoid tumors.

DOI: https://doi.org/10.1126/sciadv.adv2930
Res Sq. 2025 May 09. pii: rs.3.rs-6480518. [Epub ahead of print]

GPT2 mediates metabolic alterations in platinum-resistant ovarian cancer cells.

Adriana Ponton-Almodovar, Mary Priyanka Udumula, Vrinda Khullar, Faraz Rashid, Ramandeep Rattan, Jamie J Bernard, Sachi Horibata.

  Metabolic reprogramming is recognized as a hallmark of cancer frequently associated with drug resistance in ovarian cancer. This is problematic as ovarian cancer is one of the deadliest gynecologic cancers with platinum resistance contributing to poor survival. However, the mechanism by which ovarian cancer cell metabolism contributes to platinum resistance is not well understood. Herein, metabolic signatures were determined in platinum-resistant ovarian cancer cell lines compared to the more platinum-sensitive parental lines. Chemoresistant ovarian cancer cells showed increased oxidative phosphorylation (OXPHOS) compared to chemosensitive cells. This was associated with elevated levels of glutaminolysis and tricarboxylic acid (TCA)-related metabolites supporting their dependence on OXPHOS. Key enzymes involved in glutaminolysis, specifically, glutamic-pyruvic transaminase 2 (GPT2), were upregulated in chemoresistant compared to chemosensitive cells. Interestingly, high GPT2 gene expression is associated with worse prognosis in ovarian cancer patients, adding translational relevance to the pre-clinical findings. GPT2 knockout in chemoresistant cells restored the metabolic phenotype to that of the sensitive cells and reversed drug resistance. These data suggest that GPT2 is a critical link between glutaminolysis, the TCA cycle, and OXPHOS and is a potential target to attenuate the increased metabolic activity associated with a chemoresistant phenotype.

Keywords:  GPT2; glutamine; metabolism; ovarian cancer

DOI:  https://doi.org/10.21203/rs.3.rs-6480518/v1
Math Biosci. 2025 May 21. pii: S0025-5564(25)00081-1. [Epub ahead of print] 109455

Mathematical modelling of carbohydrate and protein metabolism in muscle.

Bandar Muidh Alharbi, Hannah E Williams, Tim Parr, John Brameld, Christopher Fallaize, Jonathan A D Wattis.

  We propose a mathematical model based on coupled ordinary differential equations (ODEs) for metabolite concentrations with the aim of investigating how modifications to the rates affects outputs from a regulatory network. Our aim is to model the relationships between energy metabolism and the biosynthesis of non-essential amino acids, such as serine. We consider a network of cytosolic glycolysis, the mitochondrial TCA cycle, and the associated serine synthesis pathway, with the aim of modelling the role of metabolic reprogramming as a mechanism to enhance protein synthesis and growth, particularly in skeletal muscle. Our objective is to explore the consequences of overexpressing two key enzymes, phosphoenolpyruvate carboxykinase 2 (PCK2), and phosphoglycerate dehydrogenase (PHGDH), on the TCA cycle and on serine production. We investigate how the rate of serine synthesis is affected by upregulating both enzymes simultaneously, or each one individually. We find a range of steady-states which depend upon input fluxes into the network. As input fluxes are altered, steady states cease to exist due to a bifurcation to one of two states in which some metabolites grow linearly in time whilst others decay to zero. Asymptotic analysis provides approximations for steady-state solutions near these bifurcation points, and conditions on parameter values which determine where in parameter space the system's behaviour changes. We also perform a parameter sensitivity analysis to determine the effect of perturbations to rate constants and input rates. Our numerical simulations show that the up-regulation of PHGDH, the initial rate limiting enzyme in the serine-synthesis pathway, causes an increase in serine production but that, contrary to our hypothesis, increased expression of PCK2 has no effect. This model aids our understanding of both the effects of drugs and changes in enzyme expression or activities which upregulate one or more reactions in a pathway.

Keywords:  Chemical kinetics; Mathematical modelling; Metabolic network; PCK2; PHGDH

DOI:  https://doi.org/10.1016/j.mbs.2025.109455
Cell Stem Cell. 2025 May 21. pii: S1934-5909(25)00179-1. [Epub ahead of print]

Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia.

Maria Sirenko, Soobeom Lee, Zhengxi Sun, Ronan Chaligne, Sanam Loghavi, Georgios Asimomitis, Charlotte K Brierley, Elsa Bernard, Sheng F Cai, Robert M Myers, Bettina Nadorp, Junya Sango, Morgan Lallo, Max F Levine, Dylan Domenico, Juan E Arango Ossa, Juan S Medina-Martinez, Kamal Menghrajani, Audrey Lasry, Alice S Mims, Helee Desai, Andrea Laganson, Chris Famulare, Minal Patel, Gerard Lozanski, Kelly L Bolton, Aaron D Viny, Mikhail Roshal, Ross L Levine, Eirini P Papapetrou, Eytan M Stein, Dan A Landau, Ann-Kathrin Eisfeld, Iannis Aifantis, Elli Papaemmanuil.

  Isocitrate dehydrogenase 1/2 (IDH) mutations are early initiating events in acute myeloid leukemia (AML). The complex clonal architecture and cellular heterogeneity in IDH-mutant AML underlies the heterogeneous clinical presentation and outcomes. Integrating single-cell genotyping and transcriptomics, we demonstrate a stem-like and inflammatory phenotype of IDH-mutant AML and identify clone-specific programs associated with NPM1, NRAS, and SRSF2 co-mutations. Furthermore, these clones had distinct responses to treatment with combination IDH inhibitors and chemotherapy, including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. At relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated major histocompatibility complex (MHC) class II antigen presentation. At the pre-leukemic stage, we observe upregulation of IDH2-associated pathways, including inflammation. We deliver a detailed phenotyping of IDH-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and following therapy, with implications for precision medicine.

Keywords:  IDH inhibitors; IDH1/2 mutations; acute myeloid leukemia; cellular hierarchy; clonal architecture; clonal evolution; relapse; single-cell transcriptomics; targeted therapy; treatment resistance

DOI:  https://doi.org/10.1016/j.stem.2025.04.012
Leukemia. 2025 May 22.

Targeting lipid metabolism in acute myeloid leukemia: biological insights and therapeutic opportunities.

Vilma Dembitz, Sophie C James, Paolo Gallipoli.

Metabolic rewiring is a hallmark of malignant transformation in leukemic cells and the potential offered by its therapeutic targeting has garnered significant attention. The development of clinically relevant metabolic targeted therapies in acute myeloid leukemia (AML) has mostly focused on targeting mitochondrial energy production, but progress has been hampered by generalized toxicities. An alternative strategy is to shift the focus from targeting energy production to targeting more specialized metabolic functions, such as energy storage, the regulation of oxidative stress and availability of cofactors needed for the function of specific metabolic reactions. Lipid metabolism plays a role in many of these metabolic functions and its importance in AML maintenance and response to therapy is being increasingly recognized but needs to be adequately interpreted in the context of its interaction with the microenvironment, particularly the adipose niche. In this review, we provide an overview of our current understanding of AML cellular metabolic dependencies on fatty acid and lipid metabolism and discuss their relevance in the context of functional interactions with adipocytes. We highlight unresolved questions about how to best target lipid metabolism and suggest approaches needed to fully understand the interplay between malignant cells and their niche in the context of metabolic dependencies.

DOI: https://doi.org/10.1038/s41375-025-02645-z
Biochim Biophys Acta Mol Basis Dis. 2025 May 15. pii: S0925-4439(25)00250-9. [Epub ahead of print]1871(6): 167902

Adenine nucleotide translocase 2 silencing promotes metabolic reprogramming in P19 embryonal carcinoma stem cells.

Gabriela L Oliveira, Jaromir Novak, Zuzana Nahacka, Petra Brisudova, Sandra I Mota, Jiri Neuzil, Paulo J Oliveira, Ricardo Marques.

  Although controversial, cancer stem cells (CSCs) are thought to be one tumor component, being characterized by their strong self-renewal and survival properties. Cancer cells, CSCs included, are thought to rely mostly on glycolysis, even in the presence of oxygen, which confers them adaptive advantages. Adenine nucleotide translocator 2 (ANT2), responsible for the exchange of ADP and ATP in the mitochondrial inner membrane, has been correlated with a higher glycolytic metabolism and is known to be overexpressed in cancer cells. Using P19 embryonal carcinoma stem cells, we inhibited ANT2 translation by using siRNA. ANT2 protein levels were shown to be overexpressed in P19 undifferentiated cells (P19SCs) when compared to their differentiated counterparts (P19dCs). Furthermore, we showed here that the OXPHOS machinery and mitochondrial membrane potential are compromised after ANT2 depletion, leading to a metabolic adaptation towards a less oxidative phenotype. Interestingly, hexokinase II levels were downregulated, which was also accompanied by decreased cell growth, and reduced ability to form spheroids. Our findings underscore ANT2 as a key regulator of metabolic remodeling and cell survival of cancer stem-like cells, suggesting its potential as a therapeutic target for controlling CSC-driven tumor progression.

Keywords:  ANT2; Hexokinase II; Metabolism; Mitochondria; Spheroids; cancer stem cells

DOI:  https://doi.org/10.1016/j.bbadis.2025.167902
Cancer Med. 2025 May;14(10): e70950

Mapping of Functional Metabolic Phenotypes in Acute Myeloid Leukemia.

Sissel Dyrstad, Kimberley Joanne Hatfield, Endre Stigen, Marte Karen Brattås, Karl Johan Tronstad, Håkon Reikvam.

   BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis, particularly in older patients. AML is highly heterogeneous, influenced by various chromosomal, genetic, and epigenetic alterations.
METHODS: This study investigated the metabolic profiles of primary AML cells from 46 patients, focusing on mitochondrial respiration and glycolysis. We hypothesized that the metabolic profiles would reflect distinct disease characteristics. Using Seahorse technology, we measured the oxygen consumption rate (OCR) for mitochondrial respiration and the extracellular acidification rate (ECAR) for glycolysis.
RESULTS: Our results showed significant variability in metabolic activity, with some samples relying more on glycolysis than mitochondrial respiration. Mature AML cells (FAB M4/M5, CD34 negative) exhibited increased rates of both mitochondrial respiration and glycolysis, indicating distinct metabolic adaptations. Higher glycolytic activity was observed in patients with adverse cytogenetic abnormalities. However, no clear associations were found between metabolic profiles and mutations in FLT3 or NPM1.
CONCLUSION: These findings highlight the role of metabolic variability in AML and suggest that targeting specific metabolic pathways could offer therapeutic opportunities, particularly for subgroups like FAB M4/M5 with unique metabolic features. Further studies are needed to refine these therapeutic strategies for clinical application.

Keywords:  acute myeloid leukemias; glycolysis; metabolic phenotypes; metabolism

DOI:  https://doi.org/10.1002/cam4.70950
J Genet Eng Biotechnol. 2025 Jun;pii: S1687-157X(25)00024-1. [Epub ahead of print]23(2): 100480

Antiproliferative effect of ketogenic diet on hormone independent mammary gland carcinoma via harnessing glucose metabolism: In-vitro and In-vivo investigations.

Sneha Yadav, Neha, Mohammad Arman, Anurag Kumar, Archana Bharti Sonkar, Neeraj Kumar Shrivastava, Jyoti Singh, Mohd Nazam Ansari, Sara A Aldossary, Abdulaziz S Saeedan, Gaurav Kaithwas.

  The ketogenic diet (KD) has been emphasized as a complementary strategy for management of several clinical conditions including cancer. Therefore, in this study we explored the effect of KD in mammary gland carcinoma through in-vitro and in-vivo studies. In-vitro studies were performed on MCF-7 and MDA-MB-231 cells with different experimental conditions such as high glucose (HG), low glucose (LG) and no glucose(NG) in conjugation with β-hydroxy butyrate(BHB) treatment. The MTT assay revealed that glucose deprivation alongwith BHB(10 mM) treatment significantly reduces the viability of MDA-MB-231 cells as compared to MCF-7 cells. Moreover, apoptotic and antiproliferative potential (via AO/EtBr, JC-1, cell migration assay) were analyzed on MDA-MB-231 cells which indicate that NG with BHB treatment induce cell death.Furthermore, we investigated the in-vivo anticancer efficacy against DMBA-induced mammary gland carcinoma in female Wistar rats. KD treatment effectively restored autonomic dysfunction, altered mammary gland morphology and histology; as evident through decrease in lobules, alveolar bud, restoration of the surface architecture and loss of tumor micro-vessels. The altered levels of antioxidants such as TBARs(0.85 ± 0.19 nM of MDA/µg of protein), SOD(2.26 ± 0.05 U/µg of protein), PC(41.36 ± 2.94 µM/µg of protein), GSH(10.58 ± 3.08 µM/µg of protein) were also restored after KD treatment. Overall findings suggested, that deprived glucose concentration alongwith BHB can impart antiproliferative and apoptotic effect as observed through MDA-MB-231cells. Moreover, KD also diminished the carcinogenic effects of DMBA in albino wistar rats. In view of above, the KD was utilised as adjuvant therapy in the management of mammary gland carcinoma,possibly by providing unfavourable microenvironment for highly proliferating tumour cells due deficiency of quickly available glucose.

Keywords:  DMBA; Ketogenic diet; Mammary gland carcinoma; Warburg effect

DOI:  https://doi.org/10.1016/j.jgeb.2025.100480
J Adv Res. 2025 May 19. pii: S2090-1232(25)00353-4. [Epub ahead of print]

Ketogenic diet and β-hydroxybutyrate inhibit HDAC1 to preserve vascular smooth muscle cell function in thoracic aortic aneurysm.

Xinyu Weng, Lihong Pan, Xiurui Ma, Wei Luo, Hongdong Su, Zhiqiang Pei, Zhen Dong, Liwei Liu, Jing Yang, Pingjin Gao, Aijun Sun.

   BACKGROUND: Thoracic aortic aneurysm (TAA) is a serious condition characterized by dilation of the thoracic aorta, often leading to aortic dissection or rupture. Current treatments involve surgical and pharmacological interventions and do not effectively address the underlying molecular mechanisms. This study explores the effects of ketogenic diet (KD) on TAA, focusing on histone deacetylase 1 (HDAC1) and vascular smooth muscle cells (VSMCs) function.
METHODS: A β-aminopropionitrile monofumarate (BAPN)-induced TAA mouse model was used. Mice were divided into groups receiving either a standard diet or KD. Additionally, β-hydroxybutyrate (BHB), a KD-derived ketone body, and parthenolide or ITSA-1 were administered. The study measured survival rates, aortic dilation, elastin degradation, VSMC contractile markers, mitochondrial function, and oxidative stress levels.
RESULTS: KD significantly improved survival rates and reduced aortic dilation and elastin degradation in the TAA mouse model. BHB also mitigated TAA development, demonstrating similar protective effects. KD and BHB were particularly effective in preserving mitochondrial function and maintaining VSMC contractile phenotype by restoring contractile marker expression. Additionally, KD and BHB significantly reduced oxidative stress levels. The addition of HDAC1 inhibitor parthenolide or HDAC agonist ITSA-1 further evaluated the protective effects of BHB against vascular damage.
CONCLUSION: Our study reveals the important roles of KD and BHB in regulating HDAC1, preserving mitochondrial function, maintaining VSMC phenotype, and reducing oxidative stress in TAA. Our findings demonstrate KD and BHB as promising therapeutic strategies for treating TAA by targeting specific molecular pathways involved in its progression. This study highlights the significance and innovation of lifestyle interventions, such as KD, in mitigating TAA by addressing its underlying molecular mechanisms.

Keywords:  Histone deacetylase 1; Ketogenic diet; Thoracic aortic aneurysm; Vascular Remodeling; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.jare.2025.05.035
Cureus. 2025 Apr;17(4): e82521

Subjective Experiences and Blood Parameter Changes in Individuals From Germany Following a Self-Conceived "Carnivore Diet": An Explorative Study.

Rainer J Klement, Johanna S Matzat.

   BACKGROUND: Animal-based, or so-called carnivore, diets largely exclude all plant-based foods and are gaining increasing popularity, mainly among individuals suffering from chronic diseases. This study aimed to explore subjective experiences and blood parameter changes of German followers of a carnivore diet.
METHODOLOGY: We conducted a statistical survey using a self-designed questionnaire and requesting blood panels. Inclusion criteria were: (i) following a carnivore-type diet for at least one month; (ii) completing the self-designed study questionnaire; and (iii) providing two sets of metabolic blood parameters from the period before and after adopting the carnivore diet. The survey was complemented by qualitative interviews with four subjects on a carnivore diet.
RESULTS: Twenty-four individuals participated in the survey. Fifteen participants (62.5%) were male, and the median age was 46 (range 26-62) years. The majority (n = 16, 67%) reported at least one clinical diagnosis, and the main reason for switching to a carnivore diet was accordingly health-related. Improved health was also the major motivation to maintain the diet. Before the carnivore diet, participants consumed a variety of other diets, of which a ketogenic (n = 8) and standard diet (n = 7) were most frequently reported. There were no significant differences between on-diet and pre-diet blood parameters except for total (pre-diet median: 224 mg/dL; on-diet: 305 mg/dL; P < 0.0001) and low-density lipoprotein (LDL) cholesterol (pre-diet: 157 mg/dL; on-diet: 256 mg/dL; P = 0.00024) concentrations. However, two participants who initially had pre-diabetic HbA1c values and six participants with initially high (>130 mg/dL) triglyceride levels all experienced a reduction of these blood parameters during the carnivore diet.
CONCLUSIONS: Individuals adopting a carnivore diet do this mainly for health-related reasons and commonly experience subjective health improvements. Most blood parameters on the carnivore diet were within the reference ranges, and initially high HbA1c and triglyceride levels were reduced. However, the significant elevation of total and LDL cholesterol concentration is striking and warrants further investigation into potential adverse effects.

Keywords:  carnivore diet; cholesterol levels; hypercholesterolemia; ketogenic diet; low-carbohydrate diet; meat

DOI:  https://doi.org/10.7759/cureus.82521
Nat Metab. 2025 May 23.

β-hydroxybutyrate inhibits Plasmodium falciparum development and confers protection against malaria in mice.

Zhiming Wei, Ning Jiang, Yiwei Zhang, Qilong Li, Ziwei Su, Yanxin Zhang, Kunying Lv, Yixin Yang, Tong Liu, Lu Sun, Kexin Zheng, Ang Li, Anni Feng, Xiaoyu Sang, Ying Feng, Ran Chen, Qijun Chen.

Environmental factors restrict malaria parasite development, but the influence of host metabolic variations on the infectivity of the blood stage parasite is not fully understood. Here we show that mice on a ketogenic diet are completely protected from infection with the malaria parasite Plasmodium berghei. We further show that administration of the ketone body β-hydroxybutyrate (βOHB), but not of acetoacetate, increases survival of infected mice and inhibits proliferation of both P. berghei and Plasmodium falciparum in vitro. Administration of either a ketogenic diet or βOHB induces metabolic reprogramming in parasites, including reduced levels of nicotinamide adenine dinucleotide, which is associated with the downregulation of genes controlling parasite development, erythrocyte invasion and pathogenicity. Our data indicate that a ketogenic diet and the ketone body βOHB confer resistance to malaria in mice by causing developmental arrest of Plasmodium parasites, highlighting the potential of dietary and metabolic strategies to fight malarial infection.

DOI: https://doi.org/10.1038/s42255-025-01302-0
Nat Commun. 2025 May 16. 16(1): 4570

Dietary lipids are largely deposited in skin and rapidly affect insulating properties.

Nick Riley, Ildiko Kasza, Isabel D K Hermsmeyer, Michaela E Trautman, Greg Barrett-Wilt, Raghav Jain, Judith A Simcox, Chi-Liang E Yen, Ormond A MacDougald, Dudley W Lamming, Caroline M Alexander.

Skin is a regulatory hub for energy expenditure and metabolism, and alteration of lipid metabolism enzymes in skin impacts thermogenesis and obesogenesis in mice. Here we show that thermal properties of skin are highly reactive to diet: within three days, a high fat diet reduces heat transfer through skin. In contrast, a dietary manipulation that prevents obesity accelerates energy loss through skins. We find that skin is the largest target for dietary fat delivery, and that dietary triglyceride is assimilated by epidermis and dermal white adipose tissue, persisting for weeks after feeding. With caloric-restriction, mouse skins thin and assimilation of circulating lipids decreases. Using multi-modal lipid profiling, keratinocytes and sebocytes are implicated in lipid changes, which correlate with thermal function. We propose that skin should be routinely included in physiological studies of lipid metabolism, given the size of the skin lipid reservoir and its adaptable functionality.

DOI: https://doi.org/10.1038/s41467-025-59869-x
J Biol Chem. 2025 May 14. pii: S0021-9258(25)02087-3. [Epub ahead of print] 110237

ABHD18 degrades cardiolipin by stepwise hydrolysis of fatty acids.

Mindong Ren, Shiyu Chen, Miriam L Greenberg, Michael Schlame.

  Cardiolipin (CL), the signature phospholipid of mitochondria, carries four fatty acids that are remodeled after de novo synthesis. In yeast, remodeling is accomplished by the joint action of Cld1, a lipase that removes a fatty acid from CL, and Taz1, a transacylase that transfers a fatty acid from another phospholipid to monolyso-CL. While taz1 homologues have been identified in all eukaryotes, cld1 homologues have remained obscure. Here we demonstrate that ABHD18, a highly conserved protein of plants, animals, and humans, is functionally homologous to Cld1. Knockdown of Abhd18 decreased the concentration of monolyso-CL in murine, Taz-knockout myoblasts. Inactivation of Abhd18 in Drosophila substantially increased the abundance of CL. Abhd18 inactivation also reversed the increase in the rate of CL degradation, as measured with 13C isotopes, and the accumulation of deacylated CLs, such as monolyso-CL and dilyso-CL, in TAZ-deficient flies. CL species with more than 5 double bonds were resistant to ABHD18. Our data demonstrate that ABHD18 is the elusive lipase that hydrolyzes CL in mice and flies and presumably in other organisms. Rather than removing just one fatty acid, we show that ABHD18 deacylates CL further. Thus, ABHD18 catalyzes the breakdown of CL whereas TAZ protects CL from degradation.

Keywords:  cardiolipin; lipase; lysophospholipid; mitochondria; phospholipid turnover; tafazzin

DOI:  https://doi.org/10.1016/j.jbc.2025.110237
Elife. 2025 May 21. pii: RP100747. [Epub ahead of print]13

Glutamine catabolism supports amino acid biosynthesis and suppresses the integrated stress response to promote photoreceptor survival.

Moloy T Goswami, Eric Weh, Shubha Subramanya, Katherine M Weh, Hima Bindu Durumutla, Heather Hager, Nicholas Miller, Sraboni Chaudhury, Anthony Andren, Peter Sajjakulnukit, Li Zhang, Cagri Besirli, Costas A Lyssiotis, Thomas J Wubben.

  Photoreceptor loss results in vision loss in many blinding diseases, and metabolic dysfunction underlies photoreceptor degeneration. So, exploiting photoreceptor metabolism is an attractive strategy to prevent vision loss. Yet, the metabolic pathways that maintain photoreceptor health remain largely unknown. Here, we investigated the dependence of photoreceptors on glutamine (Gln) catabolism. Gln is converted to glutamate via glutaminase (GLS), so mice lacking GLS in rod photoreceptors were generated to inhibit Gln catabolism. Loss of GLS produced rapid rod photoreceptor degeneration. In vivo metabolomic methodologies and metabolic supplementation identified Gln catabolism as critical for glutamate and aspartate biosynthesis. Concordant with this amino acid deprivation, the integrated stress response (ISR) was activated with protein synthesis attenuation, and inhibiting the ISR delayed photoreceptor loss. Furthermore, supplementing asparagine, which is synthesized from aspartate, delayed photoreceptor degeneration. Hence, Gln catabolism is integral to photoreceptor health, and these data reveal a novel metabolic axis in these metabolically demanding neurons.

Keywords:  cell biology; glutaminase; metabolism; mouse; neurodegeneration; neuroscience; photoreceptor

DOI:  https://doi.org/10.7554/eLife.100747
BMC Cancer. 2025 May 19. 25(1): 894

Venetoclax and hypomethylating agents versus induction chemotherapy for newly diagnosed acute myeloid leukemia patients: a systematic review and meta-analysis.

Yun Liu, Ying Zhang, Jinhong Gao, Lijuan Wang, Fang Xie, Chengtao Zhang, Peimin Mao, Jinsong Yan.

   BACKGROUND: Venetoclax with hypomethylating agents (VEN-HMAs) has shown inconsistent efficacy versus induction chemotherapy (IC) in newly diagnosed AML (ND-AML). Whether or not VEN-HMAs are of clinical benefit remains uncertain. We conducted this meta-analysis to evaluate the clinical benefit of VEN-HMAs versus IC in various subtypes of ND-AML.
METHODS: We searched PubMed, Embase, Cochrane Library, and Web of Science databases up to 17 June 2024. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS). Data were extracted to perform meta-analysis or descriptive analysis. The random-effects model was used to calculate the effect sizes and 95% confidence interval (CI). Relative risk (RR) was used to estimate complete response (CR), CR/ complete response with incomplete blood count recovery (CRi), overall response rate (ORR), and 30-day mortality. Hazard ratio (HR) was used to evaluate overall survival (OS) data.
RESULTS: Fifteen retrospective cohort studies with 3809 participants were identified. Compared to the IC group, the pooled RR estimates for VEN-HMAs were 1.05 (95% CI 0.88-1.26, P = 0.591) for CR, 1.09 (95% CI 0.96-1.23, P = 0.195) for CR/ CRi, 0.84 (95% CI 0.60-1.18, P = 0.318) for ORR, and 0.86 (95% CI 0.50-1.49; P = 0.596) for 30-day mortality. VEN-HMAs prolonged the OS advantage in the ND-AML population (HR = 0.80, 95% CI 0.66-0.97, P = 0.025), and was demonstrated in patients with nucleophosmin 1 (NPM1) mutation (HR = 0.64, 95% CI 0.44-0.92, P = 0.017). In AML patients with RUNX1::RUNX1T1 cytogenetic abnormalities, the pooled ORR was lower in the VEN-HMAs group (RR = 0.44, 95% CI 0.28-0.69, P < 0.001), but OS was of no significantly different (HR = 1.30, 95% CI 0.52-3.26,P = 0.58). However, only 2 studies were available and the results should be taken with caution. OS benefit was similar in other subgroup analyses based on cytogenetic risk, age, and AML type (de novo, secondary, treatment-related or prior therapy for myeloid disease cohort).
CONCLUSION: Compared with the IC group, VEN-HMAs improved OS in ND-AML, especially in the NPM1 mutation subgroup (HR = 0.64), ensured the efficacy of CR, CR/CRi and ORR, without increasing 30-day mortality, necessitating further head-to-head randomized controlled trials (RCTs).
TRIAL REGISTRATION: This trial was registered with PROSPERO ( www.crd.york.ac.uk/prospero/ ) on 13 July 2024, the registration number is CRD42024560585.

Keywords:  Acute myeloid leukemia; Hypomethylating agents; Intensive chemotherapy; Meta-analysis; Survival; Venetoclax

DOI:  https://doi.org/10.1186/s12885-025-14311-9