bims-medica 2025-06-29 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–06–29
35 papers selected by
Brett Chrest, Wake Forest University

The Landscape of Cancer Metabolism as a Therapeutic Target.
Ketone Bodies Inhibit Growth of Hepatoblastoma and Rhabdoid Tumor of the Kidney Cells.
Metabolic Assays for Brain Cancer Cells.
Microprotein SMIM26 drives oxidative metabolism via serine-responsive mitochondrial translation.
Cancer cells get power boost by stealing mitochondria from nerves.
Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes.
A nuclear branched-chain amino acid catabolism pathway controls histone propionylation in pancreatic cancer.
The Identification of a Key Regulator of Mitochondrial Metabolism, the LRPPRC Protein, as a Novel Therapeutic Target in SDHA-Overexpressing Ovarian Tumors.
Unlocking the Distinct Roles of the Three Mammalian VDAC Isoforms in Mitochondrial Respiration and Cancer Cell Metabolism.
Glutamine Metabolism: Molecular Regulation, Biological Functions, and Diseases.
Benserazide‑mediated targeting hexokinase 2 enhances the cytotoxicity of cisplatin in non-small cell lung cancer cell models.
β-Hydroxybutyrate dehydrogenase 1: A promising therapeutic target for diverse diseases.
Differential response of patient-derived primary glioblastoma cells to metabolic and adhesion inhibitors.
An NADH-controlled gatekeeper of ATP synthase.
ATP requirements for growth reveal the bioenergetic impact of mitochondrial symbiosis.
Metabolism-based scoring of cutaneous squamous cell carcinoma to predict tumor features and responses to treatment by DHODH inhibitors.
Intensive chemotherapy after hypomethylating agent and venetoclax in adult acute myeloid leukemia.
Intermittent Fasting Partially Alleviates Dietary Margarine-Induced Morphometrical, Hematological, and Biochemical Changes in Female Mice, but Not in Males.
Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.
Low-Carb and Ketogenic Diets in Type 1 Diabetes: Efficacy and Safety Concerns.
Genetically Predicted Gut Microbiota and Host Metabolites Mediate the Causal Link Between Dietary Factors and Acute Myeloid Leukemia.
Housing matters: experimental variables shaping metabolism in obese mice.
Dietary switch and intermittent fasting ameliorate the disrupted postprandial short-chain fatty acid response in diet-induced obese mice.
The Conditions of Non-rescuability of Methioninase-treated Cancer Cells by Methionine Replenishment: The Point of No Return.
Nerve-to-cancer transfer of mitochondria during cancer metastasis.
β-hydroxybutyrate, a ketone body, suppresses tumor growth, stemness, and invasive phenotypes in non-small cell lung cancer.
Empagliflozin restores cardiac metabolism and suppresses immune activation in acute myocardial infarction.
Post-exercise ketone monoester administration concomitant with glucose stimulates glycogen repletion in soleus muscle in mice.
Analysis of the Effects of Low-Fat Diets on Breast Cancer Mortality and Prognosis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
GLUT1 as a Potential Therapeutic Target in Glioblastoma.
Allosteric regulation of L-lactate dehydrogenase: Beyond effector-mediated tetramerization.
Analysis of IDH1 and IDH2 mutations as causes of the hypermethylator phenotype in colorectal cancer.
Changes in body mass index during chemotherapy are positively associated with height outcome in childhood cancer survivors of acute lymphoblastic leukemia.
High-Calorie Diet Consumption Induces Lac-Phe Changes in the Brain in a Time-of-Day Manner Independent of Exercise.
Associations between the consumption of red meat and processed meat and the incidence of colorectal cancer in Asia: a meta-analysis.

Pathol Int. 2025 Jun 24.

The Landscape of Cancer Metabolism as a Therapeutic Target.

Kenji Ohshima.

  Cancer cells reprogram their metabolism during progression to adapt to the tumor microenvironment, which is characterized by distinct differences in nutrient availability, oxygen concentrations, and acidity. This metabolic reprogramming can simultaneously create metabolic vulnerabilities unique to cancer cells, making cancer metabolism a promising therapeutic target. Since the clinical application of folate antimetabolites in the 1940s, numerous therapeutic strategies targeting cancer metabolism have been developed. In recent years, advancements in technologies such as metabolome analysis have facilitated the development of agents that more specifically target cancer cell metabolism. However, these newly developed agents often face challenges in demonstrating efficacy as monotherapies in clinical trials. Nevertheless, combination therapies, designed based on precise mechanistic insights and incorporating agents such as immune-checkpoint and signaling-pathway inhibitors, have shown promising efficacy. This review provides an overview of the current landscape of therapeutic strategies targeting cancer metabolism, with a particular focus on approaches targeting amino acid, fatty acid, and glucose metabolism in cancer cells.

Keywords:  amino acid metabolism; cancer metabolism; cancer therapy; combination therapy; fatty acid metabolism; glucose metabolism

DOI:  https://doi.org/10.1111/pin.70034
Anticancer Res. 2025 Jul;45(7): 3089-3097

Ketone Bodies Inhibit Growth of Hepatoblastoma and Rhabdoid Tumor of the Kidney Cells.

Eri Muto-Fujita, Bin Yamaoka, Naoko Abe, Kyoko Fujiwara, Shuichiro Uehara.

   BACKGROUND/AIM: The prognosis for high-risk pediatric cancers remains poor, necessitating the development of novel therapies. The ketogenic diet (KD) has shown efficacy in various adult cancers; however, its impact on pediatric solid tumors remains underexplored. This study investigated the impact of ketone bodies (KBs) on hepatoblastoma and rhabdoid tumor of the kidney.
MATERIALS AND METHODS: Human hepatoblastoma cell line (Huh6), human rhabdoid tumors of the kidney cell lines (G401, WT-CLS1), and human foreskin derived fibroblast cell line (HFF) were used in this study. Cells were cultured in control media, glucose-free media, and glucose-free media supplemented with acetoacetate or β-hydroxybutyrate. Cell viability was assessed using the WST-8 assay. Intracellular ATP concentrations and the expression of KBs-metabolizing enzymes, Succinyl-CoA: 3-oxoacid CoA transferase (SCOT) and 3-hydroxybutyrate dehydrogenase-1 (BDH1), were evaluated using an ATP assay and qRT-PCR, respectively.
RESULTS: The WST-8 assay demonstrated Huh6, G401, and WT-CLS1 growth inhibition in glucose-free media, which was not rescued by KBs-supplemented media. The ATP assay showed decreased intracellular ATP levels in Huh6 and G401 but not in WT-CLS1. Expression levels of SCOT and BDH1 in Huh6, G401, and WT-CLS1 cells were significantly lower than those in HFF cells.
CONCLUSION: The growth of Huh6, G401, and WT-CLS1 cells was inhibited under glucose-free conditions and not rescued by KBs. The current results strongly suggest that KD is a highly promising treatment for patients with hepatoblastoma and rhabdoid tumor of the kidney.

Keywords:  Hepatoblastoma; ketogenic diet; pediatric solid cancer; rhabdoid tumor of the kidney

DOI:  https://doi.org/10.21873/anticanres.17673
Methods Mol Biol. 2025 ;2944 49-64

Metabolic Assays for Brain Cancer Cells.

Emma Martell, Harshal Senthil, Esha Kaul, Helgi Kuzmychova, Tanveer Sharif.

  Metabolism is a fundamental foundation of all living organisms. However, cancer cells can modulate their metabolic activity to maintain their enhanced bioenergetic needs associated with uncontrolled proliferation. Some hallmarks of cancer metabolism include enhanced glucose uptake capacity and aberrations in mitochondrial metabolic activity and ATP production. In this chapter, we will outline several methods for studying critical metabolic parameters in brain cancer cells.

Keywords:  ATP; Cancer; Glucose uptake; Metabolism; Oxygen consumption

DOI:  https://doi.org/10.1007/978-1-0716-4654-0_5
Mol Cell. 2025 Jun 20. pii: S1097-2765(25)00472-1. [Epub ahead of print]

Microprotein SMIM26 drives oxidative metabolism via serine-responsive mitochondrial translation.

Jiemin Nah, Sreya Mahendran, Baptiste Kerouanton, Liang Cui, Daniella H Hock, Alfredo Cabrera-Orefice, Kyle Dunlap, David Robinson, Desmond W H Tung, Sze Huey Leong, Kiat-Yi Tan, Sonia P Chothani, Jingjing Sun, Agnieszka Dziegowska, Grazyna Leszczynska, Owen J L Rackham, Ilka Wittig, Peter Dedon, Gregory S Ducker, David A Stroud, Lena Ho.

  Mitochondrial small open reading frame (ORF)-encoded microproteins (SEPs) are key regulators and components of the electron transport chain (ETC). Although ETC complex I assembly is tightly coupled to nutrient availability, including serine, the coordinating mechanism remains unknown. A genome-wide CRISPR screen targeting SEPs revealed that deletion of the LINC00493-encoded microprotein SMIM26 sensitizes cells to one-carbon restriction. SMIM26 interacts with mitochondrial serine transporters SFXN1/2 and the mitoribosome, forming a functional triad that facilitates translation of the complex I subunit mt-ND5. SMIM26 loss impairs serine import, reduces folate intermediates, and disrupts key mitochondrial tRNA modifications (τm5U and τm5s²U), resulting in ND5 translation failure and complex I deficiency. SMIM26 deletion is embryonic lethal in mice and impedes tumor growth in a xenograft model of folate-dependent acute myeloid leukemia. These findings define SMIM26 as a critical integrator of one-carbon flux and complex I biogenesis and establish a paradigm for localized mitochondrial translation through transporter-ribosome interactions.

Keywords:  complex I; electron transport chain; micropeptides; mitochondria; mitochondrial translation; one-carbon pathway; oxidative phosphorylation; small ORF-encoded peptides

DOI:  https://doi.org/10.1016/j.molcel.2025.05.033
Nature. 2025 Jun 25.

Cancer cells get power boost by stealing mitochondria from nerves.

Traci Watson.



Keywords:  Cancer; Cell biology; Metabolism; Neuroscience

DOI:  https://doi.org/10.1038/d41586-025-01941-z
Cell Death Differ. 2025 Jun 23.

Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes.

Jan Dreute, Julia Stengel, Jonas Becher, David van den Borre, Maximilian Pfisterer, Marek Bartkuhn, Vanessa M Beutgen, Benardina Ndreshkjana, Ulrich Gärtner, Johannes Graumann, Michael Huck, Stephan Klatt, Chloe Leff, Henner F Farin, Andrea Nist, Roland Schmitz, Thorsten Stiewe, Julia Teply-Szymanski, Jochen Wilhelm, Alfredo Cabrera-Orefice, M Lienhard Schmitz.

As cancer cell specific rewiring of metabolic networks creates potential therapeutic opportunities, we conducted a synthetic lethal screen utilizing inhibitors of metabolic pathways. Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, BMS-986205, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), also restricts oxidative phosphorylation (OXPHOS), as revealed here. BMS-986205, which is being tested in multiple Phase III clinical trials, inhibits the ubiquinone reduction site of respiratory complex I and thus compromises mitochondrial ATP production. The energetic catastrophe caused by simultaneous interference with glycolysis and OXPHOS resulted in either cell death or the induction of senescence in tumor cells, with the latter being eliminated by senolytics. The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.

DOI: https://doi.org/10.1038/s41418-025-01532-5
bioRxiv. 2025 Apr 26. pii: 2025.04.23.650241. [Epub ahead of print]

A nuclear branched-chain amino acid catabolism pathway controls histone propionylation in pancreatic cancer.

Christina Demetriadou, Michael Noji, Austin L Good, Erick Mitchell-Velasquez, Sharan Venkatesh, Daniel S Kantner, Jennifer Pennise, Pedro Costa-Pinheiro, Laura V Pinheiro, Taku Harada, Phuong T T Nguyen, Adam Chatoff, Emily Megill, Claudia V Da Silva Crispim, Mariola M Marcinkiewicz, Jordan L Meier, Zoltan Arany, Irfan Asangani, Emma E Furth, Ben Z Stanger, Nathaniel W Snyder, Kathryn E Wellen.

Branched-chain amino acid (BCAA) catabolism contributes prominently to the TCA cycle in the healthy pancreas but is suppressed in pancreatic ductal adenocarcinoma (PDA). The impact of this metabolic remodeling on cancer phenotypes remains poorly understood. Here, we find that the BCAA isoleucine is a primary source of propionyl-CoA in PDA cells. Reduction of propionyl-CoA availability by either genetic perturbation or isoleucine and valine starvation decreases histone propionylation (Kpr) without impacting histone acetylation on specific lysine sites, correlating with reduced transcription of certain lipid- and immune-related genes. Mechanistically, we find that multiple enzymes of isoleucine catabolism unexpectedly localize to and carry out multi-step isoleucine oxidation within the nuclei of PDA cells. Importantly, nuclear localization of the rate-limiting branched-chain alpha ketoacid dehydrogenase (BCKDH) complex is essential for isoleucine-dependent Kpr and gene regulation. Moreover, we demonstrate that isoleucine-sensitive Kpr and its associated gene expression are driven by the MYST family of lysine acyltransferases (KATs), and that the BCKDHA subunit of the BCKDH complex interacts with KAT7 within the nuclear compartment. BCAA catabolism enzymes are apparent in the nuclei of PanIN lesions in mice and PDA tumors in patients, contrasting that in healthy pancreatic acinar and ductal cells. Collectively, these findings unveil a nuclear isoleucine catabolism pathway and highlight its role in controlling histone Kpr and tumorigenic transcriptional programs in PDA.

DOI: https://doi.org/10.1101/2025.04.23.650241
Cancers (Basel). 2025 Jun 11. pii: 1942. [Epub ahead of print]17(12):

The Identification of a Key Regulator of Mitochondrial Metabolism, the LRPPRC Protein, as a Novel Therapeutic Target in SDHA-Overexpressing Ovarian Tumors.

Anna Szulta, Lin Wang, Ameera Hasan, Michael Kinter, Atul Pranay, Jie Zhu, Kenneth M Humphries, Brooke Loveland, Timothy M Griffin, Magdalena Bieniasz.

  Background: Ovarian cancer is the deadliest of all gynecologic malignancies due to limited therapeutic options. Our data show that the tumor-specific metabolism of ovarian cancer could be effectively targetable, which highlights a path for new anti-cancer therapies. Methods and Results: Our work shows that the upregulation of mitochondrial enzyme SDHA is particularly prevalent in ovarian carcinoma. SDHA overexpression significantly induced orthotopic ovarian tumor growth, reducing mouse survival. We showed that SDHA-overexpressing tumors depend on glutaminolysis and increased activity of the tricarboxylic acid (TCA) cycle coupled with mitochondrial oxidative phosphorylation (OXPHOS), which are essential for high-energy metabolism and cell survival. We identified a distinctive vulnerability of SDHA-overexpressing tumors to agents targeting regulators of the OXPHOS pathway, particularly the LRPPRC protein. LRPPRC is a key regulator of mitochondrial energy metabolism, promoting OXPHOS and ATP generation. However, when overexpressed, the LRPPRC acts as a tumor oncogene. Our analysis of SDHA and LRPPRC gene and protein expression patterns in precursor lesions and established ovarian cancer demonstrated that the upregulation of SDHA is accompanied by LRPPRC overexpression, notably in advanced tumors. Our novel findings highlight for the first time a potential functional interaction between SDHA and LRPPRC in the development and progression of ovarian malignancy. Importantly, our in vivo data showed that pharmacological inhibition of LRPPRC results in a lasting therapeutic benefit and can be an effective therapy in SDHA- and LRPPRC-overexpressing ovarian tumors. Conclusions: Overall, our study underlines an understudied role of concomitant overexpression of SDHA and LRPPRC in ovarian cancer pathogenesis, highlighting new paths for therapeutic development.

Keywords:  LRPPRC; OXPHOS; SDHA; high-grade serous ovarian cancer; metabolism; ovarian cancer; patient-derived xenograft; shikonin; succinate dehydrogenase

DOI:  https://doi.org/10.3390/cancers17121942
bioRxiv. 2025 Apr 07. pii: 2025.02.20.639106. [Epub ahead of print]

Unlocking the Distinct Roles of the Three Mammalian VDAC Isoforms in Mitochondrial Respiration and Cancer Cell Metabolism.

Megha Rajendran, William M Rosencrans, Wendy Fitzgerald, Diana Huynh, Bethel G Beyene, Baiyi Quan, Julie Hwang, Nina A Bautista, Tsui-Fen Chou, Sergey M Bezrukov, Tatiana K Rostovtseva.

The Voltage Dependent Anion Channel (VDAC) is the most ubiquitous protein in the mitochondrial outer membrane. This channel facilitates the flux of water-soluble metabolites and ions like calcium across the mitochondrial outer membrane. Beyond this canonical role, VDAC has been implicated, through interactions with protein partners, in several cellular processes such as apoptosis, calcium signaling, and lipid metabolism. There are three VDAC isoforms in mammalian cells, VDAC 1, 2, and 3, with varying tissue-specific expression profiles. From a biophysical standpoint, all three isoforms can conduct metabolites and ions with similar efficiency. However, isoform knockouts (KOs) in mice lead to distinct phenotypes, which may be due to differences in VDAC isoform interactions with partner proteins. To understand the functional role of each VDAC isoform within a single cell type, we created functional KOs of each isoform in HeLa cells and performed a comparative study of their metabolic activity and proteomics. We found that each isoform KO alters the proteome differently, with VDAC3 KO dramatically downregulating key members of the electron transport chain (ETC) while shifting the mitochondria into a glutamine-dependent state. Importantly, this unexpected dependence of mitochondrial function on the VDAC3 isoform is not compensated by the more ubiquitously expressed VDAC1 and VDAC2 isoforms. In contrast, VDAC2 KO did not affect respiration but upregulated ETC components and decreased key enzymes in the glutamine metabolic pathway. VDAC1 KO specifically reduced glycolytic activity linked to decreased hexokinase localization to mitochondria. These results reveal non-redundant roles of VDAC isoforms in cancer cell metabolic adaptability.

DOI: https://doi.org/10.1101/2025.02.20.639106
MedComm (2020). 2025 Jul;6(7): e70120

Glutamine Metabolism: Molecular Regulation, Biological Functions, and Diseases.

Mudasir A Kumar, Sana Khurshid Baba, Inamu Rashid Khan, Mohd Shahnawaz Khan, Fohad Mabood Husain, Saheem Ahmad, Mohammad Haris, Mayank Singh, Ammira S Al-Shabeeb Akil, Muzafar A Macha, Ajaz A Bhat.

  Glutaminolysis, the metabolic process of converting glutamine into key intermediates, plays an essential role in cellular energy production, signaling, biosynthesis, and redox balance. Deregulation of glutamine metabolism significantly influences various pathological conditions, including cancers and metabolic and neurological diseases. Emerging evidence shows that long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and oncogenic alterations in glutamine transporters and enzymes enhance glutamine's role as an alternative energy source, supporting cell survival and proliferation under nutrient and oxygen deprivation conditions. To combat the pathogenic effects of altered glutamine metabolism, researchers are developing targeted inhibitors of key enzymes and transporters involved in glutaminolysis. By interfering with the mechanisms that support the growth of cancer cells, these inhibitors may be able to stop the growth of tumors and treat metabolic and neurological conditions. This review provides a comprehensive overview of existing inhibitors and ongoing clinical trials targeting glutamine metabolism, focusing on its potential as a cancer therapeutic strategy. Additionally, the role of lncRNAs and circRNAs in regulating glutamine metabolism is explored, revealing novel avenues for therapeutic intervention in cancer and other diseases.

Keywords:  cancer; circular RNAs; glutamine metabolism; glutaminolysis; long noncoding RNAs; therapeutic targeting

DOI:  https://doi.org/10.1002/mco2.70120
Biochem Pharmacol. 2025 Jun 24. pii: S0006-2952(25)00336-3. [Epub ahead of print] 117071

Benserazide‑mediated targeting hexokinase 2 enhances the cytotoxicity of cisplatin in non-small cell lung cancer cell models.

Kaifang Wang, Suya Wang, Wenying Shan, Shuting Huang, Tong Fang, Yan Zhou, Lizhong Liu, Ou Sha, Kin Yip Tam.

  Hexokinase 2 (HK2) is a critical rate-limiting enzyme in glycolysis, significantly linked to cancer metabolism and drug resistance. We hypothesized that targeting HK2 with Benserazide (BenZ), a known HK2 inhibitor, could potentiate the cytotoxicity of cisplatin (DDP) in non-small-cell lung cancer (NSCLC) cells. Our findings demonstrated that combination of DDP and BenZ significantly enhanced anticancer effects in NSCLC cells, either with or without acquired DDP resistance. In particular, BenZ effectively inhibited ATP and lactate productions. ATP supplementation mitigated the cytotoxicity of the combination treatment, which was restored when both the cisplatin efflux transporters, ATP7A and ATP7B, were simultaneously knocked down. Moreover, BenZ suppressed NF-κB activation and downregulated inflammatory gene expressions, including IκB and RELA phosphorylation, TNF-α, BCL-2, and IL-1β. These effects were attributed to inhibition of HK2 by BenZ leading to the suppression of IκBα phosphorylation. It has been shown that combined use of DDP and BenZ significantly inhibited tumor growth in NSCLC cell xenograft mouse models, while BenZ alleviated the DDP-induced nephrotoxicity. Our findings demonstrate that BenZ inhibits the kinase activity of HK2, reduces ATP level and cisplatin efflux, as well as alleviates NF-κB activation. These multifaceted actions enhance the anticancer efficacy of cisplatin in NSCLC cell models, indicating its potential as an effective adjunct therapy.

Keywords:  Benserazide (BenZ); Glycolysis; Hexokinase 2 (HK2); NF-κB pathway; Non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.1016/j.bcp.2025.117071
Biochem Pharmacol. 2025 Jun 23. pii: S0006-2952(25)00335-1. [Epub ahead of print]239 117070

β-Hydroxybutyrate dehydrogenase 1: A promising therapeutic target for diverse diseases.

Xiaotong Ma, Ze Wang, Haoyang Gao, Danlin Zhu, Mingyu Wu, Linlin Zhao, Weihua Xiao.

  β-Hydroxybutyrate dehydrogenase 1 (BDH1), a short-chain dehydrogenase located in the inner mitochondrial membrane, has been extensively studied for its critical role in ketone body metabolism. Recent research has expanded its known functions and revealed its involvement in the regulation of various physiological and pathological processes, including glucose metabolism, oxidative stress, inflammation, and apoptosis. As a result, BDH1's role in diverse pathological conditions, such as metabolic disorders, cancer, and cardiomyopathy, has garnered substantial research attention. This paper reviews the functions of BDH1 in different diseases and explores the effects of diet and pharmacological agents on BDH1 expression. In addition, the potential of BDH1 as a therapeutic target, especially in the context of metabolic diseases, is examined. Future research should focus on elucidating the mechanisms underlying BDH1's action in diseases, which can provide a solid theoretical foundation for its clinical application.

Keywords:  Disease; Function; Mechanism of action; Therapeutic target; β-Hydroxybutyrate dehydrogenase 1

DOI:  https://doi.org/10.1016/j.bcp.2025.117070
Clin Exp Med. 2025 Jun 26. 25(1): 220

Differential response of patient-derived primary glioblastoma cells to metabolic and adhesion inhibitors.

Rasha Rezk, Fikret Basar, John Mediavillo, Rebecca Donaldson, Colin Watts, Kristian Franze, Alexandre J Kabla.

  This study aims to investigate the cellular response of Glioblastoma (GBM) to adhesion and metabolic inhibitors, focusing on cell migration and matrix adhesion properties. GBM is the most common incurable brain tumor. Despite decades of research into GBM's chemical and molecular classification, identifying mechanisms of drug resistance has been challenging. Studies on inhibitors targeting cancer cell migration and proliferation rarely consider the heterogeneous migration properties among cells, which may impact patient responses to treatment. In this work, tissue samples were obtained from spatially distinct locations with different 5-aminolevulinic acid (5-ALA) fluorescent intensities-including strongly fluorescent tumor cores, a weakly fluorescent tumor rim, and non-fluorescent tumor margins. These samples were previously shown to be associated with significantly different motility and adhesion properties. We tested the response of tumor cells to adhesion and metabolic inhibitors using metabolic MTT and Cell Titer Glo viability assays, respectively. We also monitored cell survival using time-lapse microscopy, while culturing them on low-modulus polydimethylsiloxane (representing the stiffness of brain tissue). Metabolic viability assays revealed substantial heterogeneity in drug potency across cells from different regions of the tumor. Highly fluorescent tumor core cells were significantly more resistant to an F0F1 ATP synthase inhibitor (Gboxin), and a FAK inhibitor (GSK2256098), while their proliferation ceased post-treatment in vitro. In contrast, cells derived from non-fluorescent tumor margins exhibited higher potency for the ATP synthase inhibitor (Gboxin), but their proliferation persisted post-treatment. Our study demonstrates a correlation between the adhesive and migration properties of cells and their sensitivity to therapeutics in different regions of the tumor within individual patients and between patients with GBM.

Keywords:  Drug discovery; Glioblastoma; Mechanobiology

DOI:  https://doi.org/10.1007/s10238-025-01736-6
Mol Cell. 2025 Jun 24. pii: S1097-2765(25)00507-6. [Epub ahead of print]

An NADH-controlled gatekeeper of ATP synthase.

Fabian Schildhauer, Petra S J Ryl, Simon M Lauer, Swantje Lenz, Ayşe Berçin Barlas, Vasileios R Ouzounidis, Kate Jeffrey, Daniel-Cosmin Marcu, Francis J O'Reilly, Andrea Graziadei, Marchel Stuiver, Kita Schmidt, Helge Ewers, Christian M T Spahn, Ezgi Karaca, Karl Emanuel Busch, Dhanya Cheerambathur, David Schwefel, Juri Rappsilber.

  ATP fuels crucial cellular processes and is obtained mostly by oxidative phosphorylation (OXPHOS) at the inner mitochondrial membrane. While significant progress has been made in mechanistic understanding of ATP production, critical aspects surrounding its substrate supply logistics are poorly understood. We identify an interaction between mitochondrial apoptosis-inducing factor 1 (AIFM1) and adenylate kinase 2 (AK2) as gatekeeper of ATP synthase. This interaction is NADH dependent and influenced by glycolysis, linking it to the cell's metabolic state. Genetic interference with AIFM1/AK2 association impedes the ability of Caenorhabditis elegans animals to handle altered metabolic rates and nutrient availability. Together, the results imply AIFM1 as a cellular NADH sensor, placing AK2 next to the OXPHOS complexes for local ADP regeneration as the substrate for ATP synthesis. This metabolic signal relay balances ATP synthase substrate supply against ATP conservation, enabling cells to adapt to fluctuating energy availability, with possible implications for AIFM1-related mitochondrial diseases.

Keywords:  AIFM1; AK2; ATP synthesis; OXPHOS; adenylate kinase 2; apoptosis-inducing factor 1; cell signaling; crosslinking mass spectrometry; energy metabolism; mitochondria; mitochondrial; oxidative phosphorylation; protein structure; protein-protein interaction

DOI:  https://doi.org/10.1016/j.molcel.2025.06.007
Biochim Biophys Acta Bioenerg. 2025 Jun 23. pii: S0005-2728(25)00030-1. [Epub ahead of print] 149564

ATP requirements for growth reveal the bioenergetic impact of mitochondrial symbiosis.

William F Martin.

  Studies by microbiologists in the 1970s provided robust estimates for the energy supply and demand of a prokaryotic cell. The amount of ATP needed to support growth was calculated from the chemical composition of the cell and known enzymatic pathways that synthesize its constituents from known substrates in culture. Starting in 2015, geneticists and evolutionary biologists began investigating the bioenergetic role of mitochondria at eukaryote origin and energy in metazoan evolution using their own, widely trusted-but hitherto unvetted-model for the costs of growth in terms of ATP per cell. The more recent model contains, however, a severe and previously unrecognized error that systematically overestimates the ATP cost of amino acid synthesis up to 200-fold. The error applies to all organisms studied by such models and leads to conspicuously false inferences, for example that the synthesis of an average amino acid in humans requires 30 ATP, which no biochemistry textbook will confirm. Their ATP 'cost' calculations would require that E. coli obtains ~100 ATP per glucose and that mammals obtain ~240 ATP per glucose, untenable propositions that invalidate and void all evolutionary inferences so based. By contrast, established methods for estimating the ATP cost of microbial growth show that the first mitochondrial endosymbionts could have easily doubled the host's available ATP pool, provided (i) that genes for growth on environmental amino acids were transferred from the mitochondrial symbiont to the archaeal host, and (ii) that the host for mitochondrial origin was an autotroph using the acetyl-CoA pathway. SIGNIFICANCE STATEMENT: Life is a chemical reaction. It requires energy release in order to proceed. The currency of energy in cells is adenosine triphosphate ATP. Five decades ago, microbiologists were able to measure and understand the amount of ATP that cells require to grow. New studies by evolutionary biologists have appeared in the meantime that brush aside the older microbiological findings, using their own methods to calculate the ATP cost of growth instead. Science is, however, an imperfect undertaking. The new studies contain a major error, similar to conflating centimeters with yards. The error affects many publications and their conclusions. Using the old methods, we can still meaningfully study the role of energy in evolution, including the origin of complex, nucleus-bearing cells.

Keywords:  ATP costs; Bioenergetics; Costs of a gene; Energy in evolution; Eukaryogenesis; Mitochondria

DOI:  https://doi.org/10.1016/j.bbabio.2025.149564
Br J Dermatol. 2025 Jun 27. pii: ljaf253. [Epub ahead of print]

Metabolism-based scoring of cutaneous squamous cell carcinoma to predict tumor features and responses to treatment by DHODH inhibitors.

Lea Dousset, Ferial Khalife, Domitille Chalopin-Fillot, Benjamin Dartigues, Fatima Naji, Walid Mahfouf, Elodie Muzotte, Benoît Rousseau, Nivea Amoedo, Stéphane Claverol, Mathieu Bondaz, Fanny Beltzung, Marie-Laure Jullie, Beatrice Vergier, Alain Taieb, Laure Favot-Laforge, Rodrigue Rossignol, Marie Beylot-Barry, Macha Nikolski, Hamid-Reza Revani.

BACKGROUND: Alteration in metabolic activities is a critical step in cancer progression, and a myriad of metabolic-based therapy options are increasingly being proposed for human tumors. However, emerging evidence highlights interpatient metabolic heterogeneity and underscores the importance of metabolic phenotyping in cancer treatment.
OBJECTIVES: To investigate metabolic heterogeneity in cutaneous squamous cell carcinoma (cSCC), and its impact on cSCC characteristics and treatment responses.
METHODS: We applied combined proteomic and bioenergetic analyses to patient samples representing various stages of cSCC, ranging from precancerous actinic keratosis (AK) to metastatic cSCC. To investigate the functional impacts of the identified metabolic heterogeneities on tumor characteristics and treatment responses, we employed patient-derived tumor cell (PDC) and patient-derived xenograft (PDX) models by transplanting tumor cells and freshly resected patient tumors into immunocompromised mice.
RESULTS: Three subgroups with low-, medium-, and high-metabolic scores were identified across all stages of carcinogenesis. Our functional analyses indicated that, in both models (PDC and PDX), the sensitivities of tumors to leflunomide, an inhibitor of dihydroorotate dehydrogenase (DHODH), were inversely correlated with their metabolic scores and directly correlated with DHODH protein expression level. Moreover, DHODH overexpression in nonresponding groups rendered them sensitive to leflunomide.
CONCLUSIONS: These findings demonstrate the relevance of metabolic profiling and scoring in the design of therapeutic approaches targeting the bioenergetic vulnerabilities of tumors and suggest DHODH as a promising therapeutic target in the low-metabolic score subgroup of cSCC.

DOI: https://doi.org/10.1093/bjd/ljaf253
Blood Neoplasia. 2024 Dec;1(4): 100038

Intensive chemotherapy after hypomethylating agent and venetoclax in adult acute myeloid leukemia.

Kuo-Kai Chin, Yannis Valtis, Andriy Derkach, Meira Yisraeli Salman, Leora Boussi, Jenna Ciervo, Mark B Geyer, Jae H Park, Martin S Tallman, Jacob L Glass, Aaron D Goldberg, Eytan M Stein.

The combination of a hypomethylating agent (HMA) and venetoclax (VEN) is approved for adults aged >75 years with newly diagnosed acute myeloid leukemia (AML) as well as those ineligible for intensive chemotherapy (IC). HMA/VEN is increasingly substituted for IC in adults with AML aged <75 years, particularly in those with adverse cytogenetic and molecular features. When patients fail to respond or relapse after HMA/VEN, the utility of salvage IC is largely unknown. We performed a retrospective single-institution study and identified 46 patients who received IC after HMA/VEN, including 24 patients who received HMA/VEN as their first treatment for AML. This population had complete remission (CR)/CR with incomplete count recovery (CRi)/morphologic leukemia-free state rate of 37%, CR/CRi rate of 28%, and a median overall survival (mOS) of 7.2 months (95% confidence interval, 5.0-10.3). Patients who relapsed after an initial response to HMA/VEN and subsequently received IC were more likely to achieve a CR/CRi than those refractory to HMA/VEN (50% vs 19%; P = .04), although there was no statistically significant difference in survival (mOS, 8.8 vs 5.4 months; P = .64). Age >65 years predicted poorer survival (mOS, 4.3 vs 10.6 months; P < .001). IC after HMA/VEN should be further studied and chosen with caution.

DOI: https://doi.org/10.1016/j.bneo.2024.100038
Biochem Res Int. 2025 ;2025 2163104

Intermittent Fasting Partially Alleviates Dietary Margarine-Induced Morphometrical, Hematological, and Biochemical Changes in Female Mice, but Not in Males.

Viktoriia V Hurza, Maria M Bayliak, Myroslava V Vatashchuk, Oksana M Sorochynska, Maria P Lylyk, Oleksandra B Abrat, Dmytro V Gospodaryov, Kenneth B Storey, Volodymyr I Lushchak.

  Margarine is a popular high-calorie component of the Western diet and was shown to be associated with the development of metabolic syndrome. Intermittent fasting (IF) is an effective approach to improve health and prevent metabolic disorders. This study aimed to investigate the effects of margarine consumption, both ad libitum and in combination with IF regimens, using young C57BL/6J mice of both sexes. Female mice fed margarine ad libitum as a supplement to the standard diet showed significant body mass gain, reduced food intake, lower blood paraoxonase activity, and higher lipid peroxide (LOOH) levels, along with higher activities of antioxidant enzymes in the liver. Margarine-fed males showed higher food intake and had lower blood triacylglycerol levels, higher LOOH levels in adipose tissue, and lower LOOH levels in the liver than their control counterparts. When a margarine-supplemented diet was provided to mice with an IF regimen, males gained body mass faster and experienced severe metabolic changes, including elevated fasting blood glucose levels, higher total leukocyte count, triacylglycerol accumulation, and reduced glycogen levels in the liver compared to their margarine ad libitum counterparts. Females treated with margarine + IF showed a partial improvement in metabolic status and a decrease in proinflammatory markers compared to the group receiving margarine ad libitum. Hence, responses to the diets were sex-specific. Females that consumed margarine ad libitum had higher metabolic sensitivity than males. Meanwhile, IF provided some protective effects in females but worsened metabolic outcomes in males when combined with a high-fat margarine diet.

Keywords:  every-other-day fasting; food consumption; inflammation; liver; metabolic health; sex differences; western diet

DOI:  https://doi.org/10.1155/bri/2163104
Nat Metab. 2025 Jun 27.

Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.

Marcus J Tol, Yuta Shimanaka, Alexander H Bedard, Jennifer Sapia, Liujuan Cui, Mariana Colaço-Gaspar, Peter Hofer, Alessandra Ferrari, Kevin Qian, John P Kennelly, Stephen D Lee, Yajing Gao, Xu Xiao, Jie Gao, Julia J Mack, Thomas A Weston, Kevin J Williams, Baolong Su, Calvin Pan, Aldons J Lusis, Daniel P Pike, Alex Reed, Natalia Milosevich, Benjamin F Cravatt, Makoto Arita, Stephen G Young, David A Ford, Rudolf Zechner, Stefano Vanni, Peter Tontonoz.

Genetic and dietary cues are known drivers of obesity, yet how they converge at the molecular level is incompletely understood. Here we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, an endoplasmic reticulum (ER)-resident O-acyltransferase that selectively enriches diet-derived omega-6 polyunsaturated fatty acids (n-6 PUFAs) in the membrane lipidome. In mice fed a high-fat diet, lowering membrane n-6 PUFA levels through genetic or dietary interventions results in aberrant adipose triglyceride (TG) turnover, ectopic fat deposition and insulin resistance. Additionally, we detail a non-canonical adaptive response in 'lipodystrophic' Lpcat3-/- adipose tissues that engages a futile lipid cycle to increase metabolic rate and offset lipid overflow to ectopic sites. Live-cell imaging, lipidomics and molecular dynamics simulations reveal that adipocyte LPCAT3 activity enriches n-6 arachidonate in the phosphatidylethanolamine (PE)-dense ER-lipid droplet interface. Functionally, this localized PE remodelling optimizes TG storage by driving the formation of large droplets that exhibit greater resistance to adipose TG lipase activity. These findings highlight the PPARγ-LPCAT3 axis as a mechanistic link between dietary n-6 PUFA intake, adipose expandability and systemic energy balance.

DOI: https://doi.org/10.1038/s42255-025-01320-y
Nutrients. 2025 Jun 14. pii: 2001. [Epub ahead of print]17(12):

Low-Carb and Ketogenic Diets in Type 1 Diabetes: Efficacy and Safety Concerns.

Emmanouil Korakas, Aikaterini Kountouri, Goran Petrovski, Vaia Lambadiari.

  Despite advances in technology, the overall management of type 1 diabetes mellitus (T1DM) remains suboptimal. The idea of restricting carbohydrate intake to decrease glycemic spikes and insulin requirements has been revisited in recent years. After impressive results in the fields of type 2 diabetes (T2DM) and epilepsy, low-carbohydrate (LCD) and ketogenic (KD) diets have gained renewed interest as a possible treatment option for T1DM. In this narrative review, we discuss the available data regarding LCDs and KDs in both the adult and pediatric populations. Research data is still scarce, as most studies are short-term and show considerable heterogeneity in dietary composition and patient outcomes. In general, carbohydrate restriction enhances glycemic control by reducing postprandial glucose excursions, improving time-in-range, and lowering HbA1c, with conflicting effects on other parameters such as lipid profile and body weight. Adverse effects such as hypoglycemia and diabetic ketoacidosis are rarely reported, although some concerns have been raised regarding growth in children. The correct implementation of these diets requires a multidisciplinary approach by highly specialized healthcare professionals, who will address the medical, social, and psychological concerns that a restrictive diet entails. Large-scale and long-term studies are needed to provide more robust data before carbohydrate restriction can be widely applied to patients with T1DM.

Keywords:  adolescents; glycemic control; insulin; ketogenic diet; ketosis; low-carbohydrate diet; pediatric; type 1 diabetes mellitus

DOI:  https://doi.org/10.3390/nu17122001
Food Sci Nutr. 2025 Jun;13(6): e70456

Genetically Predicted Gut Microbiota and Host Metabolites Mediate the Causal Link Between Dietary Factors and Acute Myeloid Leukemia.

Jiading Qin, Ling Zhang, Guangcheng Zhang, Weijie Liao, Li Yu.

  Dietary factors may have a causative influence on acute myeloid leukemia (AML), a hematologic cancer known to be highly fatal. It is still mostly unknown whether causal mechanisms connect dietary exposures to AML, particularly through the gut microbiota and host metabolism. A two-sample Mendelian randomization (MR) analysis was conducted using genome-wide association study (GWAS) data to assess the causal effect of 20 routine dietary factors on AML. A two-step MR framework was employed to assess the mediating roles of gut microbiota and host metabolites. Sensitivity analyses, including inverse variance weighted (IVW), MR-Egger, and MR-PRESSO, were performed to ensure the robustness of results. Processed meat consumption was causally associated with an increased risk of AML (IVW OR = 15.111; 95% CI = 1.253-182.262; p = 0.033). The gut microbiota-associated L-histidine degradation I pathway was identified as a pro-carcinogenic mediator, accounting for 19.5% of the effect. Conversely, host metabolites, including circulating glycerol levels and the free cholesterol-to-total lipids ratio in very large high-density lipoprotein (HDL), functioned as protective mediators. No substantial horizontal pleiotropy or heterogeneity was observed, thereby reinforcing the validity of these findings. This research offers a new understanding of the role of processed meat in the development of AML via the microbiota-metabolite axis and emphasizes possible metabolic compensatory pathways.

Keywords:  acute myeloid leukemia; gut microbiota; host metabolites; mendelian randomization study; processed meat intake

DOI:  https://doi.org/10.1002/fsn3.70456
Mol Metab. 2025 Jun 17. pii: S2212-8778(25)00097-3. [Epub ahead of print] 102190

Housing matters: experimental variables shaping metabolism in obese mice.

Béatrice So-Yun Choi, Jacob Bak Holm, Asker Brejnrod, Even Fjære, Zhongkui Xia, Marie-Louise Allingbjerg, Ida Søgaard Larsen, David Møbjerg Kristensen, Morten Dall, Lene Secher Myrmel, Janne Koch, Niels Banhos Danneskiold-Samsøe, Otto Kalliokoski, Jonas T Treebak, Liang Xiao, Axel Kornerup Hansen, Helle Sørensen, Lise Madsen, Manimozhiyan Arumugam, Karsten Kristiansen, Benjamin A H Jensen.

  Diet-induced obesity in mice is an important model for investigating host-diet interactions as well as dietary and pharmacological treatments of metabolic diseases. Experimental reproducibility is, however, a recurrent challenge. To determine key controllable experimental drivers of mouse metabolism, we distributed 338 C57BL/6JBomTac mice (males and females) into six research units across two countries, divided them into a variety of housing conditions (i.e., diets, cage types, temperatures, group-housing vs. single-housing) and kept 26 reference mice at the vendor. We applied linear mixed models to rank the influence of each variable on metabolic phenotype (i.e., body weight gain, glucose intolerance, liver, and visceral adipose tissue weight). Group-housing was the most potent driver of metabolic dysfunction apart from sex and diet. Accordingly, single-housed mice exhibited reduced weight gain (∼50%), increased energy expenditure, and diminished respiratory exchange ratio concomitant with improved glucose tolerance (∼20%) compared to their group-housed counterparts. Our results may aid in clarifying the impact of experimental design and promote rational, transparent reporting to increase reproducibility.

Keywords:  animal models; high-fat diet; housing conditions; reproducibility; sex differences; thermoneutrality

DOI:  https://doi.org/10.1016/j.molmet.2025.102190
EBioMedicine. 2025 Jun 24. pii: S2352-3964(25)00271-3. [Epub ahead of print]117 105827

Dietary switch and intermittent fasting ameliorate the disrupted postprandial short-chain fatty acid response in diet-induced obese mice.

Victòria Ceperuelo-Mallafré, M-Mar Rodríguez-Peña, Joan Badia, Teresa Villanueva-Carmona, Lídia Cedó, Anna Marsal-Beltran, Ester Benaiges, Catalina Núñez-Roa, Laura Salmerón-Pelado, Francisco J Osuna-Prieto, Ramón Bosch, Silvia Pellitero, Sonia Fernández-Veledo, Joan Vendrell.

   BACKGROUND: Intermittent fasting holds promise as a prevention for obesity, but its effects on established obesity remain uncertain.
METHODS: We examined two intermittent fasting regimens in diet-induced obese mice, either maintained on a hypercaloric diet or switched to normal chow diet, and compared their effects with those of dietary switch alone (12 mice/group). We assessed metabolic parameters, gut microbiota composition, and fasting and postprandial short-chain fatty acids (SCFAs) levels. Additionally, faecal microbiota was analysed before and after diet-induced weight loss in 18 individuals with obesity.
FINDINGS: Intermittent fasting with a hypercaloric diet effectively mitigated weight gain and improved metabolic health-glucose, insulin, total cholesterol, triglycerides, and glucose tolerance (p < 0.05) to an extent comparable with dietary switch. Intermittent fasting increased faecal SCFAs levels, especially postprandially (acetate, propionate, and butyrate, p < 0.05), mirroring dietary switch. Combining intermittent fasting with dietary switch yielded the greatest improvement in glucose tolerance (p < 0.01) and exerted a more pronounced effect on gut microbiota composition (28 significant genera), albeit with reduced SCFA changes. The relative abundance of Alistipes finegoldii was associated with postprandial SCFAs levels and/or metabolic parameters in both mice and humans.
INTERPRETATION: Intermittent fasting on a hypercaloric diet protects against obesity, while combining intermittent fasting with dietary switch improves glucose metabolism independently of body weight. Both effects are associated with specific microbiota changes and postprandial SCFA dynamics, highlighting the connection between intermittent fasting, microbiota, and metabolic health.
FUNDING: Supported by the Institute of Health "Carlos III", Ministry of Science and Innovation and "La Caixa" Foundation.

Keywords:  Dietary switch; Gut microbiota; Intermittent fasting; Obesity; Postprandial; SCFAs

DOI:  https://doi.org/10.1016/j.ebiom.2025.105827
Anticancer Res. 2025 Jul;45(7): 2817-2823

The Conditions of Non-rescuability of Methioninase-treated Cancer Cells by Methionine Replenishment: The Point of No Return.

Byung Mo Kang, Qinghong Han, Shukuan Li, Kohei Mizuta, Jin Soo Kim, Yohei Asano, Michael Bouvet, Robert M Hoffman.

   BACKGROUND/AIM: The aim of the present study was to determine the extent of methioninase treatment beyond which methionine-addicted cancer cells could no longer be rescued by methionine repletion.
MATERIALS AND METHODS: Methionine-addicted HCT-116 human colon-cancer cells were treated in vitro with 1, 3, and 6 unit/ml of recombinant methioninase (rMETase) in methionine-containing growth media in 96-well culture dishes for eight days. rMETase was removed from six culture wells at various time points, and the cells were subsequently given normal growth medium containing 100 μM methionine. Cell number was determined every other day using the WST-8 cell-counting kit.
RESULTS: When HCT-116 human colon-cancer cells were treated with 1 unit rMETase/ml, the cells could be fully rescued on days 2, 4, and 6 by removing rMETase and adding normal methionine-containing growth medium. When treated with 3 units of rMETase/ml, the cells could be fully rescued by methionine replenishment after two days of treatment. However, after four and six days of treatment, the cells were partially rescued; the cells did not die, but stopped proliferating. In contrast, treatment with 6 units of rMETase/ml led to proliferation arrest when rescue was attempted on days 2 and 4, and no rescue was possible on day 6, as the cells continued to die.
CONCLUSION: Three distinct responses to methionine replenishment following rMETase treatment were observed in HCT-116 cells. First, complete recovery and resumption of proliferation occurred with low-dose rMETase at all time points and with short-term treatment at intermediate doses of r-METase. Second, prolonged intermediate-dose treatment or short-term high-dose treatment, resulted in continued proliferation arrest without further cell death. Third, high-dose rMETase treatment for six days led to cell death.

Keywords:  HCT-116 cells; Hoffman effect; Methionine rescue; colon cancer; methioninase; methionine addiction; methionine restriction

DOI:  https://doi.org/10.21873/anticanres.17650
Nature. 2025 Jun 25.

Nerve-to-cancer transfer of mitochondria during cancer metastasis.

Gregory Hoover, Shila Gilbert, Olivia Curley, Clémence Obellianne, Mike T Lin, William Hixson, Terry W Pierce, Joel F Andrews, Mikhail F Alexeyev, Yi Ding, Ping Bu, Fariba Behbod, Daniel Medina, Jeffrey T Chang, Gustavo Ayala, Simon Grelet.

The nervous system has a pivotal role in cancer biology, and pathological investigations have linked intratumoural nerve density to metastasis1. However, the precise impact of cancer-associated neurons and the communication channels at the nerve-cancer interface remain poorly understood. Previous cancer denervation models in rodents and humans have highlighted robust cancer dependency on nerves, but the underlying mechanisms that drive nerve-mediated cancer aggressivity remain unknown2,3. Here we show that cancer-associated neurons enhance cancer metabolic plasticity by transferring mitochondria to cancer cells. Breast cancer denervation and nerve-cancer coculture models confirmed that neurons significantly improve tumour energetics. Neurons cocultured with cancer cells undergo metabolic reprogramming, resulting in increased mitochondrial mass and subsequent transfer of mitochondria to adjacent cancer cells. To precisely track the fate of recipient cells, we developed MitoTRACER, a reporter of cell-to-cell mitochondrial transfer that permanently labels recipient cancer cells and their progeny. Lineage tracing and fate mapping of cancer cells acquiring neuronal mitochondria in primary tumours revealed their selective enrichment at metastatic sites following dissemination. Collectively, our data highlight the enhanced metastatic capabilities of cancer cells that receive mitochondria from neurons in primary tumours, shedding new light on how the nervous system supports cancer metabolism and metastatic dissemination.

DOI: https://doi.org/10.1038/s41586-025-09176-8
Cancer Biol Ther. 2025 Dec;26(1): 2516825

β-hydroxybutyrate, a ketone body, suppresses tumor growth, stemness, and invasive phenotypes in non-small cell lung cancer.

Yunlong Huang, Jiaxuan Ding, Yufeng Zhu, Jin Shi, Rong Liu, Chunmei Wu, Liangfu Han, Mingfeng Zhang.

  Lung cancer is the most common cancer worldwide. The stemness and metastasis of tumor cells present major challenges to effective lung cancer treatment. Beta-hydroxybutyrate (BHB), a ketone body, plays a key role in various cancers. However, whether BHB mediates the progression of non-small cell lung cancer (NSCLC) remains unclear. The effects of BHB on the proliferation, apoptosis, and metastasis of NSCLC cells were assessed using the Cell Counting Kit 8, flow cytometry, western blotting, and Transwell assays. The sphere formation assay was used to evaluate the impact of BHB on NSCLC cell stemness. The underlying molecular mechanism was investigated through knockdown and overexpression of free fatty acid receptor 3 (FFAR3) using shRNAs and expression vectors in two NSCLC cell lines (NCI-H1975 and PC-9). In vivo, xenograft tumor and liver metastasis models were established in nude mice. BHB treatment reduced viability, stemness, and migratory and invasive abilities of NSCLC cells. BHB also induced apoptosis and increased cleaved caspase-3 levels in these cells. Moreover, BHB suppressed tumor growth and metastasis, and reduced cell stemness in NSCLC tissues in vivo. Mechanistically, FFAR3 knockdown abolished, while FFAR3 overexpression enhanced, the tumor-suppressive effects of BHB, identifying FFAR3 as a key mediator. These data shed light on the role of BHB in NSCLC development and its underlying molecular mechanisms, suggesting a promising treatment strategy for patients with NSCLC.

Keywords:  Beta-hydroxybutyrate; FFAR3; metastasis; non-small cell lung cancer; stemness

DOI:  https://doi.org/10.1080/15384047.2025.2516825
Atherosclerosis. 2025 Jun 12. pii: S0021-9150(25)01302-4. [Epub ahead of print]407 120404

Empagliflozin restores cardiac metabolism and suppresses immune activation in acute myocardial infarction.

Nikolaos Mylonas, Panagiota Efstathia Nikolaou, Georgios Siokatas, Ioannis V Kostopoulos, Ourania Tsitsilonis, Konstantinos Drosatos, Ioanna Andreadou.

   BACKGROUND AND AIMS: Empagliflozin (EMPA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i), is cardioprotective in acute myocardial infarction (AMI) including fewer hospitalizations for heart failure. However, the underlying metabolic and immunomodulatory mechanisms remain incompletely characterized. This study investigates the metabolic effects of EMPA in diabetic and non-diabetic conditions, as well as on AMI-induced immune responses.
METHODS: C57BL/6J mice were fed on either a control Chow diet (CD) or Western diet (WD) to induce hyperglycemia, followed by treatment with EMPA (10 mg/kg/day) for six weeks and subsequent AMI (30 min of ischemia/2 h of reperfusion). Infarcted hearts were subjected to metabolomic and lipidomic analyses. Cardiac necrosis and immune cell abundance were assessed 7 days post-AMI in blood, spleen, and cardiac tissue with Hematoxylin/Eosin (H/E) staining and flow cytometry, respectively.
RESULTS: Besides the already established effects of EMPA in lowering body weight, blood glucose and cholesterol levels, we found that it fully restored cardiac ATP and 3-hydroxybutyrate (3-BHB) levels in mice with AMI. Additionally, it suppressed UDP-glucose and GM3 ganglioside levels. Notably, the ability of EMPA to restore cardiac metabolome and lipidome was similar between the two dietary groups, with a more pronounced effect observed in WD-fed mice. Furthermore, EMPA reduced myeloid cells in spleen (15.42 ± 2.60 % vs. 21.20 ± 4.45 %) and cardiac tissue (15.94 ± 5.93 % vs. 32.42 ± 8.77 %) and suppressed cardiac necrosis 7 days post-AMI (11.15 ± 3.42 % vs. 21.74 ± 3.30 %).
CONCLUSIONS: EMPA restores cardiac energetics and attenuates the metabolic complications of AMI, independent of the presence of diabetes. These metabolic effects correlate with lower immune cell infiltration and cardiac necrosis, providing long-term benefits in AMI.

Keywords:  Acute myocardial infarction; Empagliflozin; Inflammation; Lipidomics; Metabolomics; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.atherosclerosis.2025.120404
Am J Physiol Cell Physiol. 2025 Jun 25.

Post-exercise ketone monoester administration concomitant with glucose stimulates glycogen repletion in soleus muscle in mice.

Yumiko Takahashi, Tatsuya Matsumoto, Wenxin Wang, Takeru Inaba, Shin Terada, Hideo Hatta.

  Although our group has demonstrated that the administration of β-hydroxybutyrate, a major type of ketone body, stimulated post-exercise glycogen repletion in isolated skeletal muscle, investigations of the effects of ketone supplementation on post-exercise muscle glycogen repletion in vivo have obtained conflicting results. Here, we investigated the effects of an oral intake of the ketone monoester ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate) on post-exercise glycogen repletion in mouse skeletal muscles. Ten-week-old male Institute of Cancer Research mice ran on a treadmill at 25 m/min speed for 60 min. Immediately after the exercise, the mice were orally administered a solution containing 1.0 g/kg body weight (BW) of glucose and 2.0 g/kg BW of ketone monoester (KE solution) or a solution containing glucose and 1.11 g/kg BW of triolein for the adjustment of total calories to match the KE solution's (Con solution). The KE-treated group showed significantly lower post-administration blood glucose concentrations and higher plasma insulin concentrations compared to those of the Con-treated group. The KE-treated group showed a 42.1% higher glycogen concentration in soleus muscle (slow-twitch fiber-dominant) at 60 min post-administration compared to that of Con group. There was no significant between-group difference in the glycogen concentration in the plantaris muscle (fast-twitch fiber-dominant). The KE-treated group's soleus muscle also showed significantly lower phosphorylation levels of AMP-activated kinase Thr172 at 30 min post-exercise compared to the level immediately post-exercise. These results demonstrated that a post-exercise administration of ketone monoester enhanced glycogen repletion, particularly in slow-twitch fiber-dominant muscle.

Keywords:  AMP-activated kinase; glycogen repletion; insulin; ketone monoester; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00311.2025
Nutr Rev. 2025 Jun 26. pii: nuaf074. [Epub ahead of print]

Analysis of the Effects of Low-Fat Diets on Breast Cancer Mortality and Prognosis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Wanzhi Li, Zhexiao Zhang, Anyang Tang, Hang Huang, Wanyi Yao, Ming Chen, Tangbin Zou.

   CONTEXT: Dietary habits may significantly influence human health, potentially more than specific foods or nutrients. These habits also play crucial roles in the treatment and prevention of breast cancer (BC). Although the association between low-fat diets (LFDs) and BC has been extensively investigated, the effects of LFDs on BC-related mortality and prognosis remain insufficiently elucidated.
OBJECTIVE: In this meta-analysis we sought to elucidate the relationship between LFDs and BC risk and prognosis.
DATA SOURCES: The search spanned PubMed, Cochrane Library, Web of Science, and Clinical Trials.gov from database inception up to September 13, 2024. Qualified randomized controlled trials were included.
DATA EXTRACTION: Thirteen studies met the inclusion criteria, encompassing 63,373 participants. These investigations focused on the relationship between LFDs and BC mortality and prognosis.
DATA ANALYSIS: A significant connection exists between LFDs and lower mortality rates following BC (hazard ratio [HR] = 0.84; 95% CI, 0.74-0.95) and deaths specifically attributed to BC (HR = 0.77; 95% CI, 0.64-0.93). Additionally, LFDs significantly enhanced overall survival (HR = 0.76; 95% CI, 0.64-0.89). However, the beneficial effect of LFDs on BC incidence (HR = 0.96; 95% CI, 0.87-1.06) and other BC-related outcomes (HR = 1.02; 95% CI, 0.83-1.26) did not reach statistical significance. Low-fat diets decreased energy intake compared to standard control diets (total weighted mean difference [WMD], -122.01 (kcal); 95% CI, -185.35 to -58.67). Similarly, analysis of fat intake indicated that LFDs reduced energy derived from fat relative to usual control diets (total WMD, -6.28 (%); 95% CI, -7.56 to -4.99). The consumption of saturated fat also revealed a statistically significant effect (total WMD, -2.25 (%); 95% CI, -3.09 to -1.40). Egger's test (P = 0.346) suggested no significant publication bias in the findings. Sensitivity analysis affirmed the robustness of the results.
CONCLUSIONS: This meta-analysis demonstrates that LFDs are significantly associated with improved mortality rates and prognostic outcomes in BC patients. Larger prospective cohorts are needed to confirm these findings and explore causal mechanisms.

Keywords:  breast cancer; low-fat diets; mortality; prognosis

DOI:  https://doi.org/10.1093/nutrit/nuaf074
Brain Sci. 2025 May 28. pii: 585. [Epub ahead of print]15(6):

GLUT1 as a Potential Therapeutic Target in Glioblastoma.

Fnu Ruchika, Sanika Suvarnapathaki, Antolin Serrano-Farias, Chetan Bettegowda, Jordina Rincon-Torroella.

  Glioblastoma (GBM) is the most common primary brain tumor in adults, with a median survival of 15-18 months. GBM cells, like all tumors, exhibit a metabolic shift known as the Warburg effect, favoring glycolysis even under normoxic conditions. GLUT1 is a primary glucose transporter in GBM cells and has been found to be overexpressed in these cells. The acidic microenvironment created by glycolysis facilitates immune evasion, therapy resistance, and tumor growth. Overexpression of GLUT1 is driven by hypoxia-inducible factor-1α (HIF-1α), c-Myc, and other pathways which have been correlated with tumor aggressiveness as well as poor prognosis Recent studies have highlighted the therapeutic potential of targeting GLUT1 in GBM. Preclinical research shows that GLUT1 inhibitors, such as WZB117 and BAY-876, effectively impair tumor metabolism, reduce cell viability, and improve survival in vitro and in animal models. GLUT1 expression also serves as a prognostic marker, with elevated levels linked to poor outcomes. This review highlights the importance of GLUT1 in GBM biology as a potential therapeutic target and biomarker.

Keywords:  GLUT1; Warburg effect; glioblastoma; hypoxia

DOI:  https://doi.org/10.3390/brainsci15060585
Protein Sci. 2025 Jul;34(7): e70206

Allosteric regulation of L-lactate dehydrogenase: Beyond effector-mediated tetramerization.

Hanfeng Cai, Smadar Shulami, Zoran Štefanić, Tomica Hrenar, Aleksandra Maršavelski, Ayelet Fishman.

  The activity of allosterically regulated enzyme is modulated through structural changes induced by effectors. L-lactate dehydrogenase from Geobacillus stearothermophilus (GsLDH) catalyzes the reversible conversion between pyruvate and lactate using NAD(H), and its activity is known to be activated by fructose 1,6-bisphosphate (FBP). However, the molecular basis of this regulation has not been explored using molecular dynamics (MD) simulations. In this study, we integrated MD simulations with biochemical assays to investigate the impact of FBP on GsLDH structure and function. MD revealed that FBP stabilizes the tetrameric form, reduces residue flexibility, and enhances pyruvate interactions with active site residues, despite a 23 Å distance between binding sites. Using MDavocado, we identified three P-axis-related dimer interface regions critical for stability and structural integrity. Microcalorimetry titration revealed that NADH binding (Kd = 1.2 ± 0.3 μM) occurs only in the presence of FBP, indicating an enthalpy-driven interaction involving a hydrogen-bond network. Single amino acid replacement, Gln189Leu, maintains tetrameric structure without FBP and enhances the substrate inhibition effect. However, this mutant fails to trigger the allosteric transition toward a conformation with higher affinity for the substrate, resulting in a high K0.5 value (2.3 ± 0.2 mM) and a low kcat/K0.5 (32 ± 4 s-1 mM-1), comparable to that of the WT without FBP. These findings suggest that oligomerization alone does not confer allosteric responsiveness, emphasizing the essential role of specific interactions in allosteric regulation. Collectively, our results advance the molecular understanding of FBP as a key allosteric effector to stabilize quaternary structure and improve enzyme activity.

Keywords:  Geobacillus stearothermophilus; allosteric regulation; fructose 1,6‐bisphosphate; lactate dehydrogenase; microcalorimetric titration; molecular dynamics

DOI:  https://doi.org/10.1002/pro.70206
J Pathol. 2025 Jun 22.

Analysis of IDH1 and IDH2 mutations as causes of the hypermethylator phenotype in colorectal cancer.

S:CORT Consortium

  The CpG island methylator phenotype (CIMP) occurs in many colorectal cancers (CRCs). CIMP is closely associated with global hypermethylation and tends to occur in proximal tumours with microsatellite instability (MSI), but its origins have been obscure. A few CRCs carry oncogenic (gain-of-function) mutations in isocitrate dehydrogenase IDH1. Whilst IDH1 is an established CRC driver gene, the low frequency of IDH1-mutant CRCs (about 0.5%) has meant that the effects and molecular covariates of those mutations have not been established. We first showed computationally that IDH2 is also a CRC driver. Using multiple public and in-house CRC datasets, we then identified IDH mutations at the hotspots (IDH1 codons 132 and IDH2 codons 140 and 172) frequently mutated in other tumour types. Somatic IDH mutations were associated with BRAF mutations and expression of mucinous/goblet cell markers, but not with KRAS mutations or MSI. All IDH-mutant CRCs were CIMP-positive, mostly at a high level. Cell and mouse models showed that IDH mutation was plausibly causal for DNA hypermethylation. Whilst the aetiology of hypermethylation generally remains unexplained, IDH-mutant tumours did not form a discrete methylation subcluster, suggesting that different underlying mechanisms can converge on similar final methylation phenotypes. Although further analysis is required, IDH mutations may be the first cause of hypermethylation to be identified in a common cancer type, providing evidence that CIMP and DNA methylation represent more than aging-related epiphenomena. Cautious exploration of mutant IDH inhibitors and DNA demethylating agents is suggested in managing IDH-mutant CRCs. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords:  DNA methylation; cancer driver genes; cancer genomics; colorectal cancer; epigenetics; isocitrate dehydrogenase

DOI:  https://doi.org/10.1002/path.6446
Endocr J. 2025 Jun 26.

Changes in body mass index during chemotherapy are positively associated with height outcome in childhood cancer survivors of acute lymphoblastic leukemia.

Tamaki Wada, Ayaha Hata, Takatoshi Maeyama, Shinobu Ida, Kohei Higuchi, Maho Sato, Akihisa Sawada, Yuri Etani, Masanobu Kawai.

  Impaired linear growth is an important morbidity in childhood cancer survivors (CCS); however, chemotherapy-associated factors that affect height outcomes remain elusive. Accordingly, we conducted a single-center, retrospective cohort study that included survivors of childhood-onset acute lymphoblastic leukemia (ALL) diagnosed between 2002 and 2021 who achieved complete remission through chemotherapy alone. Anthropometric parameters and treatment protocols were evaluated based on medical records. Individuals with background disorders or impaired growth were excluded from the study. Associations between anthropometric parameters during chemotherapy and height standard deviation scores (height-SDS) at the current visit were investigated. The results are expressed as the median (interquartile range). Seventy-three individuals (males, N = 44) were included in the study. The median age (years) at diagnosis, end of chemotherapy, and current visit were 4.2 (3.2 to 7.9), 6.3 (5.1 to 10.0), and 15.9 (11.4 to 19.2), respectively. Height-SDS at diagnosis was -0.25 (-0.65 to 0.35), which significantly declined during chemotherapy and recovered thereafter, resulting in a current height-SDS of -0.31 (-0.84 to 0.22). The height-SDS at the investigated time points and its changes during chemotherapy did not differ among the treatment protocols. Multivariate analysis revealed that height-SDS at the current visit was positively associated with changes in body mass index (BMI)-SDS during chemotherapy (β = 0.22, p = 0.01) after adjusting for sex, current age, height-SDS at diagnosis, changes in height-SDS during chemotherapy, and treatment protocols. Since changes in BMI are potentially influenced by nutritional status, our results may underscore the importance of nutritional status during chemotherapy on height outcomes in childhood ALL survivors.

Keywords:  Acute lymphoblastic leukemia; Body mass index; Chemotherapy; Childhood cancer survivors; Height

DOI:  https://doi.org/10.1507/endocrj.EJ24-0545
Metabolites. 2025 Jun 06. pii: 375. [Epub ahead of print]15(6):

High-Calorie Diet Consumption Induces Lac-Phe Changes in the Brain in a Time-of-Day Manner Independent of Exercise.

Jarne Jermei, Han Jiao, Ayano Shiba, Julia C Goedhart, Roberta Tandari, Andries Kalsbeek, Eduard A Struys, Chun-Xia Yi.

  Background/Objectives: N-lactoyl-phenylalanine (Lac-Phe), an exercise-induced metabolite, has been shown to reduce food intake, decrease body weight and adiposity, and improve glucose homeostasis without affecting energy expenditure. Until now, Lac-Phe has mainly been investigated in blood plasma, showing its appetite-suppressing effects. Interestingly, these beneficial effects were caused by a temporary increase in Lac-Phe levels after exercise. Second, despite the central role of the central nervous system in the homeostatic control of energy metabolism, little is known about the presence and function of Lac-Phe in the brain. The goal of this study is to investigate how Lac-Phe concentrations in the brain change during the 24 h light/dark cycle. Methods: We conducted an experiment in rats in which time-restricted running was combined with time-restricted feeding (TRF) of a high-calorie diet, after which Lac-Phe levels were measured in the hypothalamus and cortex using stable isotope dilution LC-MS/MS. Microglia were isolated from rat brains to study Lac-Phe-related gene expression. Results: We found that Lac-Phe levels changed over time within the 24 h light/dark cycle in the hypothalamus and/or cortex, even without exercise. Our study indicates that brain Lac-Phe is not only induced by exercise but also by high-calorie diet intake independent of exercise. Finally, we showed that microglial cells are cytosolic nonspecific dipeptidase 2 (CNDP2) positive and therefore able to produce Lac-Phe. Hereby, we identified SLC16A1 in microglia as a possible key mediator of Lac-Phe production. Conclusions: We conclude that high-calorie diet consumption induces Lac-Phe changes in the brain in a time-of-day manner independent of exercise. This study provides new knowledge on the presence and production of Lac-Phe in the brain. Further research is needed to elucidate the potential mechanism by which Lac-Phe reduces food intake and body weight by targeting appetite-suppressing neurons.

Keywords:  CNDP2; Lac-Phe; SLC16A1; brain; circadian rhythm; exercise; high-calorie diet; microglia; time-restricted feeding

DOI:  https://doi.org/10.3390/metabo15060375
Front Med (Lausanne). 2025 ;12 1555717

Associations between the consumption of red meat and processed meat and the incidence of colorectal cancer in Asia: a meta-analysis.

Zhiyuan Liao, Wenjiang Wu, Shijun Xia, Linchong Yu, Zhigang Xu, Yue Li.

   Objective: This study aimed to evaluate the correlation between the consumption of red meat and processed meat and the incidence of colorectal cancer (CRC) in Asia and provide a scientific basis for reducing the incidence of CRC.
Methods: PubMed, Embase, Cochrane Library, and other databases were searched electronically to collect studies on the correlation between the consumption of red meat and processed meat and the incidence of CRC in Asia. After the quality evaluation of the Newcastle-Ottawa scale, meta-analyses of the selected studies were performed using RevMan 5.4.1. The odds ratio (OR) and 95% confidence interval (95% CI) were combined, and the heterogeneity among the included studies was analyzed via sensitivity analysis. I 2 was used to evaluate the heterogeneity among the included studies.
Results: Twelve articles were included, which involved 13,292 and 12,544 cases in the case and control groups, respectively. The results of the meta-analysis revealed that in the study of the correlation between the consumption of red meat and the incidence of colon cancer, the combined OR was 2.14 (P < 0.00001); that for the consumption of red meat and the incidence of CRC, the OR was 1.77 (P = 0.006); that for the consumption of red meat and the incidence of rectal cancer, the OR was 2.42 (P = 0.0009); and that for the consumption of processed meat and the incidence of CRC, the combined OR was 1.51 (P > 0.05).
Conclusion: The results suggest that red meat is a risk factor for the incidence of colon, colorectal, and rectal cancers. However, no significant correlation was found between the consumption of processed meat and the incidence of CRC.

Keywords:  colon cancer; colorectal cancer; meta-analysis; processed meat; rectal cancer; red meat

DOI:  https://doi.org/10.3389/fmed.2025.1555717