bims-medica 2025-07-06 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–07–06
34 papers selected by
Brett Chrest, Wake Forest University

The anti-tumour role of ketogenic diet based on energy metabolism.
A phase 1 safety and feasibility trial of a ketogenic diet plus standard of care for patients with recently diagnosed glioblastoma.
Spatial patterns of hepatocyte glucose flux revealed by stable isotope tracing and multi-scale microscopy.
Amino acid transporter LAT1 (SLC7A5) promotes metabolic rewiring in TNBC progression through the L-Trp/QPRT/NAD+ pathway.
SIRT5 inhibition impairs mitochondrial metabolism and enhances venetoclax-induced elimination of acute myeloid leukemia cells.
Beyond glucose and Warburg: finding the sweet spot in cancer metabolism models.
Microgliosis, neuronal death, minor behavioral abnormalities and reduced endurance performance in alpha-ketoglutarate dehydrogenase complex deficient mice.
Cardiometabolic disorders affect myocardial [18F]fluorodeoxyglucose uptake- impact on diagnostic PET/CT imaging.
Triglycerides are an important fuel reserve for synapse function in the brain.
The role of B12 deficiency and methionine synthase in methionine-dependent cancer cells.
Imaging cancer metabolism using magnetic resonance.
Protocol for measuring D-amino acid transport in mammalian cells using a fluorescent biosensor.
Mitochondrial thermal proteome profiling reveals aberrant activation of pyruvate dehydrogenase upon cuproptosis.
Muscle needs NAD, but how much?
Moonlighting functions of phosphoglycerate dehydrogenase in cancer.
The long-term effects of chemotherapy on normal blood cells.
MTHFD2 in healthy and cancer cells: Canonical and non-canonical functions.
From genotype to phenotype: decoding mutations in blasts by holo-tomographic flow cytometry.
Carboxylic acid metabolism in cancer: Mechanisms, microenvironment interactions, and therapeutic opportunities.
U-shaped association of serum lactate dehydrogenase with all-cause mortality in cancer patients: a retrospective cohort study.
A phase 1, first-in-human, dose-escalation study of JNJ-74856665 (dihydroorotate dehydrogenase inhibitor) alone or in combination in patients with AML or MDS.
Effect of a ketogenic diet, time-restricted eating, or alternate-day fasting on weight loss in adults with obesity: a randomized clinical trial.
Consumption of fast foods and ultra-processed foods and breast cancer risk: a systematic review and meta-analysis.
Dietary carbohydrate intake and risks of overall and 21 site-specific cancers: a prospective cohort study.
Non-canonical nuclear function of glutaminase cooperates with Wnt signaling to drive EMT during neural crest development.
The role of cardiolipin in mitochondrial dynamics and quality control in neuronal ischemia/reperfusion injury.
The effect of high-sugar feeding on rodent metabolic phenotype: a systematic review and meta-analysis.
Targeting Creatine and Creatine Kinase in Cancer: Exploring Potential Therapeutic Strategies.
Sphingolipid synthesis maintains nuclear membrane integrity and genome stability during cell division.
Rosuvastatin Improved LDL Subfractions Profile in a Patient with Type 1 Diabetes Following a Ketogenic Diet: A Case Report.
Metabolic and hormonal effects of an 8 days water only fasting combined with exercise in middle aged men.
Association between vitamin intake and prostate cancer: a cross-sectional study.
Anti-cancer efficacy of novel lonidamine derivatives: Design, synthesis, in vitro, in vivo, and computational studies targeting hexokinase-2.
Functional cure with single agent olutasidenib in relapsed IDH1/NPM1 co-mutated AML.

Clin Nutr. 2025 Jun 13. pii: S0261-5614(25)00160-8. [Epub ahead of print]51 174-186

The anti-tumour role of ketogenic diet based on energy metabolism.

Jiasheng Wu, Xinyu Sun, Hanmou Luo, Xiaoqi Luo, Suxia Sun.

   BACKGROUND: Unlike the energy metabolism of normal cells, tumour cells favor aerobic glycolysis to meet their unique energy demands, while disrupting normal mitochondrial metabolism. This specialized energy metabolic pathway promotes tumour growth, proliferation, and metastasis. The ketogenic diet (KD) is a high-fat diet inducing ketone bodies (KBs) for energy metabolism by restricting carbohydrate intake and promoting fatty acid breakdown. Due to the unique energy metabolism of tumours, KD has the potential to counteract tumour energy metabolism.
METHODS: The current literature was reviewed for potential anti-tumour mechanisms of KD based on energy metabolism and the clinical evidence suggested for KD roles in tumours.
RESULTS: KD exerts anti-tumour effects by inhibiting tumour aerobic glycolysis, inducing KBs, activating AMP-activated protein kinase (AMPK), and regulating reactive oxygen species (ROS) levels.
CONCLUSION: This review groundbreakingly concludes that KD manifests the potential of anti-tumour effects based on energy metabolism. Furthermore, this study establishes a theoretical foundation for exploring the anti-cancer properties of KD and its potential as a adjunctive therapy for cancer.

Keywords:  Energy metabolism; Glycolysis; Ketogenic diet; Tumour

DOI:  https://doi.org/10.1016/j.clnu.2025.06.006
Sci Rep. 2025 Jul 01. 15(1): 21064

A phase 1 safety and feasibility trial of a ketogenic diet plus standard of care for patients with recently diagnosed glioblastoma.

L J Amaral, Gillian Gresham, Sungjin Kim, Mourad Tighiouart, Thomas A Nelson, Amelia Welborn, Laura Lockshon, Brandon Noorvash, Jeremy D Rudnick, Scott A Irwin, Stephen J Freedland, Jethro Hu.

  Despite great interest, there is limited clinical evidence to support the use of a ketogenic diet (KD) for cancer patients. We conducted a single-arm phase 1 trial of a KD among patients with recently diagnosed glioblastoma (GBM) receiving standard-of-care (SOC) treatment. Adults with GBM within 3 months of diagnosis followed a supervised 16-week intervention of a 3:1 KD (Fat(g): Carbohydrate + Protein(g)) plus SOC chemoradiation. The primary outcome was safety, evaluated by weekly assessments of weight and body mass index (BMI). Secondary outcomes included feasibility (pre-specified as > 50% of patients maintaining blood ketone levels > 0.3 mM over 50% of study days), progression-free survival (PFS), overall survival (OS), health-related quality-of-life, and cognitive function. Twice daily blood glucose and ketones, weight/BMI, physical activity, and sleep were assessed by remote monitoring. Seventeen patients were evaluable: 53% women, median age 55, median Karnofsky Performance Status 85. All subjects met the primary safety objective with no instances of excessive weight loss or related serious adverse events. Adherence was high: all 17 patients maintained nutritional ketosis (≥ 0.3 mM/dL) > 50% of study days. Median PFS and OS were 12.9 months and 29.4 months from KD initiation respectively. Quality of Life, symptom control, and cognitive function remained stable or improved, although these did not reach statistical significance. This phase 1 trial demonstrates that KD is safe and feasible for GBM patients receiving SOC, may improve outcomes, and provides a foundation for an NCI-funded multicenter randomized diet trial to assess efficacy that is currently underway.

Keywords:  Cancer metabolism; Glioblastoma; Ketogenic diets; Ketosis; Physical activity; Quality of life; Supportive care; Warburg effect

DOI:  https://doi.org/10.1038/s41598-025-06675-6
Nat Commun. 2025 Jul 01. 16(1): 5850

Spatial patterns of hepatocyte glucose flux revealed by stable isotope tracing and multi-scale microscopy.

Aliyah Habashy, Christopher Acree, Keun-Young Kim, Ali Zahraei, Martin Dufresne, Sebastien Phan, Melanie Cutler, Emilee Patterson, Alexandra G Mulligan, Kristopher Burkewitz, Charles Robert Flynn, Louise Lantier, Thomas Deerinck, Owen P McGuinness, Jeffrey M Spraggins, Mark H Ellisman, Rafael Arrojo E Drigo.

Metabolic homeostasis requires engagement of catabolic and anabolic pathways consuming nutrients that generate and consume energy and biomass. Our current understanding of cell homeostasis and metabolism, including how cells utilize nutrients, comes largely from tissue and cell models analyzed after fractionation, and that fail to reveal the spatial characteristics of cell metabolism, and how these aspects relate to the location of cells and organelles within tissue microenvironments. Here we show the application of multi-scale microscopy, machine learning-based image segmentation, and spatial analysis tools to quantitatively map the fate of nutrient-derived 13C atoms across spatiotemporal scales. This approach reveals the cellular and organellar features underlying the spatial pattern of glucose 13C flux in hepatocytes in situ, including the timeline of mitochondria-ER contact dynamics in response to changes in blood glucose levels, and the discovery of the ultrastructural relationship between glycogenesis and lipid droplets.

DOI: https://doi.org/10.1038/s41467-025-60994-w
J Exp Clin Cancer Res. 2025 Jul 03. 44(1): 190

Amino acid transporter LAT1 (SLC7A5) promotes metabolic rewiring in TNBC progression through the L-Trp/QPRT/NAD+ pathway.

Margot Y Fedoroff, Lei Zhao, Shaomin Wang, Alok Bhushan, Haifeng Yang, Karen M Bussard, Stephen C Peiper, Jun He.

   BACKGROUND: Cancer cells uptake excessive nutrients by expressing higher levels of glucose and/or amino acid transporters to meet their increased energy demands. L-type amino acid transporter 1 (LAT1), is regarded as a cancer-specific transporter for the uptake of large neutral amino acids such as L-tryptophan. However, the mechanism by which LAT1 rewires cellular metabolism to promote cancer progression and chemoresistance have not yet been investigated.
METHODS: The protein levels of LAT1, p-PKM2, and p-LDHA were determined in breast cancer tissue arrays by immunohistochemistry staining followed by survival analysis. The orthotopic breast cancer models in mice, syngeneic breast cancer models, and patient-derived xenograft (PDX) mouse models were used to study the effects of LAT1 inhibition in tumor growth and chemoresistance. Steady-state polar metabolite analysis was performed to profile changes in cellular metabolism by LC-MS. The pyruvate and lactate assays as well as the seahorse assay using LAT1 knockdown cells and control cells were conducted to evaluate cellular glycolytic activities.
RESULTS: The LAT1 protein levels were positively correlated with poor survival in triple-negative breast cancer (TNBC) patients. LAT1 silencing resulted in reduced TNBC cell viability, proliferation, migration, invasion in vitro, as well as tumor growth in vivo. The knockdown of LAT1 reduced glycolytic activities via activating PKM2 and LDHA, two key glycolytic enzymes essential for cancer cell growth. Mechanistically, we demonstrated that LAT1 promoted de novo NAD + synthesis by facilitating L-tryptophan uptake and upregulating quinolinate phosphoribosyltransferase (QPRT), the rate-limiting enzyme in this pathway. This resulted in an increased cytosolic NAD+/NADH ratio, which enhanced the phosphorylation of pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), thus promoting TNBC tumor progression. Notably, upregulation of this pathway was observed in primary cells from doxorubicin (Dox)-resistant TNBC patient-derived xenograft (PDX) tumors and in Dox-resistant MDA-MB-231 cells. LAT1 inhibition sensitized resistant cells to Dox-induced cytotoxicity while supplementation of L-Trp/NAD + partially reversed the enhanced sensitivity to Doxorubicin induced by LAT1 knockdown. Furthermore, treatment with a LAT1-specific inhibitor JPH203 synergistically enhanced the efficacy of doxorubicin in TNBC cells.
CONCLUSION: These findings identify a novel role of LAT1 in promoting TNBC progression and chemo-resistance by amplifying the Warburg effect, positioning LAT1 as a promising therapeutic target for TNBC treatment.

Keywords:  Glycolysis; L-Tryptophan; LAT1 (SLC7A5); LDHA; NAD +/NADH; PKM2; QPRT; TNBC

DOI:  https://doi.org/10.1186/s13046-025-03446-z
Leukemia. 2025 Jun 30.

SIRT5 inhibition impairs mitochondrial metabolism and enhances venetoclax-induced elimination of acute myeloid leukemia cells.

Moran Wang, Ruiqi Zhu, Donald Small, Lan Lin, Li Li, Shengling Ma, Linghui Xia, Shanshan Luo, Wenjuan He, Jianming Yu, Junying Li, Ruowen Wei, Ao Zhang, Wei Shi, Yu Hu.

Metabolic reprogramming is a key focus of targeted therapies in acute myeloid leukemia (AML). The mitochondrial sirtuin SIRT5 removes succinyl groups from specific lysines and impacts cell metabolism, but its role in AML tumorigenesis has not been extensively explored. A recent study highlighted that SIRT5 regulates AML cell activity by modulating glutamine metabolism, but its molecular targets in AML remain unclear. This study aims to identify the substrates of SIRT5 in AML. It was found that a total of 83 proteins with 121 lysine (K) residues showed increased succinylation after SIRT5 knockdown, as determined by succinylome analysis of MOLM-13 cells. SIRT5 was validated to interact with HADHA, a key molecule in the fatty acid oxidation pathway. Knockdown of SIRT5 resulted in hypersuccinylation and reduced enzymatic activity of HADHA. Mimetic mutations of lysine indicated that SIRT5 desuccinylates HADHA at K644. Inhibiting SIRT5 or HADHA increased sensitivity to venetoclax (VEN) in both VEN-sensitive and VEN-resistant cell lines. SIRT5 knockdown enhanced VEN-mediated suppression of mitochondrial metabolism and improved the survival of AML-transplanted NSG mice when combined with VEN. This study reveals the role of SIRT5 in AML metabolic regulation and provides valuable insights for developing SIRT5-targeted drugs and combination therapies with metabolic inhibitors.

DOI: https://doi.org/10.1038/s41375-025-02673-9
npj metabolic health and disease... 2024 Sep 02. 2(1): 11

Beyond glucose and Warburg: finding the sweet spot in cancer metabolism models.

Nia G Hammond, Robert B Cameron, Brandon Faubert.

Advances in cancer biology have highlighted metabolic reprogramming as an essential aspect of tumorigenesis and progression. However, recent efforts to study tumor metabolism in vivo have identified some disconnects between in vitro and in vivo biology. This is due, at least in part, to the simplified nature of cell culture models and highlights a growing need to utilize more physiologically relevant approaches to more accurately assess tumor metabolism. In this review, we outline the evolution of our understanding of cancer metabolism and discuss some discrepancies between in vitro and in vivo conditions. We describe how the development of physiological media, in combination with advanced culturing methods, can bridge the gap between in vitro and in vivo metabolism.

DOI: https://doi.org/10.1038/s44324-024-00017-2
Redox Biol. 2025 Jun 27. pii: S2213-2317(25)00256-3. [Epub ahead of print]85 103743

Microgliosis, neuronal death, minor behavioral abnormalities and reduced endurance performance in alpha-ketoglutarate dehydrogenase complex deficient mice.

Márton Kokas, András Budai, Andrea Kádár, Soroosh Mozaffaritabar, Lei Zhou, Tímea Téglás, Rebeka Sára Orova, Dániel Gáspár, Kristóf Németh, Daniel Marton Toth, Nabil V Sayour, Csenger Kovácsházi, Andrea Xue, Réka Zsuzsanna Szatmári, Beáta Törőcsik, Domokos Máthé, Noémi Kovács, Krisztián Szigeti, Péter Nagy, Ildikó Szatmári, Csaba Fekete, Tamás Arányi, Zoltán V Varga, Péter Ferdinandy, Zsolt Radák, Andrey V Kozlov, László Tretter, Tímea Komlódi, Attila Ambrus.

  The alpha-ketoglutarate dehydrogenase complex (KGDHc), also known as the 2-oxoglutarate dehydrogenase complex, plays a crucial role in oxidative metabolism. It catalyzes a key step in the tricarboxylic acid (TCA) cycle, producing NADH (primarily for oxidative phosphorylation) and succinyl-CoA (for substrate-level phosphorylation, among others). Additionally, KGDHc is also capable of generating reactive oxygen species, which contribute to mitochondrial oxidative stress. Hence, the KGDHc and its dysfunction are implicated in various pathological conditions, including selected neurodegenerative diseases. The pathological roles of KGDHc in these diseases are generally still obscure. The aim of this study was to assess whether the mitochondrial malfunctions observed in the dihydrolipoamide succinyltransferase (DLST) and dihydrolipoamide dehydrogenase (DLD) double-heterozygous knockout (DLST+/-DLD+/-, DKO) mice are associated with neuronal and/or metabolic abnormalities. In the DKO animals, the mitochondrial O2 consumption and ATP production rates both decreased in a substrate-specific manner. Reduced H2O2 production was also observed, either due to Complex I inhibition with α-ketoglutarate or reverse electron transfer with succinate, which is significant in ischaemia-reperfusion injury. Middle-aged DKO mice exhibited minor cognitive decline, associated with microgliosis in the cerebral cortex and neuronal death in the Cornu Ammonis subfield 1 (CA1) of the hippocampus, indicating neuroinflammation. This was supported by increased levels of dynamin-related protein 1 (Drp1) and reduced levels of mitofusin 2 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in DKO mice. Observations on activity, food and oxygen consumption, and blood amino acid and acylcarnitine profiles revealed no significant differences. However, middle-aged DKO animals showed decreased performance in the treadmill fatigue-endurance test as compared to wild-type animals, accompanied by subtle resting cardiac impairment, but not skeletal muscle fibrosis. In conclusion, DKO animals compensate well the double-heterozygous knockout condition at the whole-body level with no major phenotypic changes under resting physiological conditions. However, under high energy demand, middle-aged DKO mice exhibited reduced performance, suggesting a decline in metabolic compensation. Additionally, microgliosis, neuronal death, decreased mitochondrial biogenesis, and altered mitochondrial dynamics were observed in DKO animals, resulting in minor cognitive decline. This is the first study to highlight the in vivo changes of this combined genetic modification. It demonstrates that unlike single knockout rodents, double knockout mice exhibit phenotypical alterations that worsen under stress situations.

Keywords:  Alpha-ketoglutarate dehydrogenase complex; Cognitive decline; Dihydrolipoyl dehydrogenase; Dihydrolipoyl succinyltransferase; Fatigue test; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.redox.2025.103743
EJNMMI Res. 2025 Jul 01. 15(1): 80

Cardiometabolic disorders affect myocardial [18F]fluorodeoxyglucose uptake- impact on diagnostic PET/CT imaging.

Suvi Hartikainen, Ville Vepsäläinen, Tuomo Tompuri, Tiina M Laitinen, Marja Hedman, Tomi Laitinen.

   BACKGROUND: Corresponding to impaired insulin response in skeletal muscle, insulin resistance may occur in the myocardium, suggesting a link between cardiometabolic disorders and cardiac glucose metabolism. We aimed to investigate whether cardiometabolic disorders predict myocardial [18F]fluorodeoxyglucose ([18F]FDG) uptake suppression in cardiac positron emission tomography / computed tomography (PET/CT) following a ketogenic diet and fasting.
RESULTS: The study included 100 patients undergoing [18F]FDG-PET/CT following a ketogenic diet of 1-2 days and a 12 h fast. Blood glucose, insulin, β-hydroxybutyrate (BHB), cholesterol, triglycerides and free fatty acid (FFA) levels were measured before [18F]FDG injection and later off-diet following overnight fast. The homeostatic model assessment-insulin resistance (HOMA-IR) value was calculated. Non-contrast computed tomography was used to assess the presence of fatty liver and visceral and subcutaneous fat areas. Suppression of myocardial [18F]FDG uptake was considered adequate if myocardial uptake was equal to or lower than the blood pool background. Compared to inadequate suppression, adequate suppression was associated with higher levels of BHB (median 0.26 mmol/l for inadequate and 0.43 mmol/l for adequate suppression, p = 0.004), FFA (0.58 mmol/l and 0.76 mmol/l respectively, p < 0.001), triglycerides (0.87 mmol/l and 1.12 mmol/l respectively, p = 0.028), and lower liver-spleen attenuation ratios (1.17 and 1.04 respectively, p = 0.013). Low HDL cholesterol, high triglycerides and off-diet HOMA-IR, as well as visceral adiposity, fatty liver and hypertension, predicted adequate suppression in men. Elevated BHB and FFA were significant predictors of adequate suppression in women.
CONCLUSIONS: Cardiometabolic disorders are associated with lower myocardial [18F]FDG uptake. Insulin resistance and several other cardiometabolic risk factors are associated with attenuated uptake, especially in men. In women, factors reflecting metabolic response to a ketogenic diet and fasting have a more pronounced effect on myocardial [18F]FDG uptake.

Keywords:  BHB; Beta-hydroxybutyrate; FDG; Insulin resistance; Myocardium; PET/CT

DOI:  https://doi.org/10.1186/s13550-025-01278-8
Nat Metab. 2025 Jul 01.

Triglycerides are an important fuel reserve for synapse function in the brain.

Mukesh Kumar, Yumei Wu, Justin Knapp, Catherine L Pontius, Daehun Park, Rose E Witte, Rachel McAllister, Kallol Gupta, Kartik N Rajagopalan, Pietro De Camilli, Timothy A Ryan.

Proper fuelling of the brain is critical to sustain cognitive function, but the role of fatty acid (FA) combustion in this process has been elusive. Here we show that acute block of a neuron-specific triglyceride lipase, DDHD2 (a genetic driver of complex hereditary spastic paraplegia), or of the mitochondrial lipid transporter CPT1 leads to rapid onset of torpor in adult male mice. These data indicate that in vivo neurons are probably constantly fluxing FAs derived from lipid droplets (LDs) through β-oxidation to support neuronal bioenergetics. We show that in dissociated neurons, electrical silencing or blocking of DDHD2 leads to accumulation of neuronal LDs, including at nerve terminals, and that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion to drive local mitochondrial ATP production. These data demonstrate that nerve terminals can make use of LDs during electrical activity to provide metabolic support and probably have a critical role in supporting neuron function in vivo.

DOI: https://doi.org/10.1038/s42255-025-01321-x
Cancer Metab. 2025 Jul 02. 13(1): 34

The role of B12 deficiency and methionine synthase in methionine-dependent cancer cells.

Mohamed M A El Husseiny, Roland Nilsson.

   BACKGROUND: Human cells can synthesize methionine from homocysteine and folate-coupled methyl groups via the B12-dependent enzyme methionine synthase (MTR). Yet, it has been known for decades that cancer cells fail to grow when methionine is replaced by homocysteine, a phenomenon known as methionine dependence. The underlying mechanism remains unknown.
METHODS: Cancer cell lines were cultured with homocysteine in place of methionine, and growth responses were measured. Revertant cells capable of growing in homocysteine were generated through long-term culture with high B12 and analyzed using single-cell RNA-seq. Metabolite uptake/release was measured using isotope dilution and MTR activity was assessed using metabolic flux analysis (MFA). Functional rescue experiments were performed by overexpressing the B12-independent methionine synthase enzyme.
RESULTS: We report evidence that methionine dependence is caused by low MTR activity secondary to a B12 deficiency. High levels of the B12 cofactor were required to revert methionine-dependent cancer cells to grow on homocysteine. The adapted "revertant" cells display gene expression signatures consistent with reduced invasion and metastasis. Metabolic flux analysis indicated that methionine-dependent cells do not fully activate MTR when cultured in homocysteine. High concentrations of homocysteine partially rescued growth of methionine-dependent cells. Expression of a B12-independent methionine synthase enzyme in cancer cells restored growth on homocysteine and normalized the SAM:SAH ratio, while overexpression of the B12-dependent human enzyme had no effect.
CONCLUSION: Methionine dependence in cancer can be driven by low MTR activity secondary to B12 deficiency, at least in the cell lines studied. This mechanistic insight resolves a long-standing question in cancer metabolism and may open new avenues for exploiting the phenomenon for cancer therapy.

Keywords:  Cancer nutrition; Cobalamin; Methylation; One-carbon metabolism

DOI:  https://doi.org/10.1186/s40170-025-00405-2
Npj imaging... 2024 Jan 11. 2(1): 1

Imaging cancer metabolism using magnetic resonance.

Kevin M Brindle.

The challenge in clinical oncology is to select the most appropriate treatment for an individual patient. Transcriptome and metabolite profiling have revealed that tumours can display metabolic subtypes with different therapeutic vulnerabilities1-4. Metabolic imaging has the potential to distinguish these subtypes and therefore those treatment(s) that should be most effective. Moreover, since changes in tumour metabolism can occur early during treatment, metabolic imaging can also be used subsequently to detect early evidence of treatment response. In this Perspective I briefly review and discuss the relative advantages and disadvantages of magnetic resonance imaging of tumour metabolism using hyperpolarized 13C- and 2H-labelled substrates.

DOI: https://doi.org/10.1038/s44303-023-00004-0
STAR Protoc. 2025 Jun 28. pii: S2666-1667(25)00335-1. [Epub ahead of print]6(3): 103929

Protocol for measuring D-amino acid transport in mammalian cells using a fluorescent biosensor.

Danisha Johal, Keeley G Hewton, Sadie J Gale, Amritpal S Johal, Seth J Parker.

  The movement of amino acids into cells and organelles is facilitated by transporter proteins, which support homeostasis, metabolism, and disease progression. Here, we present a protocol to visualize amino acid transport in mammalian cells in real time using an enzyme-based biosensor. We provide instructions for plating sensor-expressing HEK293 cells, optimizing fluorescent readouts, and initiating transport measurements. Data interpretation and analysis are also discussed. For complete details on the use and execution of this protocol, please refer to Johal et al.1.

Keywords:  Cancer; Cell Membrane; Metabolism; Molecular/Chemical Probes

DOI:  https://doi.org/10.1016/j.xpro.2025.103929
Cell Rep. 2025 Jul 02. pii: S2211-1247(25)00708-9. [Epub ahead of print]44(7): 115937

Mitochondrial thermal proteome profiling reveals aberrant activation of pyruvate dehydrogenase upon cuproptosis.

Zongyu Huang, Yanjun Liu, Ya Zeng, Jun Wang, Siyuan Sun, Chris Soon Heng Tan, Peng R Chen.

  Cuproptosis, a copper-induced form of regulated cell death, holds therapeutic promise in cancer but remains mechanistically unclear. We developed Mito-TPCA, a mitochondrial thermal proximity coaggregation strategy combining enzyme-catalyzed proteome labeling with thermal profiling, to map mitochondrial protein-protein interaction dynamics during cuproptosis. This approach revealed that copper disrupts the association of pyruvate dehydrogenase kinases (PDKs) with the pyruvate dehydrogenase (PDH) complex by targeting lipoyl domains, triggering PDH dephosphorylation and aberrant activation. We demonstrate that this PDH activation is a key driver of cuproptosis and contributes to the heightened susceptibility of cancer cells. These findings establish PDH dephosphorylation/activation as a central mechanism of cuproptosis and a potential anti-cancer therapeutic target. Mito-TPCA offers a versatile platform to study mitochondrial protein complex dynamics in live cells.

Keywords:  CP: Metabolism; CP: Molecular biology; cancer cell susceptibility; cuproptosis; mitochondrial thermal proteome; proximity labeling; pyruvate dehydrogenase aberrant activation

DOI:  https://doi.org/10.1016/j.celrep.2025.115937
Cell Metab. 2025 Jul 01. pii: S1550-4131(25)00296-7. [Epub ahead of print]37(7): 1455-1456

Muscle needs NAD, but how much?

David W Frederick, Joseph P McGaunn, Joseph A Baur.

Supplements that increase nicotinamide adenine dinucleotide (NAD) have become increasingly popular, and much of the attention has focused on potential benefits to skeletal muscle. In this issue of Cell Metabolism, Chubanava et al.1 use an inducible model to lower NAD concentration in the muscles of adult mice, revealing a surprising lack of functional consequences.

DOI: https://doi.org/10.1016/j.cmet.2025.06.001
Cell Rep. 2025 Jul 02. pii: S2211-1247(25)00711-9. [Epub ahead of print]44(7): 115940

Moonlighting functions of phosphoglycerate dehydrogenase in cancer.

Chuanlong Wang, Sanqi An, Lingyang Zhao, Shuo Li, Jia Huang, Wenkai Ren.

  Phosphoglycerate dehydrogenase (PHGDH) is traditionally known for catalyzing the conversion of 3-phosphoglycerate (3-PG) to 3-phosphonooxypyruvate (3-PHP), a key step in the de novo synthesis of serine. However, recent studies have uncovered that PHGDH exhibits a wide range of non-canonical functions. In addition to its role in metabolic reactions within the glycolytic pathway, PHGDH also participates in the regulation of gene transcription and translation. These newly identified functions significantly alter our understanding of how PHGDH aberrantly regulates tumor cell fate. In this review, we summarize the mechanisms by which PHGDH promotes cancer progression through these non-canonical pathways, potentially offering new therapeutic avenues for cancer.

Keywords:  CP: Cancer; CP: Metabolism; PHGDH; moonlighting enzyme; serine; tumor

DOI:  https://doi.org/10.1016/j.celrep.2025.115940
Nat Genet. 2025 Jul 01.

The long-term effects of chemotherapy on normal blood cells.

Emily Mitchell, My H Pham, Anna Clay, Rashesh Sanghvi, Nicholas Williams, Sandra Pietsch, Joanne I Hsu, Hyunchul Jung, Aditi Vedi, Sarah Moody, Jingwei Wang, Daniel Leonganmornlert, Michael Spencer Chapman, Ellie Dunstone, Anna Santarsieri, Alex Cagan, Heather E Machado, E Joanna Baxter, George Follows, Daniel J Hodson, Ultan McDermott, Gary J Doherty, Inigo Martincorena, Laura Humphreys, Krishnaa Mahbubani, Kourosh Saeb Parsy, Koichi Takahashi, Margaret A Goodell, David Kent, Elisa Laurenti, Peter J Campbell, Raheleh Rahbari, Jyoti Nangalia, Michael R Stratton.

Several chemotherapeutic agents act by increasing DNA damage in cancer cells, triggering cell death. However, there is limited understanding of the extent and long-term consequences of collateral DNA damage in normal tissues. To investigate the impact of chemotherapy on mutation burdens and the cell population structure of normal tissue, we sequenced blood cell genomes from 23 individuals aged 3-80 years who were treated with a range of chemotherapy regimens. Substantial additional somatic mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but the effects were dependent on the drug and blood cell types. Chemotherapy induced premature changes in the cell population structure of normal blood, similar to those caused by normal aging. The results show the long-term biological consequences of cytotoxic agents to which a substantial fraction of the population is exposed as part of disease management, raising mechanistic questions and highlighting opportunities for the mitigation of adverse effects.

DOI: https://doi.org/10.1038/s41588-025-02234-x
npj metabolic health and disease... 2024 Mar 15. 2(1): 3

MTHFD2 in healthy and cancer cells: Canonical and non-canonical functions.

Natalia Pardo-Lorente, Sara Sdelci.

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme of the folate-mediated one-carbon metabolism pathway. MTHFD2 has become a highly attractive therapeutic target due to its consistent upregulation in cancer tissues and its major contribution to tumor progression, although it also performs vital functions in proliferating healthy cells. Here, we review the diversity of canonical and non-canonical functions of this key metabolic enzyme under physiological conditions and in carcinogenesis. We provide an overview of its therapeutic potential and describe its regulatory mechanisms. In addition, we discuss the recently described non-canonical functions of MTHFD2 and the mechanistic basis of its oncogenic function. Finally, we speculate on novel therapeutic approaches that take into account subcellular compartmentalization and outline new research directions that would contribute to a better understanding of the fundamental roles of this metabolic enzyme in health and disease.

DOI: https://doi.org/10.1038/s44324-024-00005-6
Light Sci Appl. 2025 Jul 02. 14(1): 233

From genotype to phenotype: decoding mutations in blasts by holo-tomographic flow cytometry.

Daniele Pirone, Concetta Di Natale, Maria Di Summa, Nicola Mosca, Giusy Giugliano, Michela Schiavo, Daniele Florio, Daniela Marasco, Pier Luca Maffettone, Lisa Miccio, Pasquale Memmolo, Pietro Ferraro.

Cup-like nuclear morphological alterations in acute myeloid leukemia (AML) blasts have been widely correlated with Nucleophosmin 1 (NPM1) mutations. NPM1-mutated AML has earned recognition as a distinct entity among myeloid tumors, but the absence of a thoroughly established tool for its morphological analysis remains a notable gap. Holographic tomography (HT) can offer a label-free solution for quantitatively assessing the 3D shape of the nucleus based on the volumetric variations of its refractive indices (RIs). However, traditional HT methods analyze adherent cells in a 2D layer, leading to non-isotropic reconstructions due to missing cone artifacts. Here we show for the first time that holo-tomographic flow cytometry (HTFC) achieves quantitative specificity and precise capture of the nucleus volumetric shape in AML cells in suspension. To retrieve nucleus specificity in label-free RI tomograms of flowing AML cells, we conceive and demonstrate in a real-world clinical case a novel strategy for segmenting 3D concave nuclei. This method implies that the correlation between the "phenotype" and "genotype" of nuclei is demonstrated through HTFC by creating a challenging link not yet explored between the aberrant morphological features of AML nuclei and NPM1 mutations. We conduct an ensemble-level statistical characterization of NPM1-wild type and NPM1-mutated blasts to discern their complex morphological and biophysical variances. Our findings suggest that characterizing cup-like nuclei in NPM1-related AML cells by HTFC may enhance the diagnostic approach for these tumors. Furthermore, we integrate virtual reality to provide an immersive fruition of morphological changes in AML cells within a true 3D environment.

DOI: https://doi.org/10.1038/s41377-025-01913-y
Metabolism. 2025 Jun 26. pii: S0026-0495(25)00203-3. [Epub ahead of print]171 156334

Carboxylic acid metabolism in cancer: Mechanisms, microenvironment interactions, and therapeutic opportunities.

Xiqing Bian, Yue Zhuo, Luo Zhou, Yi Zhun Zhu, Na Li, Jian-Lin Wu.

  Cancer cells reprogram their metabolism to favor aerobic glycolysis and enhance carboxylic acid metabolism, supporting their energy needs and promoting tumor progression. This review explores the role of carboxylic acids, such as lactate, fatty acids, and amino acids, in cancer through four key pathways: (1) lactate-mediated tumor microenvironment acidification and immune suppression, (2) fatty acid metabolism driving tumorigenesis, (3) amino acid regulation of cancer cell survival, and (4) the crosstalk between these metabolic networks. These pathways contribute to immune evasion, proliferation, and drug resistance by modulating key enzymes, transporters, and signaling mechanisms. Despite their therapeutic potential, targeting carboxylic acid metabolism remains challenging owing to tumor adaptability and metabolic heterogeneity. Future research directions include the development of isoform-specific inhibitors, combination therapies, and precision medicine approaches based on metabolic profiling. Understanding these interconnected pathways may reveal new vulnerabilities for innovative cancer treatments.

Keywords:  Amino acid metabolism; Cancer metabolism; Carboxylic acid metabolism; Fatty acid metabolism; Lactate metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.metabol.2025.156334
BMC Cancer. 2025 Jul 04. 25(1): 1143

U-shaped association of serum lactate dehydrogenase with all-cause mortality in cancer patients: a retrospective cohort study.

Mao Zhang, Rui Guo, Xinsheng Xi, Hengping Li.

   BACKGROUND: Lactate dehydrogenase (LDH) is a vital metabolic enzyme with significant prognostic value in various diseases. However, the association between LDH levels and mortality risk in cancer patients remains insufficiently characterized.
METHODS: This retrospective cohort study included 4,337 cancer patients from the National Health and Nutrition Examination Survey (NHANES) (1999-2018). The exposure variable was serum LDH levels, and the outcome was all-cause mortality. Covariates included demographic characteristics, anthropometric measures, metabolic indicators, and comorbidities. Multivariable Cox proportional hazard models were used to evaluate the association between LDH and mortality. The nonlinear relationship was further investigated using generalized additive models with penalized splines and two-piecewise Cox models. All statistical analyses were performed using EmpowerStats software.
RESULTS: During a follow-up of 39,217.58 person-years, 1,779 deaths occurred. After full adjustment, each 10 U/L increase in LDH was associated with a 5.0% increased mortality risk (Hazard ratio [HR] = 1.05, 95% confidence interval [CI]: 1.03-1.07). A U-shaped relationship between LDH levels and mortality was observed, with an inflection point at 128 U/L, with mortality risk reduced by 7% below this threshold (HR = 0.93, 95% CI: 0.89-0.97) and increasing by 8% above this threshold (HR = 1.08, 95% CI: 1.06-1.10). This pattern was consistent across sexes, with optimal thresholds of 121 U/L for males and 136 U/L for females.
CONCLUSION: LDH demonstrates a U-shaped association with all-cause mortality in cancer patients, with sex-specific optimal ranges identified. These findings suggest that LDH levels within the identified ranges are associated with improved survival outcomes in patients with cancer.

Keywords:  L-Lactate dehydrogenase; Mortality; NHANES; Neoplasms; Threshold effect

DOI:  https://doi.org/10.1186/s12885-025-14567-1
Br J Haematol. 2025 Jul 01.

A phase 1, first-in-human, dose-escalation study of JNJ-74856665 (dihydroorotate dehydrogenase inhibitor) alone or in combination in patients with AML or MDS.

Emma Searle, Thomas Cluzeau, Jenny O'Nions, Christian Recher, Emmanuel Gyan, Daniel Morillo, Jordi Esteve, Austin Kulasekararaj, Emmanuel Raffoux, Harriet S Walter, Arnaud Pigneux, David Valcárcel, Nikki Daskalakis, Jacqueline Bussolari, E Christine Pietsch, Scott Kuduk, Tammy Bush, Xiaochun Zhang, Ulrike Philippar, Adetokunbo Oluwasanjo, Kathryn Bradford, Jonathan Miller, Charlotte Van Bogaert, Martin Curtis, Shih-Yu Chang, Christina Guttke, Stan Gaj, Rachel Pearson, Joseph Murphy, Wim van Dijck, Ana Alfonso Piérola.



Keywords:  JNJ‐74856665; acute myeloid leukaemia; dihydroorotate dehydrogenase; myelodysplastic syndromes; phase 1

DOI:  https://doi.org/10.1111/bjh.20224
BMC Med. 2025 Jul 01. 23(1): 368

Effect of a ketogenic diet, time-restricted eating, or alternate-day fasting on weight loss in adults with obesity: a randomized clinical trial.

José Ignacio Martínez-Montoro, Borja Bandera, Mario Gutiérrez-Bedmar, Ana María Gómez-Pérez, Manuel Macías-González, Isabel Moreno-Indias, Francisco J Tinahones.

   BACKGROUND: Studies evaluating the effects of novel, alternative dietary approaches for weight loss compared with the Mediterranean diet (MedDiet) are lacking. We aimed to evaluate the effects of diets with varying ketogenic potential, i.e., a very-low carbohydrate diet (ketogenic diet, KD), time-restricted eating (TRE), and modified alternate-day fasting (mADF) on weight loss in obesity, compared with a MedDiet.
METHODS: Three-month, parallel-arm, randomized clinical trial including 160 adults with obesity. Participants were randomized to 1 of 5 groups: control (MedDiet), KD, early TRE (eTRE), late TRE (lTRE), or mADF. All diets were calorie-restricted. The primary outcome was differences in weight loss from baseline to 3 months between a calorie-restricted MedDiet and each of the four remaining calorie-restricted dietary interventions. Secondary outcomes included change in body mass index, body composition, and cardiometabolic risk factors.
RESULTS: The mean age was 45.7 years (SD 10.7), and 70.6% were women. One hundred forty participants completed the study. Significant differences in weight loss from baseline to 3 months were found between KD and the control group [- 3.78 kg (- 5.65 to - 1.91 kg)], between mADF and the control group [- 3.14 kg (- 4.98 to - 1.30 kg)], and between lTRE and the control group [- 2.27 kg (- 4.13 to - 0.40 kg)], but not between eTRE and the control group [- 1.22 kg (- 3.07 to 0.64 kg)].
CONCLUSIONS: These results suggest that a calorie-restricted KD, mADF, or lTRE may be more effective for weight loss than a calorie-restricted MedDiet in obesity. Further research is needed to evaluate the long-term feasibility and efficacy of these dietary interventions compared with the MedDiet.
TRIAL REGISTRATION: ClinicalTrials.gov (NCT04453150).

Keywords:  Alternate-day fasting; Ketogenic diet; Mediterranean diet; Time-restricted eating; Weight loss

DOI:  https://doi.org/10.1186/s12916-025-04182-z
Glob Health Res Policy. 2025 Jul 01. 10(1): 25

Consumption of fast foods and ultra-processed foods and breast cancer risk: a systematic review and meta-analysis.

Mehdi Karimi, Reyhaneh Rabiee, Farnaz Hooshmand, Baharak Aghapour, Mina Ahmadzadeh, Elahe Havaei, Kimia Kazemi.

   BACKGROUND: The increasing consumption of fast foods (FFs) and ultra-processed foods (UPFs) worldwide has raised concerns due to their association with carcinogenic compounds and potential links to various cancers. However, this evidence about breast cancer risk remains inconsistent. This study aimed to meta-analyze the association between FFs and UPFs consumption and the risk of breast cancer in females.
METHODS: A comprehensive search on online databases was conducted from inception to May 2025, and relevant study data were extracted. The meta-analysis utilized odds ratio (OR) with 95% confidence interval (CI) as effect size measures. Subgroup analyses, heterogeneity assessment, publication bias, and sensitivity analyses were performed to ensure robustness. All statistical analyses were conducted using STATA.
RESULTS: The pooled analysis of 17 observational studies showed a significant association between the highest FFs and UPFs consumption and increased breast cancer risk (OR 1.25, 95% CI [1.09-1.43], p = 0.001). Subgroup analysis revealed a significant positive association between FFs and UPFs consumption and breast cancer risk in case-control studies, but not in cohort studies or menopausal status and a significant association was observed in studies with sample sizes > 1000 and < 1000. Furthermore, the association was significant in Latin America when BMI adjustment was considered for 'yes' and 'no'.
CONCLUSIONS: This meta-analysis identified a significant association between the consumption of FFs and UPFs and an increased risk of breast cancer, with high intake linked to a 25% greater risk. These findings suggest that diets high in UPFs may play a role in breast cancer development. As UPF consumption continues to rise, public health strategies and regulatory policies targeting food processing, marketing, labeling, and accessibility are essential for cancer risk reduction and prevention.

Keywords:  Breast cancer; Epidemiology; Fast food; Nutrition; Processed food; Risk

DOI:  https://doi.org/10.1186/s41256-025-00425-x
Front Nutr. 2025 ;12 1607358

Dietary carbohydrate intake and risks of overall and 21 site-specific cancers: a prospective cohort study.

Shuhui Chen, Baojie Hua, Bin Liu, Le Wang, Qi Yuan, Yudan Yang, Xiaohui Sun, Ding Ye, Lingbin Du, Yingying Mao, Jiayu Li.

   Background: Cancer is among the world's top causes of death, and diet plays an important role in cancer risk. However, few studies have addressed a comprehensive atlas that details the connections between dietary carbohydrates and cancer risk.
Methods: We conducted a large population-based prospective cohort research based on the UK Biobank including 194,388 participants. The Oxford WebQ, a web-based 24-h recall questionnaire, was used to collect dietary information of each study participant. Using the Cox proportional hazards model, we calculated the hazard ratios (HRs) with 95% confidence intervals (CIs) for the associations of energy-adjusted carbohydrates intake and the incidence of overall cancer as well as 21 site-specific cancers.
Results: A total of 19,990 incidences of cancer (excluding non-melanoma skin cancer) were recorded with a median follow-up of 12.8 years. Energy-adjusted fiber was associated with a reduced risk of overall cancer [HR per IQR increase (95% CI): 0.97 (0.96, 0.99); PFDR : 0.045] and esophageal [0.79 (0.68, 0.91); 0.024], colorectal [0.92 (0.87, 0.97); 0.025], lung [0.87 (0.81, 0.94); 0.014], and kidney cancer [0.85 (0.76, 0.94); 0.031]. Energy-adjusted free sugars were tied to a higher risk of lung [1.12 (1.05, 1.19); 0.024] and kidney cancer [1.15 (1.05, 1.26); 0.039], while non-free sugars were associated with a reduced risk of overall cancer [0.97 (0.95, 0.99); 0.031], colorectal [0.89 (0.84, 0.94); 0.006] and lung cancer [0.86 (0.79, 0.93); 0.014]. Finally, energy-adjusted sucrose was associated with an elevated risk of both lung cancer [1.10 (1.04, 1.17); 0.024] and non-Hodgkin lymphoma [1.15 (1.07, 1.23); 0.008].
Conclusion: Increased consumption of dietary fiber and non-free sugars is associated with a reduced risk of certain cancers (e.g., overall cancer, esophageal, colorectal, lung, and kidney cancers), potentially due to their anti-inflammatory effects, short-chain fatty acid production, and other protective mechanisms. In contrast, higher intakes of free sugars and sucrose are associated with an elevated risk (e.g., lung, kidney cancer, and non-Hodgkin lymphoma), which may be attributed to inflammation and oxidative stress.

Keywords:  cancer; cohort study; diet; dietary carbohydrate; sugar

DOI:  https://doi.org/10.3389/fnut.2025.1607358
Nat Commun. 2025 Jul 01. 16(1): 5554

Non-canonical nuclear function of glutaminase cooperates with Wnt signaling to drive EMT during neural crest development.

Nioosha Nekooie Marnany, Alwyn Dady, Isabelle Duband-Goulet, Frédéric Relaix, Roberto Motterlini, Roberta Foresti, Sylvie Dufour, Jean-Loup Duband.

Metabolic reprograming has been linked to epithelial-to-mesenchymal transition (EMT) in cancer cells, but how it influences EMT in normal cells remains largely unknown. Here we explored how metabolism impacts delamination and migration of avian trunk neural crest cells, an important progenitor cell population of the vertebrate embryo. We report that delamination exhibits a quiescent metabolic phenotype whereas migration is characterized by OXPHOS-driven metabolism coupled to distinct expression of metabolic, EMT and developmental genes. While glucose and glutamine are required for delamination and migration, we uncover a specific role for glutamine and its catabolizing enzyme glutaminase in the unfolding of NCC delamination. Namely, glutamine is required for nuclear accumulation of glutaminase, which interacts and cooperates with Wnt signaling to regulate EMT gene expression and cell cycle during delamination. Our data indicate that similarly to cancer cells, embryonic cells engage metabolic enzymes for non-canonical signaling functions to connect metabolism with EMT.

DOI: https://doi.org/10.1038/s41467-025-58573-0
Cell Death Dis. 2025 Jul 05. 16(1): 494

The role of cardiolipin in mitochondrial dynamics and quality control in neuronal ischemia/reperfusion injury.

Katlynn J Emaus, Garrett M Fogo, Joseph M Wider, Thomas H Sanderson.

Stroke and cardiac arrest claim the lives of millions worldwide each year emphasizing the importance of understanding this injury cascade. These pathologies present as a 'two hit' injury termed ischemia/reperfusion (I/R) injury. The primary injury is the initial disruption of blood flow and ischemic state while the secondary injury, paradoxically, being the return of blood flow and oxygen availability. The injury caused by reperfusion presents a viable window for therapeutic intervention, stressing the importance of understanding this injury pathology. Constantly undergoing fission and fusion, mitochondria are dynamic organelles that play a vital role in maintaining cell health and are highly susceptible to I/R injury. Following I/R injury, disrupted mitochondrial dynamics and quality control ultimately lead to a dysfunctional mitochondrial network, energy depletion and eventually cell death. While mitochondrial dynamics and quality control have been studied extensively in the realm of I/R injuries, the role of mitochondrial lipids is emerging as an important component of injury progression. The inner mitochondrial membrane lipid, cardiolipin has been demonstrated to play an integral role in maintaining mitochondrial quality control, dynamics and energy production. In response to oxidative stress, cardiolipin has been shown to interact with several important proteins involved in mitochondrial dynamics while also contributing to integral signaling cascades. This review will highlight the role of cardiolipin in mitochondrial dynamics and quality control in response to neuronal I/R injury.

DOI: https://doi.org/10.1038/s41419-025-07786-8
npj metabolic health and disease... 2024 Dec 30. 2(1): 40

The effect of high-sugar feeding on rodent metabolic phenotype: a systematic review and meta-analysis.

Sophie Lucic Fisher, G Jean Campbell, Alistair Senior, Kim Bell-Anderson.

Dietary sugar consumption has been linked to increased cardiometabolic disease risk, although it is unclear if this is independent of increases in body weight and adiposity. Additionally, many preclinical animal studies provide liquid sugar which more readily leads to excess consumption and weight gain, confounding any outcomes driven by high-sugar intake alone. To gain clarity on this, we conducted a systematic review and meta-analysis exclusively investigating the effect of isocaloric high-sugar, low-fat solid diet formulations containing fructose or sucrose, on cardiometabolic health in rodents. Overall, we found strong evidence that fructose and sucrose have effects on metabolic health, independent of body weight gain. High-sugar feeding, with fructose in particular, altered liver phenotype; ALT (d = 1.08; 0.66, 1.5), triglyceride content (d = 0.52; 0.25, 0.78), cholesterol (d = 0.59; 0.16, 1.03) and liver mass (d = 0.93; 0.37, 1.48), and glucose tolerance; fasting glucose (d = 0.60; 0.18, 1.01) and fasting insulin (d = 0.42; 0.07, 0.77) but not body weight or energy intake. Our review also highlights the lack of data reported on adiposity and in female rodents. This is the first meta-analysis to synthesise all current rodent solid diet high-sugar studies, while adjusting them for confounders (fat content, time spent on diet and age started on diet) and suggests that high-sugar dietary intake and composition alters metabolic health of mice regardless of weight gain.

DOI: https://doi.org/10.1038/s44324-024-00043-0
Curr Drug Targets. 2025 Jun 24.

Targeting Creatine and Creatine Kinase in Cancer: Exploring Potential Therapeutic Strategies.

Mahla Abdollahzadeh, Razieh Ghodsi, Zhila Taherzadeh, Mahdi Hatamipour.

  Creatine kinases (CKs) are a family of vital enzymes implicated in the domain of cellu-lar bioenergy, fulfilling a pivotal role in facilitating the reversible transfer of phosphoryl groups between adenosine triphosphate (ATP) and creatine. This process plays a crucial role in maintain-ing optimal ATP levels during energy-demanding processes, a requirement that is amplified in rapidly proliferating cells, including cancerous cells. CKs are pivotal in supporting cancer growth and metastasis, making their inhibition a promising therapeutic strategy. The present review dis-cusses a few ways of disrupting the creatine energy production cycle with emphasis on three main areas of research: First, we consider the different strategies that attack the Creatine Transporter (SLC6A8). Since this transporter facilitates the entry of creatine into the cell, it is expected that inhibiting this transporter may lead to reduced availability of creatine for CK-mediated energy production. Second, strategies aimed at directly inhibiting the enzyme carrying out the creatine phosphorylation are described. Lastly, we consider approaches targeting the backward reaction, i.e., the re-conversion of phosphocreatine to creatine and, thereby, the equilibrium of the CK reac-tion. The current review gives an overview of the structure-activity and structure-property rela-tionships of the currently available CK inhibitors. Understanding these relations in depth is a pre-requisite for developing new and more potent and selective CK inhibitors. This review focuses on an in-depth analysis to create better CK inhibitors with possible applications in oncology.

Keywords:  Creatine kinases; cancer metabolism; cancer therapy; creatine transport; enzyme inhibition.; therapeutic strategy

DOI:  https://doi.org/10.2174/0113894501373936250609114913
J Cell Biol. 2025 Aug 04. pii: e202407209. [Epub ahead of print]224(8):

Sphingolipid synthesis maintains nuclear membrane integrity and genome stability during cell division.

Sunyoung Hwang, William Russo, Jaylah Cormier, Jillian Johnson, Sara Martin, Marica Rosaria Ippolito, Sara Cordone, Rui Li, Lihua Julie Zhu, Stefano Santaguida, Eduardo M Torres.

Lipid synthesis must be precisely regulated to support membrane growth and organelle biogenesis during cell division, yet little is known about how this process is coordinated with other cell cycle events. Here, we show that de novo synthesis of sphingolipids during the S and G2 phases of the cell cycle is essential to increasing nuclear membranes. Indeed, the products of serine palmitoyltransferase (SPT), long-chain bases, localize to the nucleus and are integral components of nuclear membranes in yeast and human cells. Importantly, inhibition of SPT fails to induce cell cycle arrest, causing nuclear membrane collapse and loss of viability in yeast cells. In human cells, this causes abnormal nuclear morphology and genomic instability, evidenced by the increased incidence of nuclear blebs, micronuclei, anaphase bridges, and multipolar mitosis. These results indicate that dysregulated cell division under low sphingolipid availability can drive several disease-associated phenotypes, including aberrant nuclear morphologies and genomic instability.

DOI: https://doi.org/10.1083/jcb.202407209
Curr Vasc Pharmacol. 2025 Jul 02.

Rosuvastatin Improved LDL Subfractions Profile in a Patient with Type 1 Diabetes Following a Ketogenic Diet: A Case Report.

Miodrag Janić, Mojca Lunder, Andrej Janež, Mišo Šabović, Viviana Maggio, Manfredi Rizzo.

   INTRODUCTION: People on a ketogenic diet may develop an increase in low-density lipoprotein cholesterol (LDL-C), known as the lean mass hyper-responder (LMHR) phenotype. However, this increase does not necessarily correspond to a heightened cardiovascular (CV) risk, and optimal treatment strategies for high-risk individuals within this group remain uncertain.
CASE PRESENTATION: A 61-year-old man with type 1 diabetes developed the LMHR phenotype after adopting a ketogenic diet. An atherosclerotic plaque was discovered in the bulb of his left common carotid artery, reclassifying him into the secondary prevention category of CV disease. After the introduction of rosuvastatin 20 mg daily, his LDL-C subfraction profile changed from a more atherogenic type B phenotype to a less atherogenic type A phenotype without significantly decreasing overall LDL-C levels. This suggests that rosuvastatin provided a beneficial effect, complementing the metabolic improvements associated with the ketogenic diet, including better blood glucose and insulin control, potential prior reductions in small dense LDL-C and triglycerides, and an increase in high-density lipoprotein cholesterol (HDL-C).In this case, no trend toward a lower threshold was observed for the development of diabetic ketoacidosis.
CONCLUSION: Assessing LDL-C subfractions before and after the initiation of lipid-lowering therapy is essential in individuals who develop the lean mass hyper-responder (LMHR) phenotype, particularly in the presence of confirmed atherosclerosis. Given the markedly elevated LDL-C levels often observed in this population, it may be difficult to accurately evaluate the burden of atherogenic cholesterol and the extent of its reduction without subfraction analysis. In such cases, statin therapy appears to be a reasonable and potentially beneficial intervention, even among LMHR individuals.

Keywords:  Type 1 diabetes; ketogenic diet; lean mass hyper-responder phenotype; low-density lipoprotein cholesterol subfractions; statin.

DOI:  https://doi.org/10.2174/0115701611370578250621183337
Sci Rep. 2025 Jul 02. 15(1): 22805

Metabolic and hormonal effects of an 8 days water only fasting combined with exercise in middle aged men.

Karol Pilis, Urszula Godlewska, Anna Pilis, Krzysztof Stec, Patrycja Dolibog, Marek Kruszewski, Adrianna Kosior-Lara, Romanbek Kalmatov, Wiesław Pilis, Sławomir Letkiewicz.

  Optimal nutrition and physical activity are vital for enhancing physical performance and preventing metabolic diseases like obesity. Recently, interest has grown in long-term fasting, particularly water-only fasting, which involves no food intake and unlimited water consumption. Our study investigated the effects of 8 days of water-only fasting combined with aerobic exercise in 13 middle-aged men, focusing on metabolic, hormonal, and immune changes. Results showed that fasting had a more significant impact than exercise, leading to changes in glucose, uric acid, IGF-1, IGF-2, GH, leptin, and cortisol, improved total antioxidant status (TAS), and reduced lipid peroxidation. While exercise enhanced the effects of fasting on triglycerides, insulin, GH, TAS, PerOX, and IL-6, changes in total protein and lactate were solely due to exercise. Overall, combining fasting and exercise led to a metabolic shift from carbohydrates to fatty acids and hormonal adaptations to stress. These results, although derived from a small group of patients, offer a promising outlook for further research into the effects of fasting combined with physical activity on health and weight maintenance.

Keywords:  Fasting; Hormonal changes; Immunity; Metabolism; Physical activity

DOI:  https://doi.org/10.1038/s41598-025-05164-0
Front Nutr. 2025 ;12 1607452

Association between vitamin intake and prostate cancer: a cross-sectional study.

Sen Pan, Chuanlin Wang, Wei Sun, Xin Zhang.

   Background: As micronutrients, vitamins play a critical role in maintaining normal physiological functions. However, the impact of different types of vitamins on PCa remains controversial. This study aimed to investigate the association between vitamin intake and PCa using a cross-sectional design.
Methods: We conducted a cross-sectional analysis of 14,977 adult men using data from the National Health and Nutrition Examination Survey (NHANES) collected between 2007 and 2018. Dietary intake was assessed using 24-h dietary recall interviews. Multivariate weighted logistic regression models were used to analyze the relationship between vitamin intake and PCa. Restricted cubic spline (RCS) was conducted to evaluate the non-linear relationship. We performed a trend test to examine the association between vitamin intake and PCa risk, and conducted an interaction analysis stratified by group covariates. The covariates included age, race, body mass index, educational attainment, the ratio of family income to poverty, alcohol intake, smoking status, diabetes, and hypertension.
Results: The study encompassed 10 vitamins with three ways of intake: diet, supplement, and total (diet plus supplement). In the fully adjusted model, the quartile-based analysis showed that individuals in the highest quartile of dietary retinol intake had a significantly increased risk of PCa (OR = 1.76, p = 0.027), while higher supplement intake of vitamin B1 (OR = 0.38, p = 0.036) and vitamin B2 (OR = 0.35, p = 0.016) was associated with a lower risk. In the continuous variable analysis, supplement intake of vitamin B9 (OR = 0.65, p = 0.049), vitamin B12 (OR = 0.83, p = 0.030), and total vitamin B12 (OR = 0.82, p = 0.037) were inversely associated with PCa risk after full adjustment. We identified significant non-linear associations between dietary intake of vitamins A, B6, B12, and C and PCa risk using RCS analysis. There is an interaction between supplementation, total vitamin B12 intake, and age groups.
Conclusion: Taken together, our study provides the latest evidence for vitamin intake and PCa prevention. Large-scale randomized controlled trials are still needed to provide additional evidence.

Keywords:  National Health and Nutrition Examination Survey; cross-sectional; diet; prostate cancer; vitamin intake

DOI:  https://doi.org/10.3389/fnut.2025.1607452
Eur J Med Chem. 2025 Jun 19. pii: S0223-5234(25)00655-5. [Epub ahead of print]296 117890

Anti-cancer efficacy of novel lonidamine derivatives: Design, synthesis, in vitro, in vivo, and computational studies targeting hexokinase-2.

Ӧzgecan Şavluğ İpek, Bilgesu Onur Sucu, Saba Selvi, Fulya Koksalar Alkan, Büşra Tiryaki, Hilmi Kaan Alkan, Ehsan Sayyah, İlayda Tolu, Mustafa Güzel, Serdar Durdağı, Nuri Öztürk, Hasan Korkaya.

  Targeting cancer metabolism has emerged as an attractive therapeutic strategy in recent years, despite the "Warburg effect" phenomenon is discovered about a century ago. Based on this phenomenon, cancer cells rely on aerobic glycolysis and require higher rate of glucose consumption compared to normal cells and the hexokinase-2 (HK-2) enzyme catalyzes the first step of glucose metabolism. Consistent with the notion, HK-2 expression is highly elevated in most malignancies and that predicts poor survival in patients. Thus, inhibiting the HK-2 activity may be a potential metabolic target for cancer therapy. Lonidamine (LND) is known as a potential anti-cancer drug through HK-2 inhibition with varying degrees of efficacy in different malignancies. LND shows potency through voltage-dependent anion channel (VDAC) and HK-2 interaction on mitochondrial membrane. Therefore, we designed and synthesized novel LND analogs to improve its molecular and functional properties. We first performed chemical and structural characterization of these LND analogs and tested their biological activity by in vitro assays and in vivo in mouse xenografts. Among these potent HK-2 inhibitors, Compound 20 was identified as a promising lead compound with anti-tumor activity. Based on the three different cancer cell lines we investigated, our novel LND analogs proved to be more potent than the original molecule. Our findings provide convincing evidence for potentially designing novel analogs of LND and beyond to further improve biological and functional properties existing drugs. Further proven in preclinical settings, our approach may lead to development of more effective therapeutics benefiting patients.

Keywords:  Anti-cancer activity; Glycolysis; Hexokinase-2 inhibitors; Lonidamine; Molecular simulations

DOI:  https://doi.org/10.1016/j.ejmech.2025.117890
NPJ Precis Oncol. 2025 Jul 01. 9(1): 211

Functional cure with single agent olutasidenib in relapsed IDH1/NPM1 co-mutated AML.

Justin Watts, Tiffany Nong, Katarina Micin, Deborah Soong, Ellen Madarang, Maurizio Affer, Shefali Mehra, Jessica Alvarez Lesmes, Jennifer Chapman, Yi Zhou, Amber Thomassen, Terrence Bradley, Tulasigeri Totiger, Ronan Swords, Justin Taylor.

Olutasidenib is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) that was recently approved by the US FDA for adult patients with relapsed or refractory acute myeloid leukemia (AML) harboring mutant IDH1. In the pivotal Phase II trial of olutasidenib, the median duration of complete response (CR) was 28.1 months. Here we report the first patient in the world to receive olutasidenib, for relapsed NPM1 and IDH1 co-mutated AML, who remains in continuous CR for over 7 years on olutasidenib monotherapy. We detail the clinical course as well as the pathologic and genomic evolution of the disease. Furthermore, using a novel single cell measurable residual disease assay and digital PCR and qPCR for the detection of IDH1 and NPM1 mutations, we found no evidence of residual detectable leukemia. To our knowledge, this is the first report of an AML patient functionally cured by IDH1 inhibitor monotherapy.

DOI: https://doi.org/10.1038/s41698-025-01013-5