bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2025–06–22
thirty-one papers selected by
Brett Chrest, Wake Forest University



  1. Expert Rev Anticancer Ther. 2025 Jun 20. 1-5
      
    Keywords:  Carnivore diet; evidence; ketone bodies; ketosis; skepticism
    DOI:  https://doi.org/10.1080/14737140.2025.2522936
  2. Biochimie. 2025 Jun 12. pii: S0300-9084(25)00117-8. [Epub ahead of print]
      13C Metabolic flux analysis (13C MFA) is a non-invasive methodology for the measurement of fluxes (rates of carbon flow) throughout a metabolic network and can be used to determine nutrient contributions to central metabolic pathways. 13C MFA was used in a systemic metabolic investigation of the nutritional physiology of preimplantation bovine blastocysts. Bovine blastocysts were cultured either singly or in groups of five in 40 μl of medium containing 13C labeled glucose and/or fructose, and the metabolites expelled into the spent media were identified through 13C MFA of heavy isotope labeling. Similarly, the metabolites in spent media following culture of a bovine trophectoderm cell line (CT-1) were monitored. Flux maps generated using 13C MFA suggest that less than 10% of metabolites from the glycolytic pathway were diverted to the pentose phosphate pathway or the tricarboxylic acid cycle in either bovine blastocysts or CT-1 cells with the majority of the hexose (70-80%) resulting in pyruvate and lactate production.
    Keywords:  (13)C; Embryo; blastocyst; isotopomer; metabolic flux analysis; trophectoderm
    DOI:  https://doi.org/10.1016/j.biochi.2025.06.004
  3. Cancer Res. 2025 Jun 20.
      Immune checkpoint blockade (ICB) has transformed cancer treatment, but success rates remain limited. Recent research suggests that dietary fiber enhances ICB efficacy through microbiome-dependent mechanisms. However, prior studies in mice compared grain-based chow (high-fiber) to low-fiber purified diet, but these diets also differed in other dimensions, including phytochemicals. Therefore, further work is needed to establish the robustness of the effect of fiber on ICB across cancer types and dietary contexts. Here, we investigated gut microbiome composition, metabolite levels, and ICB activity in mice fed grain-based chow or purified diets with differing quantities of isolated fibers (cellulose and inulin). Compared to dietary fiber content, consumption of chow versus purified diet had a greater effect on the gut microbiome and a much stronger impact on the metabolome. Studies in multiple tumor models revealed that fiber has a weaker impact on ICB (anti-PD-1) efficacy than previously reported. While diet impacted ICB in some models, the effect was not directionally consistent. None of the models tested displayed the pattern expected if fiber controlled ICB efficacy: strong efficacy in both chow and high-fiber purified diet but low efficacy in low-fiber purified diet. Thus, dietary fiber appears to have limited or inconsistent effects on ICB efficacy in mouse models, and other dietary factors that correlate with fiber intake may underlie clinical correlations between fiber consumption and immunotherapy efficacy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4378
  4. Anticancer Drugs. 2025 Jun 20.
      Tumor metabolism and metabolic reprogramming in cancer cells represent a promising area in oncology research, offering new avenues for therapeutic intervention. While the 'Warburg effect' highlights the reliance of many tumors on aerobic glycolysis, emerging evidence indicates that some cancers also depend on mitochondrial oxidative phosphorylation (OXPHOS) for energy production, cancer cell survival, tumor progression, metastasis, and drug resistance. We conducted a high-throughput, differential, phenotypic screening followed by a focused medicinal chemistry campaign, leading to the identification of novel, potent OXPHOS inhibitors. These lead compounds selectively target complex I of the mitochondrial electron transport chain, thereby disrupting ATP production and oxygen consumption in cancer cells. In-vitro studies in breast cancer cell lines, along with published data, suggest that MCT4 expression may serve as a biomarker for drug sensitivity. Notably, low MCT4 expression correlated with higher potency in cell growth assays. The identified compounds exhibited favorable drug-like properties, including good pharmacokinetics and oral bioavailability in mice. Daily oral dosing significantly inhibited tumor growth in two in-vivo breast cancer models with low MCT4 expression levels. This efficacy, however, was accompanied by body weight loss, indicating the need to enhance the therapeutic index through optimization or rational combination therapy strategies. These findings highlight the therapeutic potential of targeting mitochondrial OXPHOS in cancers with defined metabolic dependencies, offering a novel approach for exploiting tumor-specific metabolic vulnerabilities for improved cancer treatment.
    Keywords:  electron transport chain; mitochondrial complex I; oxidative phosphorylation; tumor growth inhibition
    DOI:  https://doi.org/10.1097/CAD.0000000000001750
  5. Nat Commun. 2025 Jun 20. 16(1): 5355
      Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogate how physiologically low iron availability affects CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation does not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalls proliferation (without influencing cell viability), alters histone methylation status, gene expression, and disrupts mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle is limited and partially reverses to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Despite aberrant TCA cycling, aspartate is increased in stalled iron deficient CD8+ T cells but is not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescues expansion and some functions of severely iron-deficient CD8+ T cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.
    DOI:  https://doi.org/10.1038/s41467-025-60204-7
  6. Front Oncol. 2025 ;15 1600425
      Cancer cachexia is a multifactorial syndrome characterized by involuntary weight loss, muscle mass reduction, and systemic inflammatory response, negatively impacting the quality of life and survival of cancer patients. In gastrointestinal tumors, cachexia prevalence can reach up to 80%, presenting a complex clinical challenge. This review aims to explore the efficacy of a multimodal approach integrating nutritional support and physical activity in cancer cachexia management. Targeted dietary strategies, such as a high-protein diet enriched with omega-3 and branched-chain amino acids (BCAAs), have proven effective in counteracting muscle loss and modulating inflammatory metabolism. Physical activity, particularly resistance training, contributes to preserving lean mass and improving physical function. However, current data suggest that no single strategy is sufficient to reverse cachexia, necessitating combined treatment with supportive pharmacological therapies, including progestogens, muscle metabolism modulators, and cytokine antagonists. Despite the evidence supporting these interventions, significant gaps remain, highlighting the need for randomized clinical trials to define the optimal therapeutic protocol for gastrointestinal cancer patients with cachexia.
    Keywords:  cancer cachexia; gastrointestinal tumors; multimodal approach; new drugs; nutritional support; physical activity
    DOI:  https://doi.org/10.3389/fonc.2025.1600425
  7. Eur J Cancer Prev. 2025 Jun 18.
      Observational studies indicated that the overall inflammatory potential of diets has been implicated in cancer etiology; however, the results were inconsistent. We aimed to estimate the dose-response association of dietary inflammatory potential with cancer outcomes based on prospective cohort studies. PubMed, Embase and Web of Science databases were searched up to 11 November 2023 for prospective cohort studies. The dietary inflammatory potential was assessed by the dietary inflammatory index (DII) or energy-adjusted DII (E-DII). Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. Restricted cubic splines were used to illustrate the possible linear or nonlinear associations. Ultimately, 30 articles including 33 studies with 4 090 977 participants were included. As compared the highest to the lowest DII category, the pooled RRs (95% CIs) for overall cancer, colorectal cancer, lung cancer, and renal cancer were 1.19 (1.11-1.27), 1.30 (1.16-1.44), 1.13 (1.04-1.23), and 1.45 (1.14-1.83), respectively; for E-DII, the RRs (95% CIs) was 1.08 (1.01-1.16) for overall cancer and 1.23 (1.13-1.33) for colorectal cancer. For each 1-unit increase in DII, the risk increased by 3% (RR = 1.03, 95% CI: 1.02-1.04) for overall cancer, 3% (RR = 1.03, 95% CI: 1.02-1.05) for colorectal cancer, and 7% (RR = 1.07, 95% CI: 1.03-1.12) for renal cancer; for E-DII, the risk increased by 1% (RR = 1.01, 95% CI: 1.00-1.02) for overall cancer and 3% (RR = 1.03, 95% CI: 1.02-1.05) for colorectal cancer. Additionally, restricted cubic splines showed linear relationships of DII (Pnonlinearity = 0.080) and E-DII (Pnonlinearity = 0.273) with overall cancer risk. The higher dietary inflammatory potential was associated with an increased risk of cancer.
    Keywords:  cancer; cohort study; dietary inflammatory potential; dose-response; meta-analysis
    DOI:  https://doi.org/10.1097/CEJ.0000000000000980
  8. Biochem Biophys Res Commun. 2025 Jun 18. pii: S0006-291X(25)00942-8. [Epub ahead of print]776 152227
      Intestinal ischemia-reperfusion injury (IRI) is a significant clinical challenge with limited effective treatments. This study investigated the protective effects of ketogenic diet (KD) and β-hydroxybutyrate (BHB) against intestinal IRI using mouse models and intestinal organoids. Following two weeks of KD or BHB administration, mice were subjected to superior mesenteric artery occlusion (60 min) and reperfusion (4 h). Both interventions significantly elevated blood BHB levels and reduced fasting glucose. KD and BHB markedly attenuated intestinal villous damage, preserved epithelial barrier function (E-cadherin, Occludin, ZO-1), maintained mitochondrial integrity, reduced inflammatory cytokines (IL-6, IL-1β, TNF-α), and improved 72-h survival rates, with KD demonstrating superior efficacy. In intestinal organoid oxygen-glucose deprivation models, BHB exhibited differential protective effects at two tested concentrations (2 mM vs. 5 mM), with enhanced protection at the higher concentration on cellular viability, structural integrity, and inflammatory responses. These findings provide the first evidence that ketogenic interventions protect against intestinal IRI through multiple mechanisms including inflammatory suppression and barrier preservation, suggesting potential clinical applications in intestinal IRI prevention and management, though detailed mechanistic elucidation requires further investigation.
    Keywords:  Intestinal barrier; Intestinal ischemia-reperfusion injury; Ketogenic diet; Organoids; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152227
  9. Front Nutr. 2025 ;12 1600927
      As economy is growing, the number of patients living with obesity has rapidly increased globally. Patients with obesity or diabetes have become a serious global health issue that requires the attention and participation of society as a whole. The ketogenic diet, as an emerging nutritional therapy for improving obesity, takes into consideration the differences between sexes in genetic variation, hormonal balance, and body fat distribution. The aim is to elucidate the effectiveness of sex differences in ketogenic dieting for weight loss and to explore suitable weight loss strategies. In this review, we delve into the physiological sexual differences between men and women in terms of fat and muscle tissue and discuss the sex-specific potential mechanisms underlying the differential effects of the ketogenic diet for weight loss. Based on this foundation, we further propose brief weight loss recommendations beneficial for both men and women. It is hoped that, in this direction, the optimization of short-term or long-term clinical weight loss programs can be developed based on sexes.
    Keywords:  ketogenic diet; mechanism; metabolism; obesity; sex differences
    DOI:  https://doi.org/10.3389/fnut.2025.1600927
  10. Theranostics. 2025 ;15(13): 6516-6533
      Rationale: Although it is known that High-fat diet (HFD) promotes the development of pancreatic ductal adenocarcinoma (PDAC), no direct link between HFD and cancer has been identified. Previously, we showed that ATP production by cancer cells depends on fatty acid oxidation (FAO); therefore, we hypothesized that blocking FAO may prevent HFD-induced promotion of PDAC growth. Methods: To determine whether FAO is increased in PDAC patients, we analyzed a tissue microarray by immunohistochemical staining to detect carnitine palmitoyl transferase I. To block FAO, SLC25A20 (carnitine-acylcarnitine carrier) was knocked down in cancer cells, which was implanted for xenograft in mice and treated with a high-fat diet (HFD, 60% fat). To compare cancer development including survival rates, and histopathological differences were analyzed by crossbreeding of KPC mice (KrasG12D/+; Trp53R172H/+; Pdx1-Cre) with KPC/Slc25a20+/- mice. Results: SLC25A20 knockdown in cancer cells reduced ATP production and inhibited cell growth. Proteome analysis revealed that SLC25A20 knockdown reduced cancer cell growth significantly due to inactivation of mTOR via decreased ATP production, ultimately leading to cell death. The median survival time of KPC/Slc25a20+/- tumor-bearing mice was 3.1 weeks longer than that of KPC tumor-bearing mice. In mice fed an HFD, the growth of xenografts derived from SLC25A20 knockdown PDAC cells was 65-95% lower than that of xenografts derived from control cells. Conclusion: Blocking FAO by SLC25A20 knockdown reversed HFD-induced promotion of PDAC growth.
    Keywords:  Fatty acid oxidation; High-fat diet; PDAC; Pancreatic cancer; SLC25A20
    DOI:  https://doi.org/10.7150/thno.114912
  11. Haematologica. 2025 Jun 19.
      Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs). STAT3 has also been shown to translocate to the mitochondria in AML cells, and phosphorylation at the serine 727 (pSTAT3 S727) residue has been shown to be especially important for STAT3's mitochondrial functions. We demonstrate that inhibition of STAT3 results in impaired mitochondrial function and decreased leukemia cell viability. We discovered a novel interaction of STAT3 with voltage-dependent anion channel 1 (VDAC1) in the mitochondria which provides a mechanism through which STAT3 modulates mitochondrial function and cell survival. Through VDAC1, STAT3 regulates calcium and oxidative phosphorylation in the mitochondria. STAT3 and VDAC1 inhibition also result in significantly reduced engraftment potential of LSCs, including primary samples resistant to venetoclax. These results implicate STAT3 as a therapeutic target in AML.
    DOI:  https://doi.org/10.3324/haematol.2025.287352
  12. iScience. 2025 Jun 20. 28(6): 112681
      Metabolic reprogramming is a defining feature of pancreatic cancer, influencing tumor progression and the tumor microenvironment. By integrating single-cell transcriptomics, spatial transcriptomics, and spatial metabolomics, this study visualized the spatial co-localization of metabolites and gene expression within tumor samples, uncovering metabolic heterogeneity and intercellular interactions. Spatial transcriptomics identified distinct pathological regions, which were further characterized using single-cell transcriptomic data and pathologist annotations. Pseudotime trajectory analysis revealed metabolic shifts along the malignant progression, while single-cell Metabolism (scMetabolism) delineated metabolic differences between pathological regions, classifying them as hypermetabolic or hypometabolic. Notably, aberrant cell communication between cancer cells, macrophages, and fibroblasts was observed, with key receptor-ligand pairs significantly co-expressed in malignant regions and correlated with poor prognosis. Spatial metabolomics imaging identified signature metabolites, highlighting metabolic alterations in amino acid metabolism, polyamine metabolism, fatty acid synthesis, and phospholipid metabolism. This integrated analysis provides critical insights into pancreatic cancer metabolism, offering potential avenues for targeted therapeutic interventions.
    Keywords:  Cancer; Metabolomics; Microenvironment; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.112681
  13. Eur J Clin Invest. 2025 Jun 17. e70090
       BACKGROUND: Studies implicating dysfunctional mitochondrial respiration in metabolic tissues in the development of insulin resistance in obesity have only included adults. Peripheral blood mononuclear cells (PBMCs) and platelets have been found to reflect systemic mitochondrial fitness and bioenergetic health. We sought to identify bioenergetic differences in PBMCs and platelets from children with obesity and insulin resistance and determine associations with whole-body metabolism and/or biomarkers of metabolic health and inflammation.
    METHODS: We stratified prepubertal children (ages 5-10 years) into three groups: normal weight insulin sensitive (N-IS; n = 20), overweight/obese insulin sensitive (O-IS; n = 28) and overweight/obese insulin resistant (O-IR; n = 17). We measured oxygen consumption rate and proton efflux rate in PBMCs and platelets. We estimated whole-body resting metabolic rate by bioimpedance and dietary fatty acid oxidation by oral deuterated palmitate and quantifying recovery of D2O in urine. We used ANOVA for comparisons among groups and Spearman correlations for associations between circulating cell bioenergetics and whole-body metabolism and biomarkers.
    RESULTS: O-IS and O-IR PBMCs exhibited increased maximal mitochondrial respiration and spare respiratory capacity compared to N-IS. Bioenergetics shifted towards glycolysis in O-IS PBMCs as compared to both N-IS and O-IR PBMCs. In platelets, glycolysis and ATP production rates were decreased in O-IR compared to O-IS children. PBMC respiration positively correlated with BMIz, HOMA-IR and fasting glucose and insulin, but negatively correlated with inflammatory cytokines. Dietary fatty acid oxidation was higher in O-IS compared to N-IS children and positively correlated with PBMC spare respiratory capacity. Resting metabolic rate correlated positively with several parameters of PBMC mitochondrial respiration.
    CONCLUSIONS: PBMCs from young children with overweight/obesity exhibit adaptations to the metabolic stressors associated with insulin resistance, and PBMC metabolism correlates well with whole-body metabolism.
    Keywords:  bioenergetics; circulating cells; inflammation; insulin resistance; metabolic health; paediatric obesity
    DOI:  https://doi.org/10.1111/eci.70090
  14. Magn Reson Med. 2025 Jun 16.
    HP 13C MRI Consensus Group
      MRI of hyperpolarized (HP) [1-13C]pyruvate allows in vivo assessment of metabolism and has translated into human studies across diseases at 15 centers worldwide. To determine consensus on best practice for multi-center studies for development of clinical applications. This paper presents the results of a two-round formal consensus building exercise carried out by experts with HP [1-13C]pyruvate human study experience. Twenty-nine participants from 13 sites brought together expertise in pharmacy methods, MR physics, translational imaging, and data analysis with the goal of providing recommendations and best practice statements on conduct of multi-center human studies of HP [1-13C]pyruvate MRI. Overall, the group reached consensus on approximately two-thirds of 246 statements in the questionnaire, covering HP 13C-pyruvate preparation; MRI system setup, calibration, and phantoms; acquisition and reconstruction; and data analysis and quantification. Consensus was present across categories. Examples include: (i) Different HP pyruvate preparation methods could be used in human studies, but the same release criteria have to be followed; (ii) site qualification and quality assurance must be performed with phantoms and the same field strength must be used, but the rest of the system setup and calibration methods could be determined by individual sites; (iii) the same pulse sequence and reconstruction methods were preferable, but the exact choice should be governed by the anatomical target; (iv) normalized metabolite area-under-curve values and metabolite area under curve were the preferred metabolism metrics. The consensus proces revealed that HP[1-13C] pyruvate MRI as a technology has progressed sufficiently to plan multi-center studies. The work confirmed areas of consensus for multi-center study conduct and identified where further research is required to ascertain best practice.
    DOI:  https://doi.org/10.1002/mrm.30570
  15. Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00266-9. [Epub ahead of print]
      Epidermal stem cells produce the skin's barrier that excludes pathogens and prevents dehydration. Hair follicle stem cells (HFSCs) are dedicated to bursts of hair regeneration, but upon injury, they can also reconstruct, and thereafter maintain, the overlying epidermis. How HFSCs balance these fate choices to restore physiologic function to damaged tissue remains poorly understood. Here, we uncover serine as an unconventional, non-essential amino acid that impacts this process. When dietary serine dips, endogenous biosynthesis in HFSCs fails to meet demands (and vice versa), slowing hair cycle entry. Serine deprivation also alters wound repair, further delaying hair regeneration while accelerating re-epithelialization kinetics. Mechanistically, we show that HFSCs sense each fitness challenge by triggering the integrated stress response, which acts as a rheostat of epidermal-HF identity. As stress levels rise, skin barrier restoration kinetics accelerate while hair growth is delayed. Our findings offer potential for dietary and pharmacological intervention to accelerate wound healing.
    Keywords:  dietary intervention; epidermal stem cells; fate selection; hair follicle stem cells; hair regrowth; integrated stress response; serine metabolism; tissue regeneration; tissue repair; wound healing
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.010
  16. Cancer Metab. 2025 Jun 16. 13(1): 30
       BACKGROUND: Colon cancer is strongly influenced by lifestyle factors. Sociodemographic factors like sex and socioeconomic position (SEP) might modulate the relationship between lifestyle and colon cancer risk. Metabolomics offers potential to uncover biological mechanisms linking lifestyle and colon cancer.
    METHODS: Lifestyle and untargeted metabolomic data were available from a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 1,067 colon cancer cases and 1,067 controls matched on age, sex, study centre, and blood collection time. Serum samples were analyzed using liquid chromatography-mass spectrometry. The Healthy Lifestyle Index (HLI) score was derived from smoking habits, alcohol intake, body mass index (BMI), physical activity, and diet. Penalised regression was applied in controls to derive metabolic signatures for the HLI and the lifestyle components. Associations of lifestyle factors and the metabolic signatures with colon cancer risk were estimated in conditional logistic regression models, overall and by sex and SEP.
    RESULTS: The HLI score was inversely associated with colon cancer risk, with an odds ratio (OR) per 1-standard deviation (SD) increment equal to 0.79; 95% CI: 0.71, 0.87. The metabolic signature of HLI, comprising 130 features, was moderately correlated with HLI (r = 0.59; 94% CI: 0.56, 0.61), and was inversely associated with colon cancer risk (OR = 0.86; 95% CI: 0.78, 0.95). After adjustment for the HLI score, the association of the metabolic signature of HLI and colon cancer risk was null (OR = 1.00, 95% CI 0.88, 1.13). Associations of lifestyle factors and the metabolic signature with colon cancer risk were consistently stronger for men than for women and did not differ by SEP.
    CONCLUSIONS: In this study across seven European countries, healthy lifestyle was inversely associated with colon cancer risk, with stronger associations in men than women and no differences across SEP. However, the serum metabolic signatures after adjustment for lifestyle factors were not found to be associated with colon cancer risk, suggesting that lifestyle impacts colon cancer through mechanisms not captured by the signatures.
    Keywords:  Colon cancer; Healthy Lifestyle; LASSO regression; Sex; Socioeconomic position; Untargeted metabolomics
    DOI:  https://doi.org/10.1186/s40170-025-00388-0
  17. J Neurochem. 2025 Jun;169(6): e70125
      Neurons are almost exclusively cultured in media containing glucose at much higher concentrations than found in the brain. To test whether these "standard" hyperglycemic culture conditions affect neuronal respiration relative to near-euglycemic conditions, we compared neuronal cultures grown with minimal glial contamination from the hippocampus and cortex of neonatal C57BL/6NCrl mice in standard commercially available media (25 mM Glucose) and in identical media with 5 mM glucose. Neuronal growth in both glucose concentrations proceeded until at least 14 days in vitro, with similar morphology and synaptogenesis. Neurons grown in high glucose were highly dependent on glycolysis as their primary source of ATP, measured using ATP luminescence and cellular respirometry assays. In contrast, neurons grown in 5 mM glucose showed a more balanced dependence on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), greater reserve mitochondrial respiration capacity, and increased mitochondrial population relative to standard media. Our results show that neurons cultured in artificially high glucose-containing media preferentially use glycolysis, opposite to what is known for neurons in vivo as the primary pathway for ATP maintenance. Changes in gene and protein expression levels corroborate these changes in function and additionally suggest that high glucose culture media increases neuronal inflammation. We suggest using neuronal culture systems in 5 mM glucose to better represent physiologically relevant neuronal respiration.
    Keywords:  cell culture; glucose; mitochondrial respiration; neurobasal media; neuronal bioenergetics; primary mouse neuron
    DOI:  https://doi.org/10.1111/jnc.70125
  18. BMJ. 2025 Jun 18. 389 e082007
       OBJECTIVE: To assess the effect of intermittent fasting diets, with continuous energy restriction or unrestricted (ad-libitum) diets on intermediate cardiometabolic outcomes from randomised clinical trials.
    DESIGN: Systematic review and network meta-analysis.
    DATA SOURCES: Medline, Embase, and central databases from inception to 14 November 2024.
    ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised clinical trials comparing the association of intermittent fasting diets (alternate day fasting, time restricted eating, and whole day fasting), continuous energy restriction, and ad-libitum diets were included.
    MAIN OUTCOMES: Outcomes included body weight (primary) and measures of anthropometry, glucose metabolism, lipid profiles, blood pressure, C-reactive protein, and markers of liver disease.
    DATA SYNTHESIS: A network meta-analysis based on a frequentist framework was performed with data expressed as mean difference with 95% confidence intervals (CIs). The certainty of the evidence was assessed using grading of recommendations assessment, development, and evaluation (GRADE).
    RESULTS: 99 randomised clinical trials involving 6582 adults of varying health conditions (720 healthy, 5862 existing health conditions) were identified. All intermittent fasting and continuous energy restriction diet strategies reduced body weight when compared with ad-libitum diet. Compared with continuous energy restriction, alternate day fasting was the only form of intermittent fasting diet strategy to show benefit in body weight reduction (mean difference -1.29 kg (95% CI -1.99 to -0.59), moderate certainty of evidence). Additionally, alternate day fasting showed a trivial reduction in body weight compared with both time restricted eating and whole day fasting (mean difference -1.69 kg (-2.49 to -0.88) and -1.05 kg (-1.90 to -0.19), respectively, both with moderate certainty of evidence). Estimates were similar among trials with less than 24 weeks follow-up (n=76); however, moderate-to-long-term trials (≥24 weeks, n=17) only showed benefits in weight reduction in diet strategies compared with ad-libitum. Furthermore, in comparisons between intermittent fasting strategies, alternate day fasting lowered total cholesterol, triglycerides, and non-high density lipoprotein compared with time restricted eating. Compared with whole day fasting, however, time restricted eating resulted in a small increase in total cholesterol, low density lipoprotein cholesterol, and non-high density lipoprotein cholesterol. No differences were noted between intermittent fasting, continuous energy restriction, and ad-libitum diets for HbA1c and high density lipoprotein.
    CONCLUSIONS: Minor differences were noted between some intermittent fasting diets and continuous energy restriction, with some benefit of weight loss with alternate day fasting in shorter duration trials. The current evidence provides some indication that intermittent fasting diets have similar benefits to continuous energy restriction for weight loss and cardiometabolic risk factors. Longer duration trials are needed to further substantiate these findings.
    TRIAL REGISTRATION: ClinicalTrials.gov NCT05309057.
    DOI:  https://doi.org/10.1136/bmj-2024-082007
  19. Front Nutr. 2025 ;12 1560355
       Background: The prognostic significance of the Controlling Nutritional Status (CONUT) score in colorectal cancer has been extensively reported, yet it remains unclear. This study aims to conduct an updated meta-analysis to evaluate the association between pretreatment CONUT score and long-term oncological outcomes in patients diagnosed with colorectal cancer.
    Methods: A comprehensive literature search was conducted in PubMed, Embase, and Web of Science to identify eligible studies from inception to September 01, 2024, with an update on December 23, 2024. The primary endpoints evaluated were survival outcomes. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for survival outcomes were either extracted or calculated. A random-effects model was applied to pool all of the results. Statistical analyses were performed using R software, version 4.2.1.
    Results: A total of 24 retrospective cohort studies including 9,628 colorectal cancer patients were included. The pooled results demonstrated that patients with higher CONUT score exhibited significantly poorer outcomes across multiple survival metrics: overall survival (HR = 1.73; 95%CI: 1.50-2.01; P < 0.01; I 2 = 62%), recurrence-free survival (HR = 1.51; 95% CI: 1.22-1.87; P < 0.01; I 2 = 14%), disease-free survival (HR = 1.61; 95% CI: 1.33-1.95; P < 0.01; I 2 = 35%), and cancer-specific survival (HR = 3.94; 95% CI: 2.34-6.62; P < 0.01; I 2 = 0%). Furthermore, an additional study indicated that the pre-treatment CONUT score may serve as a potential prognostic indicator for progression-free survival in colorectal cancer patients undergoing first-line chemotherapy (P < 0.05).
    Conclusion: Our study demonstrates that the pretreatment CONUT score can serve as a valuable biomarker for predicting long-term oncological outcomes in patients with colorectal cancer.
    Keywords:  cancer-specific survival; colorectal cancer; controlling nutritional status score; disease-free survival; meta-analysis; overall survival; progression-free survival; recurrence-free survival
    DOI:  https://doi.org/10.3389/fnut.2025.1560355
  20. Cancer Metab. 2025 Jun 18. 13(1): 32
       BACKGROUND: Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations represents a distinct subtype of leukemia. Emerging evidence suggests that regulation of redox metabolism contributes to tumorigenesis and reveals a metabolic vulnerability in anti-tumor therapies. However, the role of redox homeostasis between reactive oxygen species (ROS) and antioxidant systems plays in NPM1-mutated AML has not been fully elucidated.
    METHODS: First, ROS-related metabolic pathways in NPM1-mutated AML were analyzed using RNA-sequencing data. Intracellular and mitochondrial ROS levels in leukemia cells were detected using flow cytometry (FCM). The expression of nuclear factor (erythroid-derived 2)-like 2 (NRF2) was analyzed in public databases and further validated in AML primary blasts and cell lines by quantitative real-time PCR (qRT-PCR), western blotting, and immunofluorescence. Next, the mechanism underlying NRF2 expression was investigated through the RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP) and rescue experiments. Additionally, the downstream target gene of NRF2 was identified by bioinformatics analysis and chromatin immunoprecipitation (ChIP) assays. Furthermore, RNA interference and the NRF2 inhibitor ML385 were applied to explore the role of NRF2 in leukemia. Finally, the anti-leukemic effects of ML385 alone or in combination with the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax on AML cells were investigated using FCM analysis and western blotting, and further explored in cell line-derived xenograft (CDX) mouse models.
    RESULTS: In this study, we identified significant ROS accumulation in leukemia cells with NPM1 mutations. Meanwhile, elevated NRF2 expression and its nuclear localization were observed in NPM1-mutated AML cells. The high NRF2 expression levels were at least partially induced by fat mass and obesity-associated protein (FTO) via m6A modification. Functionally, NRF2 exerts its antioxidant effects by transcriptionally upregulating malic enzyme 1 (ME1) expression and enhancing its activity. Targeting NRF2/ME1 axis reduced NADPH/NADP+ ratio, increased ROS levels, impaired leukemia cell viability, and promoted apoptosis. More importantly, NRF2 inhibitor ML385 in combination with venetoclax showed synergistic anti-leukemic activity in vitro and in vivo.
    CONCLUSION: Overall, our findings provide new insight into the therapeutic potential of targeting NRF2 and guide the development of innovative combination therapies in NPM1-mutated AML.
    Keywords:  Acute myeloid leukemia; ME1; NRF2; Nucleophosmin 1; Redox homeostasis; Venetoclax
    DOI:  https://doi.org/10.1186/s40170-025-00401-6
  21. Blood Rev. 2025 Jun 11. pii: S0268-960X(25)00062-1. [Epub ahead of print] 101317
      The prognosis of patients with AML varies significantly with age, driven by biological heterogeneity and age-associated factors such as comorbidities, functional status, and hospitalization burden. Many novel therapies have been approved in recent years; however, pivotal trials often include patients within a restricted age range, limiting the extrapolation of their findings across the broader AML population. For example, the FLT3 inhibitor midostaurin was added to chemotherapy for patients aged 18-60 years, while the BCL-2 inhibitor venetoclax was combined with azacitidine in patients aged 75 years and older, leaving important knowledge gaps regarding their efficacy and safety in other age groups. Moreover, for several novel therapies, particularly in populations outside the original trial age range, supporting evidence is derived primarily from single-arm studies or real-world experience rather than randomized controlled trials, further complicating clinical decision-making. This review explores the efficacy and safety of widely used traditional and novel therapies for AML, with particular focus on the impact of age on these different therapeutic regimens.
    Keywords:  AML; Acute myeloid leukemia; Age-related outcomes; Novel therapies; Targeted therapy
    DOI:  https://doi.org/10.1016/j.blre.2025.101317
  22. Tumori. 2025 Jun 19. 3008916251346563
       OBJECTIVE: Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in approximately 6-10% of acute myeloid leukemia (AML) patients. Ivosidenib (IVO) is a small-molecule inhibitor of mutant IDH1. This study delves into the mechanism of IVO with hypomethylating agents (HMAs) (azacitidine or decitabine) for treating IDH1-mutated AML through the PI3K/AKT pathway.
    METHODS: IDH1R132H-mutated MOLM-13 (IDH1R132H-MOLM-13) cells were constructed. The effects of the drugs, both individually and in combination, on IDH1R132H-MOLM-13 cell proliferation and apoptosis were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and flow cytometry, with combination index (CI) values calculated using CompuSyn software. IDH1, DNMT1, PI3K and AKT gene mRNA levels, and the PI3K/AKT pathway- and histone lysine methylation-related protein levels in IDH1R132H-MOLM-13 cells were determined by RT-qPCR and Western blot.
    RESULTS: IDH1R132H-mutated MOLM-13 cells (IDH1R132H-MOLM-13) were successfully constructed. The IDH1 inhibitor, either as a monotherapy or combined with HMAs, effectively inhibited IDH1R132H-MOLM-13 cell proliferation, and the combination therapy exhibited synergistic effects (CI < 1). The combination therapy increased cell proportion in the G2/M phase and apoptotic rate. Both treatment modalities reduced IDH1, DNMT1, PI3K and AKT mRNA levels and histone lysine methylation levels (H3K4me3, H3K9me3, H3K27me3); besides, PI3K and AKT phosphorylation levels were reduced, with the reductions being more significant in cells undergoing combination therapy. The indexes did not differ significantly between cells undergoing the two modalities of combined treatments.
    CONCLUSION: The IDH1 inhibitor with HMAs suppressed IDH1R132H-MOLM-13 cell proliferation and viability and decreased the methylation level by repressing the phosphorylation of the PI3K/AKT pathway, showing a synergistic inhibitory effect.
    Keywords:  Acute myeloid leukemia; apoptosis; azacitidine; decitabine; demethylation; isocitrate dehydrogenase 1 inhibitor ivosidenib
    DOI:  https://doi.org/10.1177/03008916251346563
  23. Mol Cell Proteomics. 2025 Jun 11. pii: S1535-9476(25)00113-6. [Epub ahead of print] 101014
      Neuroblastoma is the most common heterogeneous solid tumor in children, and current treatment options remain limited, especially for high-risk patients. Previous studies have identified dihydroorotate dehydrogenase (DHODH), a key enzyme in pyrimidine synthesis, as a potential therapeutic target in cancer. However, none of the existing FDA-approved DHODH inhibitors have shown effective inhibition of neuroblastoma cell growth. To address this challenge, we employed virtual screening to discover potential DHODH-targeting drugs, identifying Regorafenib as a promising candidate. Regorafenib significantly inhibited neuroblastoma growth in both neuroblastoma cells and patient-derived organoids. To unravel the underlying molecular mechanisms, we conducted Tandem Mass Tag (TMT)-based quantitative proteomics using LC-MS/MS. Our proteomic profiling revealed substantial regulation of lipid metabolism proteins, specifically those in the mevalonate pathway, correlating with ferroptosis induction. Further analysis showed that DHODH inhibition led to a reduction in total cholesterol, cholesterol esters, disrupted lipid droplet formation, and significantly decreased the expression of Squalene Epoxidase (SQLE), a key enzyme in lipid metabolism. Notably, we also observed an increase in nuclear SQLE expression following DHODH inhibition. In summary, our study highlights DHODH blockade as a novel approach to induce ferroptosis through lipid metabolism reprogramming, underscoring DHODH as a viable therapeutic target for neuroblastoma treatment. These insights open new avenues for metabolic-based interventions in aggressive pediatric cancers.
    Keywords:  DHODH; ferroptosis; lipid metabolism; mevalonate pathway; neuroblastoma; proteomics
    DOI:  https://doi.org/10.1016/j.mcpro.2025.101014
  24. Biophys J. 2025 Jun 16. pii: S0006-3495(25)00376-5. [Epub ahead of print]
      The ATP molecule serves as an energy currency in eukaryotes (and all life), providing the energy needed for many essential cellular processes. But the extent to which substantial spatial differences exist in ATP concentration in the cell remains incompletely known. It is variously argued that ATP diffuses too quickly for large gradients to be established, or that the high rates of ATP production and use (sources and sinks) can support large gradients even with rapid diffusion - and microscopic models and detailed experiments in different specific cases support both pictures. Here we attempt a mesoscopic investigation, using reaction-diffusion modelling in a simple biophysical picture of the cell to attempt to ask, generally, which conditions cause substantial ATP gradients to emerge within eukaryotic cells. If ATP sources (like mitochondria) or sinks (like the nucleus) are spatially clustered, large fold changes in concentration can exist across the cell; if sources and sinks are more spread then rapid diffusion indeed prevents large gradients being established. This dependence holds in model cells of different sizes, suggesting its generality across cell types. Our theoretical work will complement developing intracellular approaches exploring ATP concentration inside eukaryotic cells.
    DOI:  https://doi.org/10.1016/j.bpj.2025.06.016
  25. Leuk Lymphoma. 2025 Jun 20. 1-6
      Acute myeloid leukemia (AML) is the most common acute leukemia in adults. We utilized Global Burden of Diseases 2021 data to assess age-standardized incidence rates (ASIR), age-standardized death rates (ASDR) per 100,000 population, and annual percentage changes (APC) of ASIR and ASDR of AML across USA states. Statistical modeling, including 2 two-sample t-test, was done. In 2021, the USA reported 21,533 AML cases (ASIR: 3.85) and 16,648 deaths (ASDR: 2.91). Both ASIR and ASDR increased from 1990 to 2021, particularly among individuals aged 70 years and older. In 2021, Kentucky and West Virginia had the highest ASIR and ASDR, respectively. From 1900 to 2021, metabolic risks related to AML death increased, while behavioral and occupational risks related to death declined. The growing AML burden in the USA, especially among older adults, underscores the need for age-sensitive care, preventive strategies targeting modifiable risks like obesity and smoking, and equitable healthcare access across states.
    Keywords:  AML; Cancer; Death; Epidemiology; Neoplasm; incidence; leukemia
    DOI:  https://doi.org/10.1080/10428194.2025.2515598
  26. Cancer Lett. 2025 Jun 13. pii: S0304-3835(25)00446-X. [Epub ahead of print] 217878
      Whole genome doubling (WGD) is among the most prevalent genomic alterations in cancer, present in approximately one third of patients at the time of diagnosis. WGD provides cancer cells with a selective advantage, by protecting against mutations in haploinsufficient genes or buffering deleterious mutations. Factors which negatively select against the WGD state are largely unexplored. Here, we review evidence indicating that cells with WGD are more sensitive to resource restriction than their non-WGD counterparts. We hypothesize that differences in energy access across tissue sites explain differences in cancer ploidy and aneuploidy at the time of detection. By shedding light on the energetic constraints that influence cancer ploidy and aneuploidy, this perspective highlights a critical yet underexplored area of cancer research.
    DOI:  https://doi.org/10.1016/j.canlet.2025.217878
  27. Commun Med (Lond). 2025 Jun 16. 5(1): 234
       BACKGROUND: Tumor immune cell infiltration is a favorable prognostic factor in triple-negative breast cancer. Most triple-negative tumors belong to the aggressive basal-like subtype. We hypothesized that immune gene expression may identify low-risk patients for whom adjuvant chemotherapy can be de-escalated.
    METHODS: The expression of 753 immune-related genes was analyzed in tumor biopsies from 45 patients with basal-like disease and no lymph node metastases (Oslo1 cohort) and evaluated for prognostic value. Findings were validated in two independent cohorts. Oslo1 biopsies were also analyzed for tumor-infiltrating lymphocytes (TIL) and tertiary lymphoid structures (TLS).
    RESULTS: Here we show that a high expression of CTLA4 (above 63rd percentile) is associated with an excellent prognosis in the Oslo1 cohort. None of the patients in the CTLA4high group suffered disease recurrence (median follow-up 7.4 years) or breast cancer-related death (median follow-up 17.7 years). Analysis of the SCAN-B (n = 233; 97% without distant recurrence in CTLA4high group) and METABRIC cohorts (n = 155; 93% disease-specific survival in CTLA4high group) validates this finding, which also applies to patients who did not receive chemotherapy. CTLA4 expression correlates with TIL score and TLS levels (Oslo1 cohort), but no TILlow/CTLA4high patients died from breast cancer, suggesting that the CTLA4 readout identifies low-risk patients not captured by TIL assessment.
    CONCLUSIONS: A high primary tumor expression of CTLA4 identifies patients with an excellent prognosis, for whom standard chemotherapy may be de-escalated or omitted.
    DOI:  https://doi.org/10.1038/s43856-025-00865-z
  28. Med. 2025 Jun 13. pii: S2666-6340(25)00027-3. [Epub ahead of print]6(6): 100600
      Resistance to isocitrate dehydrogenase (IDH) inhibitors poses a significant challenge in acute myeloid leukemia (AML), indicating a need for novel IDH inhibitors. Hu et al. report the results of a phase 1 study of the dual IDH1/2 inhibitor HMPL-306 in relapsed/refractory IDH-mutant AML.1 The study highlights its manageable safety profile and robust preliminary efficacy, suggesting that it may be a valuable AML therapy.
    DOI:  https://doi.org/10.1016/j.medj.2025.100600
  29. Cancer Metab. 2025 Jun 16. 13(1): 28
       BACKGROUND: Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses in patients with ALK-rearranged lung adenocarcinomas, yet resistance occurs almost inevitably. In addition to tumor cell-intrinsic resistance mechanisms, accumulating evidence suggests that cancer-associated fibroblasts (CAFs) within the tumor microenvironment contribute to therapy resistance. This study aimed to investigate CAF-driven molecular networks that shape the therapeutic susceptibility of ALK-driven lung adenocarcinoma cells.
    METHODS: Three-dimensional (3D) spheroid co-cultures comprising ALK-rearranged lung adenocarcinoma cells and CAFs were utilized to model the tumor microenvironment. Single-cell RNA sequencing was performed to uncover transcriptional differences between TKI-treated homotypic and heterotypic spheroids. Functional assays assessed the effects of CAF-conditioned medium and CAF-secreted factors on tumor cell survival, proliferation, lipid metabolism, and downstream AKT signaling. The therapeutic potential of targeting metabolic vulnerabilities was evaluated using pharmacological inhibition of lipid metabolism and by ferroptosis induction.
    RESULTS: CAFs significantly diminished the apoptotic response of lung tumor cells to ALK inhibitors while simultaneously enhancing their proliferative capacity. Single-cell RNA sequencing identified lipogenesis-associated genes as a key transcriptional difference between TKI-treated homotypic and heterotypic lung tumor spheroids. CAF-conditioned medium and the CAF-secreted factors HGF and NRG1 activated AKT signaling in 3D-cultured ALK-rearranged lung tumor cells, leading to increased de novo lipogenesis and suppression of lipid peroxidation. These metabolic adaptations were critical for promoting tumor cell survival and fostering therapy resistance. Notably, both dual inhibition of ALK and the lipid-regulatory factor SREBP-1, as well as co-treatment with ferroptosis inducers such as erastin or RSL3, effectively disrupted the CAF-driven metabolic-supportive niche and restored sensitivity of resistant lung tumor spheroids to ALK inhibition.
    CONCLUSIONS: This study highlights a critical role for CAFs in mediating resistance to ALK-TKIs by reprogramming lipid metabolism in ALK-rearranged lung cancer cells. It suggests that targeting these metabolic vulnerabilities, particularly through inhibition of lipid metabolism or induction of ferroptosis, could provide a novel therapeutic approach to overcome resistance and improve patient outcomes.
    Keywords:  3D cell culture; Cancer-associated fibroblasts; EML4-ALK; Lipid metabolism; Lung adenocarcinoma; Therapy resistance
    DOI:  https://doi.org/10.1186/s40170-025-00400-7
  30. Am J Physiol Endocrinol Metab. 2025 Jun 16.
      The fundamental principle of energy balance, a statement of the first law of thermodynamics, overlooks the second law, resulting in gaps in our knowledge of body weight regulation and obesity. This study develops research tools to implement non-equilibrium thermodynamics in human subjects based on a mitochondrial energy conversion model. A key advancement measures ATP phosphorylation through its relationship to the mitochondrial redox couple, beta-hydroxybutyrate, and acetoacetate. Applying this methodology in humans, utilizing data from a recent study, provides a comprehensive understanding of the impact of the second law. The results demonstrate that oxidative phosphorylation efficiency is approximately 57%, with minor but significant variations among individuals. Four out of 24 healthy subjects exhibited sufficiently higher efficiency of oxidative phosphorylation and lower free energy dissipation compared to the remaining subjects. Feeding is associated with lower efficiency, a higher rate of free energy dissipation, and a slight reduction in coupling. The amount of energy utilized for useful work represents only one-third of resting energy expenditure. These findings are integrated with the current principle of energy balance to adhere to the constraints of the first and second laws. Based on theoretical modeling, it is demonstrated that inter-individual differences and variations in mitochondrial efficiency and energy dissipation during specific metabolic conditions can lead to discrepancies between total energy balance and the balance of the fraction of energy used for useful work. Consequently, the constraints imposed by the second law should be incorporated into the current understanding of energy balance and obesity.
    Keywords:  entropy production; metabolic efficiency; second law of thermodynamics; total energy expenditure
    DOI:  https://doi.org/10.1152/ajpendo.00487.2024
  31. Radiol Phys Technol. 2025 Jun 13.
      Glioblastoma multiforme is the most malignant brain tumor and is resistant to conventional radiotherapy. Proton radiotherapy utilizes accelerated proton beams to irradiate deep-seated tumors with minimum ionization in the entrance channel, thanks to its inverted dose profile. This work aims to investigate the response of human glioma (U87) cells cultured in a 3D culture after X-ray and proton irradiation. U87 cells have been cultured in 3D bio-phantom where cells were grown in Matrigel matrix inside a 96-well plate. The morphology of U87 cells in 3D culture has been observed for 48 h, and cells have grown in their natural shape. The response of cells in 3D bio-phantom was evaluated by exposing the cells to 6 MV X-ray and 70 MeV monoenergetic proton beams. Post-irradiation, the surviving cells were determined by a colony formation assay, and the survival curve of cells in 3D culture was compared with the cells grown in 2D monolayer culture. The response of cells in the 3D bio-phantom following X-ray and proton radiation demonstrated an increased survival fraction in the high-dose region than those in 2D monolayer. However, U87 cells showed more sensitivity towards proton irradiation compared to X-rays, regardless of the culture setup. Finally, we obtained the RBE 10% value of 1.15 for cells in 3D bio-phantom and 1.29 for cells in 2D monolayer. Therefore, U87 cells grown in our 3D culture setup demonstrate radio-resistant behavior and exhibit higher sensitivity towards proton irradiation compared to X-ray irradiation in our clonogenic assay.
    Keywords:  3D cell culture; Glioblastoma; Proton radiotherapy; Survival curve
    DOI:  https://doi.org/10.1007/s12194-025-00921-2