bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2025–06–01
24 papers selected by
Brett Chrest, Wake Forest University



  1. Sci Rep. 2025 May 28. 15(1): 18736
      Glioblastomas (GBM) are the most prevalent primary brain tumors, affecting 5 in every 100,000 people. GBMs optimize proliferation through adaptive cellular metabolism, frequently exploiting the Warburg effect by increasing aerobic glycolysis and glucose utilization to facilitate rapid cell growth. This disproportionate reliance on glucose has driven interest in using the ketogenic diet (KD) as a treatment for GBM. In this study, we explored metabolic flux in three primary human GBM cell samples using a media simulating a KD. Flux analysis using a detailed metabolic modeling approach revealed three unique metabolic phenotypes in the patient GBMs that correlated with cell viability. Notably, these phenotypes are apparent in the flux modeling, but were not evidenced by changes in the metabolite pool sizes. This variability in metabolic flux may underlie the inconsistent results observed in preclinical and clinical studies using the KD as a treatment paradigm.
    Keywords:  Cancer biology; Glioblastoma; Isotopic analysis; Ketogenesis; Metabolism
    DOI:  https://doi.org/10.1038/s41598-025-02124-6
  2. Cancer Metab. 2025 May 26. 13(1): 25
      Increasing emphasis has been placed on improving the physiological relevance of cell culture media with formulations such as Human Plasma-Like Medium (HPLM). Given that shifts in mitochondrial metabolism and nutrient use are emerging as anti-cancer targets, the present study sought to investigate the impact of culture media formulation on mitochondrial bioenergetics and cancer cell growth. To do this, we used acute myeloid leukemia (AML) cells and compared acute and chronic effects of HPLM versus different supraphysiological medias. The AML mitochondrial phenotype was largely unaffected by exposure to either physiological or supraphysiological medias, establishing that the key features of AML mitochondria remain phenotypically stable under diverse nutrient conditions and proliferation rates. Both acute and chronic culturing in HPLM slowed AML cell proliferation. However, merely identifying and supplementing single nutrients that were deficient in HPLM did not improve proliferation and was not sufficient to pinpoint actionable fuel preferences. Transferring cells back to native Iscove's Modified Dulbecco's Medium (IMDM) media immediately restored the proliferative phenotype, suggesting responsiveness to the entirety of the nutrient environment. Supraphysiological culture medias other than IMDM were all characterized by slower proliferation; however, none were associated with changes in cell viability, demonstrating that the native culture medium is optimal if the experimental aim is maximal growth. Despite Dulbecco's Modified Eagle Medium (DMEM) being similar in nutrient composition to IMDM and categorized as supraphysiological, both acute and chronic culturing in DMEM resulted in slower growth, akin to what was observed with HPLM. Altogether, independent of growth, AML mitochondria remain largely unperturbed by changes in the culture media, and rather than specific nutrients or physiological relevance, AML cell proliferation is influenced by the complete nutrient profile.
    DOI:  https://doi.org/10.1186/s40170-025-00395-1
  3. Bio Protoc. 2025 May 20. 15(10): e5322
      Stable isotopes have frequently been used to study metabolic processes in live cells both in vitro and in vivo. Glutamine, the most abundant amino acid in human blood, plays multiple roles in cellular metabolism by contributing to the production of nucleotides, lipids, glutathione, and other amino acids. It also supports energy production via anaplerosis of tricarboxylic acid cycle intermediates. While 13C-glutamine has been extensively employed to study glutamine metabolism in various cell types, detailed analyses of specific lipids derived from 13C-glutamine via the reductive carboxylation pathway are limited. In this protocol, we present a detailed procedure to investigate glutamine metabolism in human glioblastoma (GBM) cells by conducting 13C-glutamine tracing coupled with untargeted metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS/MS). The method includes step-by-step instructions for the extraction and detection of polar metabolites and long-chain fatty acids (LCFAs) derived from 13C-glutamine in GBM cells. Notably, this approach enables the distinction between isomers of two monounsaturated FAs with identical masses: palmitoleic acid (16:1n-7) (cis-9-hexadecenoic acid) and palmitelaidic acid (16:1n-7) (trans-9-hexadecenoic acid) derived from 13C-glutamine through the reductive carboxylation process. In addition, using this protocol, we also unveil previously unknown metabolic alterations in GBM cells following lysosome inhibition by the antipsychotic drug pimozide. Key features • Methods for analyzing the flux of the stable isotope 13C-glutamine in cancer cells and identifying its derived polar metabolites and long-chain fatty acids (LCFAs). • Distinguishes isomers of long-chain fatty acids, such as palmitoleic acid (16:1n-7) (cis-9-Hexadecenoic acid) and palmitelaidic acid (16:1n-7) (trans-9-Hexadecenoic acid), which share the exact same mass. • The method is utilized to investigate glutamine metabolism reprogramming in cancer cells following lysosome inhibition.
    Keywords:  13C-glutamine; GBM cells; LC–MS/MS; Long-chain fatty acids; Lysosome; Pimozide; Polar metabolites
    DOI:  https://doi.org/10.21769/BioProtoc.5322
  4. Nat Commun. 2025 May 27. 16(1): 4921
      Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson's disease and cancer, driving interest in therapeutically targeting this pathway. However, measuring cellular polyamine levels, which vary across cell types and states, remains challenging. We introduce a genetically encoded polyamine reporter for real-time measurement of polyamine concentrations in single living cells. This reporter utilizes the polyamine-responsive ribosomal frameshift motif from the OAZ1 gene. We demonstrate broad applicability of this approach and reveal dynamic changes in polyamine levels in response to genetic and pharmacological perturbations. Using this reporter, we conduct a genome-wide CRISPR screen and uncover an unexpected link between mitochondrial respiration and polyamine import, which are both risk factors for Parkinson's disease. By offering a lens to examine polyamine biology, this reporter may advance our understanding of these ubiquitous metabolites and accelerate therapy development.
    DOI:  https://doi.org/10.1038/s41467-025-60147-z
  5. Molecules. 2025 May 09. pii: 2101. [Epub ahead of print]30(10):
      Malnutrition and aging are major factors that inhibit myoblast differentiation, leading to a decline in muscle function and contributing to sarcopenia development. This study aimed to elucidate the role of nutrients in myoblast differentiation by establishing a culture system at physiological glucose levels and investigating the effects of ketone bodies and oxaloacetate. We successfully cultured myoblasts at physiological glucose concentrations in a hydrophobic membrane filter-equipped culture flask. Under these conditions, ketone bodies and oxaloacetate synergistically upregulated myogenic differentiation markers (Lmod2 and Ckm), indicating enhanced differentiation. Additionally, oxaloacetate upregulated mitochondrial biogenesis markers (mitochondrial DNA copy number and Cs), whereas ketone bodies promoted Akt phosphorylation, a key regulator of differentiation, via the PI3K/Akt/mTOR pathway. These results suggest that the intake of ketone bodies and oxaloacetate effectively prevents sarcopenia by synergistically promoting myoblast differentiation via distinct molecular mechanisms, suggesting a potential new nutritional strategy.
    Keywords:  differentiation; ketone bodies; myoblast; myogenesis; myotube; oxaloacetate
    DOI:  https://doi.org/10.3390/molecules30102101
  6. Cancer Prev Res (Phila). 2025 May 27. OF1-OF2
      Growing research suggests that advanced aging and obesity are correlated with an increased risk and poorer prognosis in triple-negative breast cancer. In this issue of Cancer Prevention Research, Smith and colleagues fed young and old mice a control/low-fat diet, a high-fat diet, or an intermittent calorie restriction (ICR) diet prior to injection of E0771 breast cancer cells. The ICR mice exhibited lower rates of tumor growth across all interventions, with tumor size in ICR mice matched to that of young, lean controls. Most notably, the authors found that ICR mice also exhibited the highest antitumor immunity. These data provide encouraging preclinical evidence that immune dysfunction induced by obesogenic diets is reversible. See related article by Smith et al., p. XX.
    DOI:  https://doi.org/10.1158/1940-6207.CAPR-25-0168
  7. Am J Clin Nutr. 2025 05 24. pii: S0002-9165(25)00279-5. [Epub ahead of print]
       BACKGROUND: Ultra-processed food (UPF) accounts for more than half of caloric intake by the US population. UPF intake has been linked to weight gain and obesity, a known risk factor for cancer, including endometrial cancer.
    OBJECTIVE: The objective of this study was to evaluate the prospective association of UPF intake with ovarian and endometrial cancer risk.
    METHODS: Participants in the NIH-AARP Diet and Health Study reported baseline diet using a food frequency questionnaire (FFQ). We disaggregated FFQ items to assign Nova classification and created quintiles of energy-adjusted UPF intake (grams/day). We used Cox proportional hazard models, adjusted for potential confounding factors, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for epithelial ovarian and endometrial cancer incidence, overall and by histotype.
    RESULTS: Among 129,870 female participants, without a history of oophorectomy or cancer, 1234 epithelial ovarian cancer cases were diagnosed during >20 years of follow-up. UPF intake was not associated with ovarian cancer risk (quintile 5 compared with quintile 1: HR=0.92; 95% CI=0.77, 1.11), overall or by histotype. Among 107,592 female participants, without a history of hysterectomy or cancer, 2249 endometrial cancer cases were diagnosed. Participants in the highest quintile of UPF intake tended to have higher BMI (median [IQR] BMI, 27.4 [23.9-31.7] kg/m2) than those in the lowest quintile (24.4 [22.0-28.0] kg/m2). Higher UPF intake was associated with increased endometrial cancer risk (HR=1.25; 1.09, 1.43). The association was no longer observed after adjusting for BMI (HR=0.96; 0.83, 1.10). HR estimates were similar for Type I endometrial cancer, the subtype most strongly associated with BMI.
    CONCLUSIONS: In this cohort of US females who were at risk of developing endometrial or ovarian cancer, we found evidence of a positive association between UPF intake and endometrial, but not ovarian cancer. The positive association with endometrial cancer was not independent of BMI.
    Keywords:  Nova; cancer; endometrial cancer; epidemiology; ovarian cancer; ultra-processed food
    DOI:  https://doi.org/10.1016/j.ajcnut.2025.05.024
  8. Leuk Lymphoma. 2025 May 26. 1-6
      Childhood obesity has historically increased with time. Associations are noted between obesity and cancer in adults; but little investigation has been done in children. We conducted a matched case control study to assess the association between body mass index (BMI) and Non-Hodgkin Lymphoma (NHL) in children. Case information is from Children's Oncology Group and controls from National Health and Nutrition Examination Survey. There was no association between obesity and NHL overall, but patients less than 10 years, showed a positive association if outside of the normal BMI range, both obesity and underweight. Additionally, there was an association between NHL and underweight overall, in males, and in non-Hispanic/Latino children. Obesity showed an inverse association with NHL in females and children older than 10. We were not able to assess causality. Disease causing weight loss prior to diagnosis likely skewed baseline weights lower. Additional studies with BMI prior to diagnosis are needed.
    Keywords:  Non-Hodgkin lymphoma; body mass index; obesity; pediatrics
    DOI:  https://doi.org/10.1080/10428194.2025.2506502
  9. Epilepsia. 2025 May 24.
       OBJECTIVES: Accurate and user-friendly methods to measure beta-hydroxybutyrate (BHB) concentration are needed to guide the optimal use of ketogenic diet therapy (KDT). We aimed to determine the correlation between serum, capillary, and salivary BHB concentration, and to validate an electrochemical salivary BHB point-of-care test (POCT) in children commencing KDT for drug-resistant epilepsy.
    METHODS: This was a single center, prospective cohort study. Children <18 years with drug-resistant epilepsy electively admitted to Shenzhen Children's Hospital to initiate KDT between January 1, 2020 and June 30, 2021, were included. Over the 7-day admission, we collected paired saliva and capillary blood samples twice a day and serum blood samples on the first and last days of admission from each participant. Salivary BHB was measured using liquid chromatography mass spectrometry (LCMS) and the POCT. Primary outcome was the correlation between serum and salivary BHB concentration measured using LCMS. Secondary outcomes were the correlation between both the capillary blood and salivary BHB concentration, measured by LCMS, and the POCT device.
    RESULTS: Seventy-one serum and 334 capillary blood paired with salivary samples were collected from 42 children (median age 4.5 years, interquartile range 1 to 8 years, 45% female). Salivary BHB measured using LCMS strongly correlated with serum BHB (Spearman's ρ = 0.910) and capillary blood BHB concentrations (Spearman's ρ = 0.865). Salivary BHB concentration was 6% and 7% of serum and capillary blood BHB concentration, respectively. The POCT demonstrated excellent test-retest reliability when compared with LCMS (ICC(A,k) = 0.983, 95% confidence interval: 0.980-0.986). Salivary BHB concentration measured by the POCT showed good accuracy in predicting the capillary blood BHB concentration within the therapeutic range of 2-5 mM.
    SIGNIFICANCE: Salivary BHB concentration strongly correlates with both serum and capillary blood BHB concentration. The POCT accurately measures salivary BHB concentration and provides a simple, user-friendly method to guide the use of KDT for children with drug-resistant epilepsy.
    Keywords:  beta‐hydroxybutyrate; drug‐resistant epilepsy; ketogenic diet; ketone; point‐of‐care test; saliva
    DOI:  https://doi.org/10.1111/epi.18465
  10. J Nucl Med. 2025 May 29. pii: jnumed.124.268938. [Epub ahead of print]
      The effects of obesity on cancer treatment efficacy remain unclear, as both beneficial and detrimental modulations of the tumor immune microenvironment have been reported. We compared 68Ga-NOTA-GZP (βAla-Gly-Gly-Ile-Glu-Phe-Asp-CHO) PET images with those obtained with the gold standard, 18F-FDG PET, to quantify biologic variations in a diet-induced obesity model of triple-negative breast cancer to understand how obesity influences the tumor immune landscape and response to immunotherapy. Methods: C57BL6/J mice were fed a high-fat diet (n = 24) or low-fat diet (n = 18) for 14 wk. EO771 tumor-bearing mice were treated with a fixed or weight-based dose of saline or checkpoint-blockade immunotherapy, and tumor volume was evaluated for long-term response. Mice were imaged via 68Ga-NOTA-GZP PET on day 7 to quantify immune activation, and those images were compared with 18F-FDG PET images to characterize changes in glucose metabolism on days 0 and 6. SUV was quantified from imaging data, and a cohort of mice was euthanized to validate biologic changes via flow cytometry. Results: Mice fed a high-fat diet demonstrated increased tumor glucose metabolism at baseline, as measured by 18F-FDG PET. No significant differences were observed in 18F-FDG SUV for responder tumors on day 6. The 68Ga-NOTA-GZP PET signal was increased in tumors responsive to immunotherapy on day 7 and was highly sensitive in predicting response via analysis of receiver-operating-characteristic curves. Conclusion: Obesity decreases response to immunotherapy by altering metabolism and the tumor immune microenvironment. 68Ga-NOTA-GZP PET imaging is a sensitive and predictive imaging biomarker of immunotherapy response, but weight-based dosing is needed to achieve effective changes in tumor volume.
    Keywords:  GZP PET imaging; TNBC; granzyme B; immunotherapy; obesity
    DOI:  https://doi.org/10.2967/jnumed.124.268938
  11. J Am Acad Dermatol. 2025 May 23. pii: S0190-9622(25)02196-6. [Epub ahead of print]
       BACKGROUND: Leukemia cutis (LC) is a rare complication of acute myeloid leukemia (AML) and considered a marker of poor prognosis. Molecular and immunophenotypic characteristics of LC remain poorly understood.
    OBJECTIVE: To investigate molecular and immunophenotypic profiles of AML patients with LC and compare them with AML patients without LC.
    METHODS: This retrospective matched-cohort study examined 47 AML patients with LC propensity-matched to 141 AML patients without LC. Frequency of mutations, overall survival, and biomarker concordance between skin and bone marrow samples were analyzed and compared.
    RESULTS: LC patients showed significant enrichment in mutations including NPM1, FLT3, Trisomy/Gain 8, and NRAS/KRAS. Median overall survival for LC patients was 14.6 months, compared to 23.0 months for AML patients without LC. This difference was not statistically significant, and there were no significant differences when comparing across mutation subgroups. Immunophenotypically, high rates of discordance between skin and bone marrow were observed in CD34 and CD117.
    LIMITATIONS: Single-center study, limited sample size, potential unadjusted covariates CONCLUSION: The results show enrichment of key mutations and loss of biomarker expression in AML-associated LC without differences in overall survival. This distinct molecular and immunophenotypic profile of LC may have important pathogenic, diagnostic, and prognostic implications.
    Keywords:  acute myeloid leukemia; genotype; immunophenotype; leukemia cutis; molecular; mutation
    DOI:  https://doi.org/10.1016/j.jaad.2025.05.1414
  12. Discov Oncol. 2025 May 27. 16(1): 935
      Immunotherapy including anti-PD-1 demonstrated therapeutic promise to colorectal cancer (CRC) patients, but tumor cell resistance limits their efficacy. Butyrate may influence therapeutic outcomes by modulating tumor metabolism, but it remains unclear whether butyrate influences CRC cell resistance to anti-PD-1 therapy. We aimed to investigate whether butyrate promotes resistance to anti-PD-1 therapy in CRC and underlying metabolic and immunologic mechanisms. CRC murine models were established by subcutaneously inoculating MC38 cells or butyrate/anti-PD-1-administered tumor cells of mice, followed by treatment with butyrate, anti-PD-1, or a combination. Therapeutic efficacy was assessed by tumor growth and survival outcomes. In vitro, HCT116 cells were exposed to monotherapy or co-therapy regimens. Carnitine Palmitoyltransferase 1A (CPT1A) knockdown was conducted by shRNA transfection both in vivo and in vitro. Fatty acid oxidation (FAO) was determined by oxygen consumption rate and CPT1A expression. CD8+ T cell cytotoxicity assays and CD8 expression in tumors were performed to evaluate immune cell infiltration. The addition of butyrate into anti-PD-1 treatment combination did not improve survival or reduce tumor volume compared to anti-PD-1 alone, with a marked activation of CPT1A observed in treated tumor tissues. Butyrate significantly elevated FAO, contributing to elevated oxygen consumption rate and reduced CD8+ T cell cytotoxicity. However, in sh-CPT1A models, the combination therapy significantly improved antitumor efficacy and restored CD8+ T cell infiltration. Furthermore, CRC patient samples resistant to anti-PD-1 therapy exhibited elevated CPT1A levels. Butyrate-induced CPT1A-mediated FAO promotes resistance to anti-PD-1 therapy in CRC, suggesting that targeting CPT1A might enhance the efficacy of immunotherapy.
    Keywords:  Anti-PD-1 therapy; Butyrate; CPT1A; Colorectal cancer; Fatty acid oxidation; Immune resistance
    DOI:  https://doi.org/10.1007/s12672-025-02686-x
  13. ESC Heart Fail. 2025 May 26.
       INTRODUCTION: Cardiac energy metabolism is disrupted in heart failure with preserved ejection fraction (HFpEF), as characterized by a switch from glucose oxidation towards fatty acid oxidation. However, although oxidation of ketones is an important source of ATP it remains unclear how the heart oxidizes ketones in HFpEF. It is also unclear whether elevating ketone supply to the heart can improve cardiac energetics and/or provide functional benefit for the hearts in HFpEF.
    AIMS: The present study investigated the effects of increasing ketone supply to the heart via ketone supplementation or SGLT2 inhibitor treatment in a mouse model of HFpEF.
    METHODS: HFpEF was induced in 13-month-old C57BL/6N female mice with 60% high-fat diet and L-NAME (0.5 g/L/day in the drinking water) for 6 weeks. In parallel, two other groups of mice were maintained on the HFpEF protocol while also receiving either a ketone ester supplement (1-3 butanediol 1 g/kg/day) or SGLT2 inhibitor (empagliflozin 10 mg/kg/day) for 6 weeks. Control mice were fed with regular low-fat diet and regular drinking water. Hearts of the mice were excised and perfused in the isolated working mode aerobically with 5-mM glucose, 0.8-mM palmitate, 100-μU/mL insulin, with either low (0.6 mM) or high (1 mM) levels of β-hydroxybutyrate. Metabolic rates of the hearts were measured with radiolabelled [U-14C] glucose, [9,10-3H] palmitate and [3-14C] β-hydroxybutyrate.
    RESULTS: In HFpEF mouse hearts, glucose oxidation was significantly decreased with a parallel increase in fatty acid oxidation. Increasing β-hydroxybutyrate levels from 0.6 to 1 mM in the perfusate resulted in a rise in ketone oxidation rates in control hearts (from 861 ± 63 to 1377 ± 94 nmol g dry wt-1 min-1), which was muted in HFpEF hearts (from 737 ± 68 to 897 ± 134 nmol g dry wt-1 min-1). Following ketone ester supplement or SGLT2 inhibitor treatment, HFpEF mice presented with restored ketone oxidation rates (from 674 ± 36 to 1181 ± 115 nmol g dry wt-1 min-1 with ketone ester supplement and from 797 ± 121 to 1240 ± 120 nmol g dry wt-1 min-1 with SGLT2i). Yet, this was not associated with improvement in cardiac function.
    CONCLUSIONS: In HFpEF mice, the heart switches from glucose oxidation to fatty acid oxidation, with ketone oxidation being impaired. Increasing ketone supply to the heart via ketone ester supplementation or SGLT2 inhibitor treatment increases myocardial ketone oxidation rates but was not associated with functional improvements. Unlike HFrEF, ketone supplementation strategies may be less effective in HFpEF due to an impairment of myocardial ketone oxidation in HFpEF.
    DOI:  https://doi.org/10.1002/ehf2.15319
  14. Nature. 2025 May 28.
      
    Keywords:  Metabolism; Obesity; Physiology
    DOI:  https://doi.org/10.1038/d41586-025-01621-y
  15. Biochem Soc Trans. 2025 May 29. pii: BST20253013. [Epub ahead of print]
      Heme is a vital but highly reactive compound that is synthesized in mitochondria and subsequently distributed to a variety of subcellular compartments for utilization. The transport of heme is essential for normal cellular metabolism, growth, and development. Despite the vital importance of heme transport within the cell, data are lacking about how newly synthesized heme is shuttled within the mitochondrion or exported from the organelle. Here, we briefly summarize current knowledge about the process of mitochondrial heme distribution and discuss the current unresolved questions pertinent to this process.
    Keywords:  heme; heme biosynthesis; hemoproteins; membrane transporters; mitochondria
    DOI:  https://doi.org/10.1042/BST20253013
  16. Nat Commun. 2025 May 27. 16(1): 4920
      The lack of curative therapies for acute myeloid leukaemia (AML) remains an ongoing challenge despite recent advances in the understanding of the molecular basis of the disease. Here we identify the WNK1-OXSR1/STK39 pathway as a previously uncharacterised dependency in AML. We show that genetic depletion and pharmacological inhibition of WNK1 or its downstream phosphorylation targets OXSR1 and STK39 strongly reduce cell proliferation and induce apoptosis in leukaemia cells in vitro and in vivo. Furthermore, we show that the WNK1-OXSR1/STK39 pathway controls mTORC1 signalling via regulating amino acid uptake through a mechanism involving the phosphorylation of amino acid transporters, such as SLC38A2. Our findings underscore an important role of the WNK1-OXSR1/STK39 pathway in regulating amino acid uptake and driving AML progression.
    DOI:  https://doi.org/10.1038/s41467-025-59969-8
  17. Amino Acids. 2025 May 24. 57(1): 29
       BACKGROUND: Creatine is a semi-essential nutrient that plays a critical role in energy metabolism, with dietary intake and endogenous synthesis contributing to overall creatine availability. While dietary creatine intake has been studied extensively, limited data exist on the dietary exposure to its precursor amino acids-glycine, arginine, and methionine-and their contribution to endogenous creatine synthesis. This study aimed to assess the dietary intake of these precursors in U.S. children and adults using data from the Third National Health and Nutrition Examination Survey (NHANES III) and to compare endogenous creatine synthesis with direct dietary creatine intake.
    METHODS: We analyzed NHANES III dietary recall data from 29,945 individuals aged 2 years and older. Intakes of glycine, arginine, methionine, and creatine were calculated per kilogram of body weight. The contribution of precursor amino acids to endogenous creatine synthesis was estimated using established metabolic conversion factors.
    RESULTS: The mean daily intakes of glycine, arginine, methionine, and creatine were 59.6 ± 0.4 mg/kg, 77.2 ± 0.5 mg/kg, 31.9 ± 0.2 mg/kg, and 15.5 ± 0.1 mg/kg, respectively. Estimated endogenous creatine synthesis from precursor amino acids was significantly greater than dietary creatine intake across all age groups (P < 0.01), with precursor-derived creatine production averaging 41.9 ± 0.3 mg/kg body weight per day, approximately 2.7 times higher than dietary creatine intake. Creatine precursor availability declined with age, with the lowest values observed in individuals aged ≥ 65 years.
    CONCLUSION: This study provides the first comprehensive evaluation of total creatine availability in a representative U.S. population, highlighting the predominance of endogenous synthesis over direct dietary intake. These findings suggest that creatine metabolism is largely dependent on precursor amino acid intake and that certain populations, particularly older adults, may be at higher risk for reduced creatine availability. Future research should explore the physiological implications of these findings and potential dietary interventions to optimize creatine status across the lifespan.
    Keywords:  Amino acids; Creatine; Metabolism; NHANES; Nutrition; Precursor
    DOI:  https://doi.org/10.1007/s00726-025-03460-7
  18. Redox Biol. 2025 May 21. pii: S2213-2317(25)00207-1. [Epub ahead of print]84 103694
      Pharmacological ascorbate (P-AscH, high-dose, intravenous, vitamin C), is a pro-drug that generates hydrogen peroxide (H2O2) and is being investigated as a neoadjuvant treatment for pancreatic adenocarcinoma (PDAC). In a randomized, phase II clinical trial, P-AscH demonstrated encouraging results in terms of efficacy and safety. However, some patients do not respond to P-AscH suggesting that resistance occurs in a subset of patients. The aims of this study were two-fold: first to characterize PDAC cells resistant to P-AscH, and second, determine if these alterations enhance metastatic potential. Resistance to P-AscH increased the ability to detoxify H2O2, altered redox metabolism and cell cycle regulation, however mechanisms to P-AscH resistance were different in the cell lines studied. Transcriptomic analysis demonstrated a significant enrichment of the epithelial-to-mesenchymal gene expression pattern in the cell lines studied, suggesting that upregulation of metastatic phenotypes occur during acquisition of resistance to P-AscH. Cells resistant to P-AscH demonstrated increased invasive potential, more aggressive tumor colonization, and higher abundance of circulating tumor cells in vivo. Our data support that resistance to oxidative stress enhances metastatic disease and indicates a potential route for PDAC to tolerate high levels of P-AscH and may explain why some patients do not respond to this treatment regimen.
    Keywords:  Ascorbate; Metastasis; Oxidative stress and metabolism; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.redox.2025.103694
  19. Front Med (Lausanne). 2025 ;12 1594784
       Objective: This study aimed to evaluate the prognostic impact of methylation-related gene mutations in older patients with acute myeloid leukemia (AML).
    Methods: We conducted a retrospective analysis of clinical characteristics in 645 patients aged ≥ 60 years diagnosed with AML at Fujian Medical University Union Hospital between July 2016 and December 2024.
    Results: Methylation-related gene mutations-specifically DNMT3A, TET2, IDH1, and IDH2-were identified in 24.0%, 22.5%, 9.1%, and 13.8% of cases, respectively. Patients with single mutations in DNMT3A or TET2 exhibited similar long-term survival outcomes compared to those without these mutations, with median survival times of 25.2 and 22.3 months, respectively (p = 0.9639). However, patients with concurrent DNMT3A and TET2 mutations demonstrated the poorest treatment response and prognosis, achieving a complete remission (CR) rate of 35.5% and a median survival of only 6.2 months. In contrast, patients with IDH1/IDH2 mutations responded better to treatment, achieving a CR rate of 69.6% and a median survival of 34.7 months. Treatment regimens combining azacitidine and venetoclax did not provide additional improvement in treatment response for patients with methylation-related gene mutations compared to intensive chemotherapy (IC).
    Conclusion: Concurrent mutations in DNMT3A and TET2 were associated with significantly poorer treatment response and survival outcomes. These common methylation-related gene mutations did not influence the choice between IC and azacitidine plus venetoclax combination therapy in elderly AML patients.
    Keywords:  acute myeloid leukemia; elderly; methylation; mutation; prognosis
    DOI:  https://doi.org/10.3389/fmed.2025.1594784
  20. Nat Chem Biol. 2025 May 26.
      Small molecules that induce nonapoptotic cell death are of fundamental mechanistic interest and may be useful to treat certain cancers. Here we report that tegavivint, a drug candidate undergoing human clinical trials, can activate a unique mechanism of nonapoptotic cell death in sarcomas and other cancer cells. This lethal mechanism is distinct from ferroptosis, necroptosis and pyroptosis and requires the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase (TECR). TECR is canonically involved in the synthesis of very-long-chain fatty acids but appears to promote nonapoptotic cell death in response to CIL56 and tegavivint via the synthesis of the saturated long-chain fatty acid palmitate. These findings outline a lipid-dependent nonapoptotic cell death mechanism that can be induced by a drug candidate currently being tested in humans.
    DOI:  https://doi.org/10.1038/s41589-025-01913-4
  21. Nature. 2025 May 28.
      Mitochondrial reactive oxygen species (mROS) are central to physiology1,2. Excess mROS production has been associated with several disease states2,3; however, the precise sources, regulation and mechanism of generation in vivo remain unclear, which limits translational efforts. Here we show that in obesity, hepatic coenzyme Q (CoQ) synthesis is impaired, which increases the CoQH2 to CoQ (CoQH2/CoQ) ratio and drives excessive mROS production through reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo, we demonstrate that RET is crucial for metabolic health. In patients with steatosis, the hepatic CoQ biosynthetic program is also suppressed, and the CoQH2/CoQ ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s41586-025-09072-1
  22. Cancers (Basel). 2025 May 16. pii: 1681. [Epub ahead of print]17(10):
      Background/Objectives: We aimed to discover genes with bimodal expression linked to patient outcomes, to reveal underlying oncogenotypes and identify new therapeutic insights in lung adenocarcinoma (LUAD). Methods: We performed meta-analysis to screen LUAD datasets for prognostic genes with bimodal expression patterns. Kynureninase (KYNU), a key enzyme in tryptophan catabolism, emerged as a top candidate. We then examined its relationship with LUAD mutations, metabolic alterations, immune microenvironment states, and expression patterns in human and mouse models using bulk and single-cell transcriptomics, metabolomics, and preclinical model datasets. Pan-cancer prognostic associations were also assessed. Results: Model-based clustering of KYNU expression outperformed median-based dichotomization in prognostic accuracy. KYNU was elevated in tumors with KEAP1 and STK11 co-mutations but remained a strong independent prognostic marker. Metabolomic analysis showed that KYNU-high tumors had increased anthranilic acid, a catalytic product, while maintaining stable kynurenine levels, suggesting a compensatory mechanism sustaining immunosuppressive signaling. Single-cell and bulk data showed KYNU expression was cancer cell-intrinsic in immune-cold tumors and myeloid-derived in immune-infiltrated tumors. In murine LUAD models, Kynu expression was predominantly immune-derived and uncoupled from Nrf2/Lkb1 signaling, indicating poor model fidelity. KYNU's prognostic associations extended across cancer types, with poor outcomes in pancreatic and kidney cancers but favorable outcomes in melanoma, underscoring the need for lineage-specific considerations in therapy development. Conclusions:KYNU is a robust prognostic biomarker and potential immunometabolic target in LUAD, especially in STK11 and KEAP1 co-mutated tumors. Its cancer cell-intrinsic expression and immunosuppressive metabolic phenotype offer translational potential, though species-specific expression patterns pose challenges for preclinical modeling.
    Keywords:  KEAP1; KYNU; NAD metabolism; STK11; immune suppression; kynureninase; kynurenine pathway; lung adenocarcinoma; mouse model limitations; prognostic biomarker; tryptophan catabolism
    DOI:  https://doi.org/10.3390/cancers17101681
  23. J Exp Clin Cancer Res. 2025 05 28. 44(1): 164
       BACKGROUND: Branched-chain amino acid (BCAA) metabolism is dysregulated in colorectal cancer (CRC), with elevated plasma BCAA levels significantly associated with an increased risk of developing the disease. However, whether BCAAs directly promote CRC progression and their underlying mechanisms remain unclear.
    METHODS: In this study, we investigated the metabolic alterations in KRAS-mutant CRC. We examined the effects of restricting BCAA supply on the proliferation and metastasis of KRAS-mutant CRC cells both in vitro and in vivo.
    RESULTS: We found that in KRAS-mutant CRC, BCAAs and their metabolic products accumulate markedly. Restricting the BCAA supply specifically inhibits the proliferation of KRAS-mutant CRC cells but does not affect metastasis. In these cancer cells, enoyl-CoA hydratase-1 (ECHS1), a key enzyme in BCAA metabolism, is downregulated. Furthermore, BCAAs enhance the acetylation of lysine 204 on ECHS1, impairing its ability to bind enoyl-CoA and reducing its catalytic activity. This modification triggers the ubiquitination of ECHS1 and its subsequent degradation, diminishing BCAA catabolism and leading to its cellular accumulation. This accumulation activates the mTORC1 signaling pathway, which induces the transcriptional activation of downstream target proteins and promotes the malignant progression of CRC.
    CONCLUSIONS: Limiting BCAA intake not only suppresses tumor growth in KRAS-mutant CRC but also enhances the efficacy of the KRAS G12D inhibitor MRTX1133 and the monoclonal antibody bevacizumab. Our findings reveal a previously unknown regulatory mechanism of ECHS1 in CRC and offer new potential therapeutic targets.
    Keywords:  Acetylation; BCAAs; Colorectal cancer; KRAS
    DOI:  https://doi.org/10.1186/s13046-025-03399-3
  24. Epilepsy Behav. 2025 May 28. pii: S1525-5050(25)00220-3. [Epub ahead of print]171 110481
       BACKGROUND: While initiation and maintenance guidelines for ketogenic diet therapies (KDT) are well established, evidence guiding KDT discontinuation remains limited. We aim to explore practices surrounding KDT weaning and identify key factors influencing clinical decisions.
    METHODS: An online 24-question survey was distributed via the International Neurological Ketogenic Society (INKS) between March and May 2024. Responses from 53 healthcare professionals (HCPs), including dietitians and physicians, from diverse global regions were analyzed.
    RESULTS: Most HCPs adopt individualized KDT weaning protocols, often after 2 years of effective KDT, with weaning durations typically lasting 2 to 6 months. Factors influencing discontinuation include seizure control, epilepsy syndrome, diet tolerance, and family preferences. EEG monitoring and ketone tracking during weaning are common practices. For effective KDT, a gradual reduction in dietary ratio is preferred, with various strategies used (e.g., stepwise ratio reduction, liberalizing carbohydrates). Adherence issues and concerns about seizure recurrence are frequent challenges.
    CONCLUSION: KDT weaning remains a heterogeneous and under-studied aspect of treatment. Despite variations in protocols, common themes include cautious tapering and syndrome-specific considerations. These findings highlight the need for prospective studies to establish evidence-based data for KDT discontinuation.
    Keywords:  Drug Resistant Epilepsy; Epilepsy; Ketogenic diet; Survey; Weaning
    DOI:  https://doi.org/10.1016/j.yebeh.2025.110481