bims-medica 2025-05-04 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–05–04
24 papers selected by
Brett Chrest, Wake Forest University

Intracellular metabolic gradients dictate dependence on exogenous pyruvate.
Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.
Understanding and Targeting Metabolic Vulnerabilities in Acute Myeloid Leukemia: An Updated Comprehensive Review.
Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease.
The therapeutic potential of a polyunsaturated fatty acid-enriched high-fat diet in Leigh syndrome: Insights from a preclinical model.
Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.
Blood metabolic biomarkers and colorectal cancer risk: results from large prospective cohort and Mendelian randomisation analyses.
The association of dietary fat and fatty acid intake with ovarian cancer survival: findings from the OOPS, a prospective cohort study.
Transcription Factor YY2 inhibits tumor cell glutamine catabolism by regulating GLS1 RNA splicing isoform GAC.
Dietary factors and cancer outcomes in individuals with type 2 diabetes: A systematic review and meta-analysis of prospective observational studies.
High-fat diet restriction to adult male mice maintains normal body weight but leads to liver impairment by disrupting mitochondrial oxidative phosphorylation.
The causal relationships between mitochondria and six types of cancer: a Mendelian randomization study.
Ketogenic Diets for Body Weight Loss: A Comparison with Other Diets.
Fasting as Cancer Treatment: Myth or Breakthrough in Oncology.
The cell-division cycle is faster in cell types prone to forming cancer.
Association between Circulating Amino Acids and Childhood Obesity: A Systematic Review and Meta-Analysis.
Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.
Serum metabolite levels identify incipient metastatic progression of rectal cancer.
Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states.
NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
A retrospective analysis of pediatric patients on a ketogenic diet: A comparison of inpatient versus outpatient diet initiations.
Isotope tracing-based metabolite identification for mass spectrometry metabolomics.
Lactate Provides Metabolic Substrate Support and Attenuates Ischemic Brain Injury in Mice, Revealed by 1H-13C Nuclear Magnetic Resonance Metabolic Technique.
Ethyl p-methoxycinnamate inhibits tumor growth by suppressing of fatty acid synthesis and depleting ATP.

Nat Metab. 2025 Apr 28.

Intracellular metabolic gradients dictate dependence on exogenous pyruvate.

Benjamin T Jackson, Angela M Montero, Sangita Chakraborty, Julia S Brunner, Paige K Arnold, Anna E Bridgeman, Pavlina K Todorova, Katrina I Paras, Lydia W S Finley.

During developmental transitions, cells frequently remodel metabolic networks, including changing reliance on metabolites such as glucose and glutamine to fuel intracellular metabolic pathways. Here we used embryonic stem (ES) cells as a model system to understand how changes in intracellular metabolic networks that characterize cell state transitions affect reliance on exogenous nutrients. We find that ES cells in the naive ground state of pluripotency increase uptake and reliance on exogenous pyruvate through the monocarboxylate transporter MCT1. Naive ES cells, but not their more committed counterparts, rely on exogenous pyruvate even when other sources of pyruvate (glucose, lactate) are abundant. Pyruvate dependence in naive ES cells is a consequence of their elevated mitochondrial pyruvate consumption at the expense of cytosolic NAD+ regeneration. Indeed, across a range of cell types, increased mitochondrial pyruvate consumption is sufficient to drive demand for extracellular pyruvate. Accordingly, restoring cytosolic NAD+ regeneration allows naive ES cells to tolerate pyruvate depletion in diverse nutrient microenvironments. Together, these data demonstrate that intracellular metabolic gradients dictate uptake and reliance on exogenous pyruvate and highlight mitochondrial pyruvate metabolism as a metabolic vulnerability of naive ES cells.

DOI: https://doi.org/10.1038/s42255-025-01289-8
Nat Metab. 2025 May 02.

Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.

Kyle M Flickinger, Carlos A Mellado Fritz, Kimberly S Huggler, Gina M Wade, Gavin R Chang, Kathryn C Fox, Judith A Simcox, Jason R Cantor.

Nicotinamide adenine dinucleotide kinase (NADK) catalyses the phosphorylation of NAD+ to produce NAD phosphate, the oxidized form of NADPH, a cofactor that serves a critical role in driving reductive metabolism. Cancer cells co-express two distinct NAD kinases that differ by localization (NADK, cytosol; NADK2, mitochondria). CRISPR screens performed across hundreds of cancer cell lines indicate that both are dispensable for growth in conventional culture media. By contrast, NADK deletion impaired cell growth in human plasma-like medium. Here we trace this conditional NADK dependence to the availability of folic acid. NADPH is the preferred cofactor of dihydrofolate reductase (DHFR), the enzyme that mediates metabolic activation of folic acid. We find that NADK is required for enabling cytosolic NADPH-driven DHFR activity sufficient to maintain folate-dependent nucleotide synthesis under low folic acid conditions. Our results reveal a basis for conditional NADK essentiality and suggest that folate availability determines whether DHFR activity can be sustained by alternative electron donors such as NADH.

DOI: https://doi.org/10.1038/s42255-025-01272-3
Cancers (Basel). 2025 Apr 18. pii: 1355. [Epub ahead of print]17(8):

Understanding and Targeting Metabolic Vulnerabilities in Acute Myeloid Leukemia: An Updated Comprehensive Review.

Sridevi Addanki, Lana Kim, Alexandra Stevens.

  Acute Myeloid Leukemia (AML) is characterized by aggressive proliferation and metabolic reprogramming that support its survival and resistance to therapy. This review explores the metabolic distinctions between AML cells and normal hematopoietic stem cells (HSCs), emphasizing the role of altered mitochondrial function, oxidative phosphorylation (OXPHOS), and biosynthetic pathways in leukemic progression. AML cells exhibit distinct metabolic vulnerabilities, including increased mitochondrial biogenesis, reliance on glycolysis and amino acid metabolism, and unique signaling interactions that sustain leukemic stem cells (LSCs). These dependencies provide potential therapeutic targets, as metabolic inhibitors have demonstrated efficacy in disrupting AML cell survival while sparing normal hematopoietic cells. We examine current and emerging metabolic therapies, such as inhibitors targeting glycolysis, amino acid metabolism, and lipid biosynthesis, highlighting their potential in overcoming drug resistance. However, challenges remain in translating these strategies into clinical practice due to AML's heterogeneity and adaptability. Further research into AML's metabolic plasticity and precision medicine approaches is crucial for improving treatment outcomes. Understanding and exploiting AML's metabolic vulnerabilities could pave the way for novel, more effective therapeutic strategies.

Keywords:  acute myeloid leukemia; atovoquone; azactidine; glycolysis; hematopoietic stem cells; leukemic stem cells; metabolism; oxidative phosphorylation; venetoclax

DOI:  https://doi.org/10.3390/cancers17081355
Biomolecules. 2025 Apr 14. pii: 580. [Epub ahead of print]15(4):

Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease.

Varshini V Suresh, Sathish Sivaprakasam, Yangzom D Bhutia, Puttur D Prasad, Muthusamy Thangaraju, Vadivel Ganapathy.

  Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by "keto" diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is β-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for β-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease.

Keywords:  GPR109A; HMGCS2; cancer; epigenetic modification; inflammation; ketoacidosis; ketone body transporters; loss-of-function mutations; neurodegeneration; β-hydroxybutyrate

DOI:  https://doi.org/10.3390/biom15040580
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 25. pii: S0925-4439(25)00221-2. [Epub ahead of print] 167873

The therapeutic potential of a polyunsaturated fatty acid-enriched high-fat diet in Leigh syndrome: Insights from a preclinical model.

Luciano Willemse, Karin Terburgh, Roan Louw.

   INTRODUCTION: Leigh syndrome is often caused by Ndufs4 mutations. The Ndufs4 knockout (KO) mouse model recapitulates key disease features, including systemic inflammation, neurodegeneration, and motor deficits. While dietary interventions such as the ketogenic diet show promise in mitigating mitochondrial dysfunction, conflicting results highlight uncertainties regarding its efficacy. Here, we evaluate the therapeutic potential of a polyunsaturated fatty acid (PUFA)-enriched high-fat diet (HFD) in Ndufs4 KO mice.
METHODS: Dietary intervention began at postnatal day 23, with mice receiving either a normal diet (ND) or a HFD enriched with PUFAs. Phenotypic evaluation, including locomotor function, clasping behaviour, and survival, continued until natural death. In a second group of animals, biochemical analyses were conducted after three weeks on the diets, using Western blot to evaluate neurometabolic and inflammatory regulators, flow cytometry to quantify serum inflammation markers, and metabolic profiling to identify alterations in neurometabolism and the neurolipidome.
RESULTS: The HFD significantly extended lifespan and improved clasping behaviour in Ndufs4 KO mice but had no effect on locomotor activity or grip strength decline. While whole-brain mTOR (p70S6K1, 4E-BP1) and SIRT1 (PGC1-α, TNF-α) signalling pathways remained unaffected, the diet significantly reduced serum pro-inflammatory markers TNF and IL-6. Furthermore, the PUFA-enriched HFD partially restored disruptions in TCA cycle, ketone body, branched-chain amino acid, and lipid metabolism, indicating potential metabolic reprogramming.
CONCLUSION: Dietary interventions, such as a PUFA-enriched HFD, may alleviate systemic inflammation, partially correct metabolic imbalances, and mitigate specific disease phenotypes in Leigh syndrome, warranting further investigation into the underlying mechanisms and broader therapeutic applications.

Keywords:  Flow cytometry; Ketogenic diet; Lipidomics; Metabolomics; Mitochondrial disease; Polyunsaturated fatty acids; mTOR

DOI:  https://doi.org/10.1016/j.bbadis.2025.167873
EMBO Rep. 2025 Apr 29.

Time-resolved mitochondrial screen identifies regulatory components of oxidative metabolism.

Marcos Zamora-Dorta, Sara Laine-Menéndez, David Abia, Pilar González-García, Luis C López, Paula Fernández-Montes, Enrique Calvo, Jesús Vázquez, José Antonio Enríquez, Eduardo Balsa.

  Defects in mitochondrial oxidative metabolism underlie many genetic disorders with limited treatment options. The incomplete annotation of mitochondrial proteins highlights the need for a comprehensive gene inventory, particularly for Oxidative Phosphorylation (OXPHOS). To address this, we developed a CRISPR/Cas9 loss-of-function library targeting nuclear-encoded mitochondrial genes and conducted galactose-based screenings to identify novel regulators of mitochondrial function. Our study generates a gene catalog essential for mitochondrial metabolism and maps a dynamic network of mitochondrial pathways, focusing on OXPHOS complexes. Computational analysis identifies RTN4IP1 and ECHS1 as key OXPHOS genes linked to mitochondrial diseases in humans. RTN4IP1 is found to be crucial for mitochondrial respiration, with complexome profiling revealing its role as an assembly factor required for the complete assembly of complex I. Furthermore, we discovered that ECHS1 controls oxidative metabolism independently of its canonical function in fatty acid oxidation. Its deletion impairs branched-chain amino acids (BCAA) catabolism, disrupting lipoic acid-dependent enzymes such as pyruvate dehydrogenase (PDH). This deleterious phenotype can be rescued by restricting valine intake or catabolism in ECHS1-deficient cells.

Keywords:  CRISPR Screening; ECHS1; Mitochondria; OXPHOS; RTN4IP1

DOI:  https://doi.org/10.1038/s44319-025-00459-9
Br J Cancer. 2025 Apr 30.

Blood metabolic biomarkers and colorectal cancer risk: results from large prospective cohort and Mendelian randomisation analyses.

Fangcheng Yuan, Guochong Jia, Wanqing Wen, Shuai Xu, Valerie Gunchick, Kui Deng, Jirong Long, Danxia Yu, Xiao-Ou Shu, Wei Zheng.

BACKGROUND: Emerging evidence suggests metabolic dysregulation may contribute to colorectal cancer (CRC) aetiology. We aimed to identify pre-diagnostic metabolic biomarkers for CRC risk in 230,420 UK Biobank participants.
METHODS: Nuclear magnetic resonance spectroscopy was used to quantify 249 metabolic biomarkers in plasma samples collected at baseline. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CIs) for associations of metabolic biomarkers with CRC risk after adjusting for potential confounders. To infer the potential causality of biomarkers that were associated with CRC independent of the others, we performed genome-wide association analyses among 199,732 UK Biobank participants of European ancestry to identify biomarker-associated genetic variants, followed by two-sample Mendelian randomization (MR) analyses using summary statistics of 78,473 CRC cases and 107,143 controls of European ancestry.
RESULTS: During a median follow-up time of 9.7 years, 2,410 incident primary CRC cases were identified. Among 43 CRC-associated (P-value < 0.001) metabolic biomarkers, ten biomarkers including fatty acids (FAs), inflammation, ketone bodies, and lipoprotein lipids were associated with CRC risk after mutual adjustment. MR analyses provided strong evidence for potential causal associations of CRC risk with percentages of linolic acid [odds ratio (OR) = 0.89, 95% CI = 0.83-0.96, P-value = 3 × 10-3] and saturated FAs (OR = 1.14, 95% CI = 1.03-1.25, P-value = 9 × 10-3) to total FAs.
CONCLUSIONS: We identified multiple CRC-associated metabolic biomarkers. Perturbed lipid and lipoprotein metabolism may promote colorectal carcinogenesis.

DOI: https://doi.org/10.1038/s41416-025-02997-4
Nutr J. 2025 Apr 30. 24(1): 70

The association of dietary fat and fatty acid intake with ovarian cancer survival: findings from the OOPS, a prospective cohort study.

Yi-Fan Wei, Yi-Lin Xu, Yi-Zi Li, Shu-Hong Huang, Xue Qin, Shi Yan, Jin Xu, Fang-Hua Liu, Song Gao, Meng Luan, Ting-Ting Gong, Qi-Jun Wu.

   BACKGROUND: Dietary fat and fatty acid intakes impact the occurrence and development of several cancers. However, the evidence regarding fat and fatty acid intake and ovarian cancer (OC) survival is limited.
METHODS: The Ovarian Cancer Follow-Up Study (OOPS), a prospective cohort study, analyzed data collected from 703 OC patients. Deaths were ascertained via medical records and active follow-up. Dietary intake was derived from a validated food frequency questionnaire. Cox proportional hazard models were used to calculate hazard ratio (HR) and 95% confidence interval (CI) for association evaluation. Furthermore, several subgroup and sensitivity analyses were also performed.
RESULTS: A total of 130 patients died during a median follow-up of 37.17 (interquartile: 24.73-50.17) months. Relative to the lowest tertile of intake, patients with the highest tertile of total fat (HR = 1.87, 95% CI = 1.01-3.49), total fatty acid (HR = 2.20, 95% CI = 1.27-3.80), total saturated fatty acid (SFA) (HR = 2.02, 95% CI = 1.22-3.34), shorter-chain SFA (HR = 1.59, 95% CI = 1.03-2.47), long-chain SFA (HR = 1.69, 95% CI = 1.03-2.77), total monounsaturated fatty acid (MUFA) (HR = 1.77, 95% CI = 1.02-3.05), and animal-based MUFA (HR = 2.05, 95% CI = 1.17-3.58) intake had higher all-cause mortality risk. In contrast, individuals in the highest tertile of egg fat (HR = 0.57, 95% CI = 0.35-0.92) and fruit and vegetable fat (HR = 0.48, 95% CI = 0.31-0.75) intake exhibited a reduced risk of all-cause mortality. Additionally, significant positive associations with all-cause mortality were identified for the consumption of several common fatty acids, including capric acid (HR = 1.92, 95% CI = 1.23-3.00), myristic acid (HR = 1.86, 95% CI = 1.15-3.02), palmitic acid (HR = 1.72, 95% CI = 1.07-2.76), stearic acid (HR = 1.93, 95% CI = 1.12-3.31), and oleic acid (HR = 1.96, 95% CI = 1.13-3.40), when comparing the highest to the lowest tertile of intake.
CONCLUSIONS: We identified a linkage of higher intake of total fats, total fatty acids, SFAs, shorter-chain SFAs, long-chain SFAs, total MUFAs, and animal-based MUFAs with increased all-cause mortality of OC patients. Conversely, consumption of egg fats and fruit and vegetable fats demonstrated inverse associations with all-cause mortality.

Keywords:  Cohort study; Diet; Fat; Fatty acid; Ovarian cancer; Survival

DOI:  https://doi.org/10.1186/s12937-025-01135-3
Am J Pathol. 2025 Apr 29. pii: S0002-9440(25)00142-7. [Epub ahead of print]

Transcription Factor YY2 inhibits tumor cell glutamine catabolism by regulating GLS1 RNA splicing isoform GAC.

Jingyi Liu, Juan Li, Yanjun Li, Mankun Wei, Debing Xiang, Hezhao Zhao, Makoto Miyagishi, Vivi Kasim, Shourong Wu.

Amino acids metabolic reprogramming is critical for tumorigenesis. Alterations in amino acid metabolism are frequently observed in tumors and are crucial for fulfilling the demand for macromolecular biosynthesis, redox balance, and energy production in tumor cells. Despite its importance, the mechanism regulating amino acid metabolic reprogramming in tumor cells has not been completely elucidated. Herein, using colorectal cancer and hepatocarcinoma cells, we reveal that YY2 significantly reduced the transcriptional activity of glutaminase 1 (GLS1), which hydrolyzes glutamine to glutamate, by decreasing the expression of glutaminase C (GAC), a splicing isoform of GLS1. This, in turn, promoted glutamine accumulation while decreasing that of glutamate, leading to a drop in DNA and de novo glutathione synthesis, followed by a reduction in tumor cell proliferation and antioxidant capacity. Subsequently, we showed that YY2/GLS1-mediated inhibition of glutamine catabolism significantly suppressed tumorigenic potential in vivo. Critically, mutant YY2, often found in clinical tumor samples, failed to exert this effect. Together, these results identify YY2/GAC as a negative regulator of glutamine catabolism in tumor cells and reveal a novel molecular mechanism underlying the tumor-suppressive effect of YY2. Moreover, these findings suggest that YY2 could serve as an antitumor therapeutic agent by targeting glutamine metabolism.

DOI: https://doi.org/10.1016/j.ajpath.2025.04.003
J Diabetes Complications. 2025 Apr 28. pii: S1056-8727(25)00113-8. [Epub ahead of print]39(7): 109060

Dietary factors and cancer outcomes in individuals with type 2 diabetes: A systematic review and meta-analysis of prospective observational studies.

Janett Barbaresko, Alexander Lang, Tim Benedict Schiemann, Edyta Schaefer, Christina Baechle, Lukas Schwingshackl, Manuela Neuenschwander, Sabrina Schlesinger.

   INTRODUCTION: Cancer is a major health concern in persons with type 2 diabetes (T2D). Diet plays an important role in progression of diabetes and cancer. We aimed to systematically summarize the evidence on diet and cancer in individuals with T2D.
METHODS: PubMed and Web of Science were searched until August 2023 and followed up via PubMed alert until December 2024. Prospective studies investigating any dietary factor in association with cancer in individuals with T2D were eligible.
RESULTS: We identified 68 studies and conducted 20 meta-analyses. A general low-carbohydrate diet was not associated with cancer outcomes, whereas an inverse association was found for vegetable-based low-carbohydrate diet (HR per 5 points [95 % CI]: 0.90 [0.84, 0.97]; n = 2). We found indications of lower cancer incidence for higher adherence to Dietary Approaches to Stop Hypertension diet, (Alternate) Healthy Eating Index, higher intakes of n-3 fatty acids (0.73 [0.55, 0.98]; n = 2) and higher serum vitamin D (0.95 [0.93, 0.97]; n = 2), as well as a positive association for serum manganese concentrations (1.44 [1.11, 1.87]; n = 2), rated with low to very low certainty of evidence.
CONCLUSION: So far, the certainty of evidence is very limited due to the small numbers of primary studies. There is an indication of a possible association between diet and cancer risk among persons with T2D, but further well-designed prospective cohort studies are warranted.

Keywords:  Cancer; Diet; Meta-analysis; Systematic review; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.jdiacomp.2025.109060
J Nutr Biochem. 2025 Apr 30. pii: S0955-2863(25)00104-4. [Epub ahead of print] 109941

High-fat diet restriction to adult male mice maintains normal body weight but leads to liver impairment by disrupting mitochondrial oxidative phosphorylation.

Chun-Hsien Chiang, Pu-Sheng Hsu, Shau-Ping Lin, Ching-Yi Chen.

  Dietary restriction (DR) delays aging and supports health primarily through its effects on mitochondrial function. Conversely, a high-fat diet (HFD) with excess calories promotes obesity and health risks via mitochondrial dysfunction. However, the role of an HFD in the benefits of DR remains unclear. This study investigated whether sustainable and intermittent DR with an HFD positively affects liver and heart health. Mice were assigned to four groups: chow diet ad libitum (CTR), HFD ad libitum (H), 60% HFD intake (HDR), and intermittent HFD restriction with weight cycling (WC). The results showed that the mice in the HDR and WC groups had reduced body weight, while animals in neither group had lower blood glucose levels compared to the H group. Hepatic steatosis, fibrosis, and NAFLD activity scores were similar in H, HDR, and WC mice but were higher than in CTR mice. The livers of mice in the HDR and WC groups also showed reduced ATP content and altered protein expressions related to mitochondrial dynamics. Liver in animals from the H group exhibited reduced LC3I expression and an increased LC3II to LC3I ratio compared with liver CTR. In contrast, livers of animals in the HDR and WC groups showed lower levels of p62, LC3I, and LC3II expression. Fibrosis was observed in the hearts of mice in the CTR and H groups, and DR did not reverse this damage. In conclusion, although HFD restriction maintained body weight, it adversely affected liver health by disrupting mitochondrial function. These findings emphasize the critical role of dietary fat in liver health when adopting calorie-restricted therapy.

Keywords:  Dietary restriction; High-fat diet; Liver fibrosis; Mitochondria; Weight cycling

DOI:  https://doi.org/10.1016/j.jnutbio.2025.109941
BMC Cancer. 2025 Apr 28. 25(1): 794

The causal relationships between mitochondria and six types of cancer: a Mendelian randomization study.

Jincheng Tang, Jingting Zhang, Renyi Yang, Hongyao Chen, Xiaopeng Yu, Wei Peng, Puhua Zeng.

   BACKGROUND: Mitochondria play a multifaceted role in tumorigenesis, influencing energy metabolism, redox balance, and apoptosis. However, whether mitochondrial traits causally affect cancer risk remains unclear. This study aimed to evaluate the potential causal effects of 82 mitochondrial-related exposures on six major cancers-hepatic, colorectal, lung, esophageal, thyroid, and breast-using Mendelian randomization (MR).
METHODS: Two-sample MR analysis was performed using the inverse variance weighted (IVW) method, with MR-Egger regression and weighted median as complementary approaches. Sensitivity analyses (Cochran's Q test, MR-Egger intercept, leave-one-out) and the Steiger test were applied to assess heterogeneity, pleiotropy, and causal directionality.
RESULTS: We observed a negative correlation between "39S ribosomal protein L34, mitochondrial", and others, with hepatic cancer, while "[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial", and others exhibited a positive correlation with hepatic cancer. "Phenylalanine-tRNA ligase, mitochondrial", and others demonstrated a negative association with colorectal cancer, whereas "Methylmalonyl-CoA epimerase, mitochondrial", and others exhibited a positive correlation with colorectal cancer. "Succinate dehydrogenase assembly factor 2, mitochondrial" exhibited a negative correlation with lung cancer, while "Superoxide dismutase [Mn], mitochondrial levels" showed a positive correlation with lung cancer. "Lon protease homolog, mitochondrial" demonstrated a positive correlation with esophageal cancer. "Iron-sulfur cluster assembly enzyme ISCU, mitochondrial", and others exhibited a negative correlation with thyroid cancer, while "Diablo homolog, mitochondrial", and others showed a positive correlation with thyroid cancer. "ADP-ribose pyrophosphatase, mitochondrial", and others exhibited a negative correlation with breast cancer, while "39S ribosomal protein L34, mitochondrial", and others showed a positive correlation with breast cancer.
CONCLUSIONS: This study provides MR-based evidence that specific mitochondrial-related traits have causal effects on the risk of several common cancers. Notably, certain single-nucleotide polymorphisms (SNPs) acted as instrumental variables across multiple cancer types through shared mitochondrial mechanisms, such as oxidative stress regulation and metabolic reprogramming. These findings highlight mitochondria as cross-cutting contributors to cancer susceptibility and suggest potential avenues for mitochondrial-targeted prevention and therapy. The identification of pleiotropic genetic variants also offers insights for developing shared biomarkers and therapeutic targets across malignancies.

Keywords:  Cancers; Causal inference; Mendelian randomization; Mitochondria

DOI:  https://doi.org/10.1186/s12885-025-14201-0
Nutrients. 2025 Mar 10. pii: 965. [Epub ahead of print]17(6):

Ketogenic Diets for Body Weight Loss: A Comparison with Other Diets.

Damian Dyńka, Łukasz Rodzeń, Mateusz Rodzeń, Anna Pacholak-Klimas, Georgia Ede, Shebani Sethi, Dorota Łojko, Karolina Bartoń, Ken Berry, Adam Deptuła, Żaneta Grzywacz, Peter Martin, Jen Unwin, David Unwin.

  With the prevalence of obesity and overweight increasing at an alarming rate, more and more researchers are focused on identifying effective weight loss strategies. The ketogenic diet (KD), used as a treatment in epilepsy management for over 100 years, is additionally gaining popularity as a weight loss method. Although its efficacy in weight loss is well documented, the areas where it may be beneficial to other dietary approaches need to be carefully examined. The objective of this paper is to identify the potential benefits of the KD over alternative dietary weight loss strategies based on a comprehensive literature review. It has been shown that the KD may be more bioenergetically efficient than other dietary strategies, inter alia owing to its effect on curtailing hunger, improving satiety and decreasing appetite (influence on hunger and satiety hormones and the sensation of hunger), inducing faster initial weight loss (associated with lower glycogen levels and reduced water retention), and controlling glycaemia and insulinemia (directly attributable to the low-carbohydrate nature of KD and indirectly to the other areas described). These effects are accompanied by improved insulin sensitivity, reduced inflammation (through ketone bodies and avoidance of pro-inflammatory sugars), reduced need for pharmacological obesity control (the diet's mechanisms are similar to those of medication but without the side effects), and positive impacts on psychological factors and food addiction. Based on the authors' review of the latest research, it is reasonable to conclude that, due to these many additional health benefits, the KD may be advantageous to other diet-based weight loss strategies. This important hypothesis deserves further exploration, which could be achieved by including outcome measures other than weight loss in future clinical trials, especially when comparing different diets of equal caloric value.

Keywords:  appetite; body weight; glycaemic; hunger; inflammation; insulin resistance; ketogenic diet; low carb; metabolic psychiatry; obesity; weight loss

DOI:  https://doi.org/10.3390/nu17060965
Cureus. 2025 Mar;17(3): e81395

Fasting as Cancer Treatment: Myth or Breakthrough in Oncology.

Ghizal Fatima, Abbas A Mehdi, Jan Fedacko, Najah Hadi, Aminat Magomedova, Ammar Mehdi.

  The concept of fasting as a potential cancer treatment has garnered increasing interest, particularly in light of emerging evidence linking dietary interventions to cancer progression and therapy outcomes. This article explores whether fasting, either intermittent or prolonged, can be a viable standalone treatment for cancer or if its therapeutic potential lies in its adjunctive role. Current research suggests that fasting induces a metabolic shift, which may inhibit cancer cell proliferation by depriving them of essential nutrients. Additionally, fasting has been shown to enhance the body's stress resistance, promote autophagy, and possibly make cancer cells more vulnerable to standard treatments such as chemotherapy and radiotherapy. However, the application of fasting as a sole treatment for cancer remains controversial and lacks substantial clinical validation. While animal models and in vitro studies indicate promising results, the translation to human trials is complex, with various types of cancer responding differently to dietary interventions. Moreover, concerns about malnutrition, loss of muscle mass, and the overall health of cancer patients undergoing fasting without supervision must be addressed. The paper critically examines the myth and reality surrounding fasting as a cancer treatment, reviewing key studies and clinical trials to provide a comprehensive understanding of its efficacy and safety. While fasting may hold promise as a supportive therapy, particularly in combination with traditional treatments, there is currently insufficient evidence to support its use as a primary treatment modality. Further research is needed to establish the parameters in which fasting might be beneficial, such as specific cancer types, patient populations, and optimal fasting regimens. Thus, while the idea of fasting as a cancer breakthrough is compelling, it remains a complementary approach rather than a standalone solution in oncology.

Keywords:  autophagy; cancer treatment; chemotherapy; fasting; metabolism

DOI:  https://doi.org/10.7759/cureus.81395
Nature. 2025 Apr 30.

The cell-division cycle is faster in cell types prone to forming cancer.

Helen K Matthews.



Keywords:  Cancer; Medical research

DOI:  https://doi.org/10.1038/d41586-025-01138-4
J Clin Res Pediatr Endocrinol. 2025 Apr 30.

Association between Circulating Amino Acids and Childhood Obesity: A Systematic Review and Meta-Analysis.

Yingli Si, Tingting Zhang, Xiangyu Wang.

  This systematic review and meta-analysis aim to synthesize the existing literature to clarify the role of amino acids as potential indicators or contributors to childhood obesity. The study follows the PRISMA 2020 guidelines. A comprehensive search was conducted across multiple electronic databases, including PubMed, Cochrane Library, Embase, Web of Science, Google Scholar, Semantic Scholar, and ResearchRabbit, using relevant keywords such as "childhood obesity," "amino acids," and "branched-chain amino acids (BCAAs)."Heterogeneity among studies was assessed using the chi-square test and the I² statistic. Publication bias was evaluated using funnel plots and Egger's test. Five studies involving a total of 1,229 participants met the inclusion criteria. A significant association was observed between amino acid levels and obesity in children. Specifically, glutamine was inversely associated with obesity (SMD = -0.48, 95% CI: -0.85 to -0.11), while leucine (SMD = 0.79, 95% CI: 0.20 to 1.38) and valine (SMD = 0.67, 95% CI: 0.18 to 1.15) were positively associated. Additionally, odds ratio analysis indicated that higher glutamine levels were associated with 56% lower odds of obesity (OR = 0.44, 95% CI: 0.21-0.94, P < .01), suggesting a potential protective role. Elevated levels of specific amino acids, particularly BCAAs, were consistently linked to increased body mass index (BMI) and other obesity-related indicators in children. Future research should focus on longitudinal and interventional studies to better understand these associations and explore targeted strategies involving amino acid metabolism to help prevent and manage childhood obesity.

Keywords:  amino acids; branched-chain amino acids (BCAA); childhood obesity; metabolomics

DOI:  https://doi.org/10.4274/jcrpe.galenos.2025.2024-11-11
Dev Cell. 2025 Apr 18. pii: S1534-5807(25)00206-0. [Epub ahead of print]

Mitochondrial CCN1 drives ferroptosis via fatty acid β-oxidation.

Wanxin Guo, Congcong Zhang, Qianjun Zhou, Tianxiang Chen, Xin Xu, Jianfeng Zhang, Xuewen Yu, Han Wu, Xiao Zhang, Lifang Ma, Kun Qian, Daniel J Klionsky, Rui Kang, Guido Kroemer, Yongchun Yu, Daolin Tang, Jiayi Wang.

  Ferroptosis is a type of oxidative cell death, although its key metabolic processes remain incompletely understood. Here, we employ a comprehensive multiomics screening approach that identified cellular communication network factor 1 (CCN1) as a metabolic catalyst of ferroptosis. Upon ferroptosis induction, CCN1 relocates to mitochondrial complexes, facilitating electron transfer flavoprotein subunit alpha (ETFA)-dependent fatty acid β-oxidation. Compared with a traditional carnitine O-palmitoyltransferase 2 (CPT2)-ETFA pathway, the CCN1-ETFA pathway provides additional substrates for mitochondrial reactive oxygen species production, thereby stimulating ferroptosis through lipid peroxidation. A high-fat diet can enhance the anticancer efficacy of ferroptosis in lung cancer mouse models, depending on CCN1. Furthermore, primary lung cancer cells derived from patients with hypertriglyceridemia or high CCN1 expression demonstrate increased susceptibility to ferroptosis in vitro and in vivo. These findings do not only identify the metabolic role of mitochondrial CCN1 but also establish a strategy for enhancing ferroptosis-based anticancer therapies.

Keywords:  CCN1; cell death; mitochondria

DOI:  https://doi.org/10.1016/j.devcel.2025.04.004
Commun Med (Lond). 2025 Apr 27. 5(1): 142

Serum metabolite levels identify incipient metastatic progression of rectal cancer.

Kine M Bakke, Paula A Bousquet, Sebastian Meltzer, Tonje Bjørnetrø, Frode Rise, Alistair L Wilkins, Kathrine Røe Redalen, Anne Hansen Ree.

BACKGROUND: The cellular metabolism undergoes reprogramming during the metastatic process. We hypothesised that serum metabolites at the time of primary tumour diagnosis might identify rectal cancer patients prone to metastatic progression.
METHODS: One hundred twenty-three rectal cancer patients from a prospective observational biomarker study were followed up to 5 years after study entry. We have assessed metabolites in serum sampled at the time of diagnosis by 1H-nuclear magnetic resonance spectroscopy, using the internal reference trimethylsilylpropanoic acid for quantification.
RESULTS: Here we show that patients who develop overt metastatic disease more than 6 months after the primary tumour diagnosis have elevated serum levels (Kruskal-Wallis test) of alanine (P = 0.005), lactate (P = 0.023), pyruvate (P = 0.041) and citrate (P = 0.007) compared to those without metastases at the 5-year follow-up or with metastases already 6 months or sooner after the cancer diagnosis. Patients with serum citrate above 0.24 mmol/L have poorer progression-free survival compared to those with levels below (P < 0.001; log-rank test).
CONCLUSIONS: We observe a distinct serum metabolite profile, in particular involving citrate to the best of our knowledge shown for the first time clinically, in rectal cancer patients at heightened risk of metastasis already when the primary tumour is diagnosed, offering insights into the metabolism of metastatic progression.

DOI: https://doi.org/10.1038/s43856-025-00868-w
Nat Metab. 2025 Apr 25.

Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states.

Junichi Okada, Austin Landgraf, Alus M Xiaoli, Li Liu, Maxwell Horton, Victor L Schuster, Fajun Yang, Simone Sidoli, Yunping Qiu, Irwin J Kurland, Carolina Eliscovich, Kosaku Shinoda, Jeffrey E Pessin.

Hepatocytes are organized along a spatial axis between the portal triad and the central vein to form functionally repetitive units known as lobules. The hepatocytes perform distinct metabolic functions depending on their location within the lobule. Single-cell analysis of hepatocytes across the liver lobule demonstrates that gluconeogenic gene expression is relatively low in the fed state and gradually increases in the periportal hepatocytes during the initial fasting period. As fasting progresses, pericentral hepatocyte gluconeogenic gene expression and gluconeogenic activity also increase and, following entry into a starvation state, the pericentral hepatocytes show similar gluconeogenic gene expression and activity to the periportal hepatocytes. In parallel, starvation suppresses canonical β-catenin signalling and modulates the expression of pericentral and periportal glutamine synthetase and glutaminase, respectively, resulting in enhanced incorporation of glutamine into glucose. Thus, hepatocyte gluconeogenic gene expression and glucose production are spatially and temporally plastic across the liver lobule, underscoring the complexity of defining hepatic insulin resistance and glucose production on a whole-organ level, as well as for a particular fasted or fed condition.

DOI: https://doi.org/10.1038/s42255-025-01269-y
Cell Metab. 2025 Apr 24. pii: S1550-4131(25)00212-8. [Epub ahead of print]

NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.

Sabina Chubanava, Iuliia Karavaeva, Amy M Ehrlich, Roger M Justicia, Astrid L Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N Rodrigues, Jesper F Havelund, Farina L Schlabs, Steen Larsen, Caio Y Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Zachary Gerhart-Hines, Thomas Moritz, Juleen R Zierath, Kei Sakamoto, Thomas E Jensen, Nils J Færgeman, Gareth G Lavery, Atul S Deshmukh, Jonas T Treebak.

  Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.

Keywords:  NAD metabolism; NAD(+) biosynthesis; NAMPT; aging; epigenetic clock; exercise; mitochondrial supercomplexes; nicotinamide; reactive oxygen species; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2025.04.002
Epilepsy Res. 2025 Apr 29. pii: S0920-1211(25)00057-9. [Epub ahead of print]214 107556

A retrospective analysis of pediatric patients on a ketogenic diet: A comparison of inpatient versus outpatient diet initiations.

Chelsey Stillman, Kelly Knupp, Jennifer Oliver, Alison Conley, Kaitlyn Kennedy, Lori Silveira, Charuta Joshi.

   INTRODUCTION: Ketogenic diet therapies are effective therapies for drug-resistant epilepsy. Conventional initiation of the ketogenic diet occurs via inpatient (IP) admission to a hospital. The COVID19 pandemic forced changes to practices allowing for comparison between inpatient (IP) and outpatient (OP) initiations. Our aim was to evaluate differences between IP and OP initiations including laboratory results, seizure reduction and communications with patients.
METHODS: This is a retrospective chart review of patients initiated on a ketogenic diet (modified Atkins [MAD] or classic ketogenic [CKD]) between 2007 and 2022. We compared variables such as demographic data, communications, lab values, seizure counts, IP or OP initiation, presence of a gastrostomy tube (g-tube), and diet type.
RESULTS: Of the 157 total subjects, 139 subjects initiated CKD and 18 subjects initiated MAD. 39 initiated OP and 118 initiated IP. The odds of a 50 % reduction in seizures at 65 days post initiation increased four times for IP initiation after adjusting for the impact of serum beta hydroxybutyrate (BHB). This difference was no longer present at 196 days post initiation. Number of communications between diet initiation and the first visit post initiation were similar for IP and OP. G-tube presence or absence did not impact outcomes.
CONCLUSION: IP initiation resulted in better seizure control at the first visit post initiation. CKD was the only variable associated with increased communications. Since seizure improvement rates were similar at 196 days, a gradual approach with lower CKD ratios may be considered. G-tube presence had no impact on outcomes and should be weighted less when considering admission.

Keywords:  Diet therapies; Initiation type; Ketogenic diet; Ketosis; Modified Atkins; Pediatric epilepsy; seizures

DOI:  https://doi.org/10.1016/j.eplepsyres.2025.107556
bioRxiv. 2025 Apr 08. pii: 2025.04.07.647691. [Epub ahead of print]

Isotope tracing-based metabolite identification for mass spectrometry metabolomics.

Deniz Secilmis, Arjana Begzati, Nina Grankvist, Irena Roci, Jeramie Watrous, Amit R Majithia, Gordon I Smith, Samuel Klein, Mohit Jain, Roland Nilsson.

Modern mass spectrometry-based metabolomics is a key technology for biomedicine, enabling discovery and quantification of a wide array of biomolecules critical for human physiology. Yet, only a fraction of human metabolites have been structurally determined, and the majority of features in typical metabolomics data remain unknown. To date, metabolite identification relies largely on comparing MS 2 fragmentation patterns against known standards, related compounds or predicted spectra. Here, we propose an orthogonal approach to identification of endogenous metabolites, based on mass isotopomer distributions (MIDs) measured in an isotope-labeled reference material. We introduce a computational measure of pairwise distance between metabolite MIDs that allows identifying novel metabolites by their similarity to previously known peaks. Using cell material labeled with 20 individual 13 C tracers, this method identified 62% of all unknown peaks, including previously never seen metabolites. Importantly, MID-based identification is highly complementary to MS 2 -based methods in that MIDs reflect the biochemical origin of metabolites, and therefore also yields insight into their synthesis pathways, while MS 2 spectra mainly reflect structural features. Accordingly, our method performed best for small molecules, while MS 2 -based identification was stronger on lipids and complex natural products. Among the metabolites discovered was trimethylglycyl-lysine, a novel amino acid derivative that is altered in human muscle tissue after intensive lifestyle treatment. MID-based annotation using isotope-labeled reference materials enables identification of novel endogenous metabolites, extending the reach of mass spectrometry-based metabolomics.

DOI: https://doi.org/10.1101/2025.04.07.647691
Biomedicines. 2025 Mar 24. pii: 789. [Epub ahead of print]13(4):

Lactate Provides Metabolic Substrate Support and Attenuates Ischemic Brain Injury in Mice, Revealed by 1H-13C Nuclear Magnetic Resonance Metabolic Technique.

Kefan Wu, Yajing Liu, Yuxuan Wang, Jiabao Hou, Meng Jiang, Shaoqin Lei, Bo Zhao, Zhongyuan Xia.

  Background/Objectives: Lactate, classically considered a metabolic byproduct of anaerobic glycolysis, is implicated in ischemic acidosis and neuronal injury. The recent evidence highlights its potential role in sustaining metabolic networks and neuroprotection. This study investigates lactate's compensatory mechanisms in ischemic brain injury by analyzing post-ischemic metabolic enrichments and inter-regional metabolite correlations. Methods: Dynamic metabolic profiling was conducted using 13C-labeled glucose combined with 1H-13C NMR spectroscopy to quantify the metabolite enrichment changes in a murine cerebral ischemia model (n = 8). In vivo validation included intracerebroventricular pH-neutral lactate infusion in ischemic mice to assess the behavioral, electrophysiological, and mitochondrial outcomes. In vitro, HT22 hippocampal neurons underwent oxygen-glucose deprivation (OGD) with pH-controlled lactate supplementation (1 mM), followed by the evaluation of neuronal survival, mitochondrial membrane potential, and glycolytic enzyme expression. Results: NMR spectroscopy revealed a 30-50% reduction in most cerebral metabolites post-ischemia (p < 0.05), while the quantities of lactate and the related three-carbon intermediates remained stable or increased. Correlation analyses demonstrated significantly diminished inter-metabolite coordination post-ischemia, yet lactate and glutamate maintained high metabolic activity levels (r > 0.80, p < 0.01). Lactate exhibited superior cross-regional metabolic mobility compared to those of the other three-carbon intermediates. In vivo, lactate infusion improved the behavioral/electrophysiological outcomes and reduced mitochondrial damage. In the OGD-treated neurons, pH-neutral lactate (7.4) reduced mortality (p < 0.05), preserved the mitochondrial membrane potential (p < 0.05), and downregulated the glycolytic enzymes (HK, PFK, and PKM; p < 0.01), thereby attenuating H+ production. Conclusions: Under ischemic metabolic crisis, lactate and the three-carbon intermediates stabilize as critical substrates, compensating for global metabolite depletion. pH-neutral lactate restores energy flux, modulates the glycolytic pathways, and provides neuroprotection by mitigating acidotoxicity.

Keywords:  NMR; cerebral ischemia; glycolytic; lactate

DOI:  https://doi.org/10.3390/biomedicines13040789
Sci Rep. 2025 May 02. 15(1): 15317

Ethyl p-methoxycinnamate inhibits tumor growth by suppressing of fatty acid synthesis and depleting ATP.

Yutaro Sasaki, Niina Mizushima, Toshio Norikura, Isao Matsui-Yuasa, Akiko Kojima-Yuasa.

  Cancer cells reprogram their energy metabolism pathways, but the mechanisms that enable them to meet their energy demands remain poorly understood. This study investigates the anticancer effects of ethyl p-methoxycinnamate (EMC) in Ehrlich ascites tumor cells (EATCs) and reveals that de novo fatty acid synthesis, rather than glycolysis, plays a pivotal role in sustaining energy homeostasis in cancer cells. EMC significantly reduced ATP levels despite enhancing glycolytic activity. It suppressed the expression of key enzymes involved in de novo fatty acid synthesis, including Acly, Acc1, and Fasn, resulting in decreased intracellular triglyceride (TG) levels. The addition of exogenous palmitic acid reversed EMC-induced ATP depletion and mitigated its anti-proliferative effects. Mechanistically, the ATP reduction caused by EMC was associated with inhibition of the c-Myc/SREBP1 pathway and arrest of the G1/S cell cycle transition. These findings demonstrate that EMC inhibits EATC proliferation by reducing ATP levels via suppression of de novo fatty acid synthesis. This study highlights the critical role of de novo fatty acid synthesis, rather than glycolysis, in maintaining energy homeostasis in cancer cells and provides novel insights into targeting cancer metabolism.

Keywords:   De Novo fatty acid synthesis; Kaempferia galanga L.; ATP; Ehrlich Ascites tumor cells; Ethyl p-methoxycinnamate; Glycolysis

DOI:  https://doi.org/10.1038/s41598-025-00131-1