bims-medica 2025-02-23 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–02–23
thirty papers selected by
Brett Chrest, Wake Forest University

Anaplerosis by medium-chain fatty acids through complex interplay with glucose and glutamine metabolism.
Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
Metabolism and therapeutic response in acute myeloid leukemia with IDH1/2 mutations.
A Ketogenic Diet Enhances Aerobic Exercise Adaptation and Promotes Muscle Mitochondrial Remodeling in Hyperglycemic Mice.
Mitochondrial glutamic-oxaloacetic transaminase (GOT2) in the growth of C2C12 myoblasts.
The effects of dietary fat on gut microbial composition and function in ovarian cancer.
Gemcitabine Alters Phosphatidylcholine Metabolism in Mouse Pancreatic Tumors.
Ketogenic diet suppresses colorectal cancer through the gut microbiome long chain fatty acid stearate.
High Glucose Contribution to the TCA Cycle Is a Feature of Aggressive Non-Small Cell Lung Cancer in Patients.
Uridine Metabolism as a Targetable Metabolic Achilles' Heel for chemo-resistant B-ALL.
A data-driven approach for improved quantification of in vivo metabolic conversion rates of hyperpolarized [1-13C]pyruvate.
Associations of dietary fat types (MUFA, PUFA, SFA) and sources (animal, plant) with colorectal cancer risk: A comprehensive systematic review and dose-response meta-analysis of prospective cohort studies.
Ultra-processed food, obesity, and colon cancer: A systematic review and meta-analysis.
IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response.
An organism-level quantitative flux model of energy metabolism in mice.
A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
Time-dependent relationship between urinary biomarkers of nucleic acid oxidation and colorectal cancer risk.
STAT1 inhibition promotes oxidative stress to sustain leukemia stem cell maintenance.
Partial Regulation of Ketone Metabolism by Hypoxia in H9C2 Cardiomyocytes.
Myocardial metabolic flexibility following ketone infusion demonstrated by hyperpolarized [2-13C]pyruvate MRS in pigs.
Temporal and spatial composition of the tumor microenvironment predicts response to immune checkpoint inhibition.
M8OI toxicity is associated with an inhibition of ubiquinone reduction by complex I in the mitochondrial electron transport chain.
Snapshots of acyl carrier protein shuttling in human fatty acid synthase.
Mitochondria-Targeted Temozolomide Probe for Overcoming MGMT-Mediated Resistance in Glioblastoma.
Impact of time-restricted feeding on glycemic indices, vascular oxidative stress, and inflammation in an obese prediabetes rat model induced by a high-fat diet and sugar drink.
Targeting both the enzymatic and non-enzymatic functions of DHODH as a therapeutic vulnerability in c-Myc-driven cancer.
Genetically encoded biosensor for fluorescence lifetime imaging of PTEN dynamics in the intact brain.
GDP-mannose 4,6-dehydratase is a key driver of MYCN-amplified neuroblastoma core fucosylation and tumorigenesis.
Analysis of fatty acid metabolism in prostate cancer and discovery of a new programmed cell death-associated luminal cell subpopulation.
Genetically Encoded Single-Wavelength Sensor with High Specificity for Imaging ATP in Living Cells.

J Biol Chem. 2025 Feb 13. pii: S0021-9258(25)00155-3. [Epub ahead of print] 108307

Anaplerosis by medium-chain fatty acids through complex interplay with glucose and glutamine metabolism.

Hannah M German, Jolita Ciapaite, Nanda M Verhoeven-Duif, Judith J M Jans.

  The constant replenishment of tricarboxylic acid (TCA) cycle intermediates, or anaplerosis, is crucial to ensure optimal TCA cycle activity in times of high biosynthetic demand. In inborn metabolic diseases, anaplerosis is often affected, leading to impaired TCA cycle flux and ATP production. In these cases, anaplerotic compounds can be a therapy option. Triheptanoin, a triglyceride containing three heptanoate chains, is thought to be anaplerotic through production of propionyl- and acetyl-CoA. However, the precise mechanism underlying its anaplerotic action remains poorly understood. In this study, we performed a comprehensive in vitro analysis of heptanoate metabolism and compared it to that of octanoate, an even-chain fatty acid which only provides acetyl-CoA. Using stable isotope tracing, we demonstrate that both heptanoate and octanoate contribute carbon to the TCA cycle in HEK293T cells, confirming direct anaplerosis. Furthermore, by using labeled glucose and glutamine, we show that heptanoate and octanoate decrease the contribution of glucose-derived carbon and increase the influx of glutamine-derived carbon into the TCA cycle. Our findings also point towards a change in redox homeostasis, indicated by an increased NAD+/NADH ratio, accompanied by a decreased lactate/pyruvate ratio and increased de novo serine biosynthesis. Taken together, these results highlight the broad metabolic effects of heptanoate and octanoate supplementation, suggesting that therapeutic efficacy may strongly depend on specific disease pathophysiology. Furthermore, they underline the need for careful selection of fatty acid compound and concentration to optimize anaplerotic action.

Keywords:  Anaplerosis; fatty acids; isotopic tracer; mass spectrometry (MS); metabolic disease; metabolomics; redox regulation

DOI:  https://doi.org/10.1016/j.jbc.2025.108307
bioRxiv. 2025 Feb 08. pii: 2025.02.07.637120. [Epub ahead of print]

Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.

Kimberly S Huggler, Carlos A Mellado Fritz, Kyle M Flickinger, Gavin R Chang, Meghan F McGuire, Jason R Cantor.

Hexokinase (HK) catalyzes the synthesis of glucose-6-phosphate, marking the first committed step of glucose metabolism. Most cancer cells express two homologous isoforms (HK1 and HK2) that can each bind to the outer mitochondrial membrane (OMM). CRISPR screens across hundreds of cancer cell lines indicate that both are dispensable for cell growth in traditional culture media. By contrast, HK2 deletion impairs cell growth in Human Plasma-Like Medium (HPLM). Here, we find that HK2 is required to maintain sufficient cytosolic (OMM-detached) HK activity under conditions that enhance HK1 binding to the OMM. Notably, OMM-detached rather than OMM-docked HK promotes "aerobic glycolysis" (Warburg effect), an enigmatic phenotype displayed by most proliferating cells. We show that several proposed theories for this phenotype cannot explain the HK2 dependence and instead find that HK2 deletion severely impairs glycolytic ATP production with little impact on total ATP yield for cells in HPLM. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis underlies the Warburg effect.

DOI: https://doi.org/10.1101/2025.02.07.637120
Trends Cancer. 2025 Feb 14. pii: S2405-8033(25)00012-3. [Epub ahead of print]

Metabolism and therapeutic response in acute myeloid leukemia with IDH1/2 mutations.

Ludovic Gabellier, Enzo Bosetta, Maël Heiblig, Jean-Emmanuel Sarry.

  Pathogenic variants of isocitrate dehydrogenase 1 and 2 (IDH1/2) genes are present in approximately 20% of acute myeloid leukemia (AML) cases, resulting in the oncometabolite R-2-hydroxyglutarate (R-2-HG). The accumulation of R-2-HG in leukemic cells and in their niche induces epigenetic modifications, profound rewiring of the cellular metabolism, and microenvironmental remodeling. These changes promote cellular differentiation bias, enhancing the survival and proliferation of leukemic cells, and thus playing a pivotal role in leukemogenesis and resistance to standard AML therapy. This review focuses on the different perspectives offered by studying metabolism and resistance to standard treatments in AML with IDH1 or IDH2 pathogenic variants, for the development of new biomarkers and therapeutic solutions.

Keywords:  isocitrate dehydrogenase; leukemia; metabolism; resistance; therapy

DOI:  https://doi.org/10.1016/j.trecan.2025.01.011
Res Sq. 2025 Jan 29. pii: rs.3.rs-5814971. [Epub ahead of print]

A Ketogenic Diet Enhances Aerobic Exercise Adaptation and Promotes Muscle Mitochondrial Remodeling in Hyperglycemic Mice.

Sarah Lessard, Pattarawan Pattamaprapanont, Roberto Nava, Mia Formato, Eileen Cooney, Ana Pinto, Ana Alves-Wagner, Anamica Das, Yuntian Guan.

VO2peak is a key health benefit of aerobic exercise; however, chronic hyperglycemia is associated with persistently low VO2peak due to an impaired adaptive response to training. Here, we tested whether reducing blood glucose with a low-carbohydrate/high-fat "ketogenic" diet could restore aerobic exercise adaptation in a mouse model of hyperglycemia. Hyperglycemia was induced by streptozotocin (STZ) and mice were stratified to standard chow (STZ-CHOW), or a ketogenic diet (STZ-KETO), which rapidly normalized blood glucose. After aerobic exercise training, improvements in VO2peak were blunted in STZ-CHOW, but exercise response was restored in STZ-KETO. Improved VO2peak in STZ-KETO was associated with enhanced aerobic remodeling of skeletal muscle, including a more oxidative fiber-type and increased capillary density, along with restoration of circulating angiogenic markers. Moreover, KETO induced exercise-independent effects on muscle mitochondrial remodeling and mitochondrial dynamics, significantly increasing fatty acid oxidation. Our results identify a ketogenic diet as a potential therapy to improve aerobic exercise response in the growing population with hyperglycemia due to diabetes and other metabolic conditions.

DOI: https://doi.org/10.21203/rs.3.rs-5814971/v1
J Bioenerg Biomembr. 2025 Feb 15.

Mitochondrial glutamic-oxaloacetic transaminase (GOT2) in the growth of C2C12 myoblasts.

Ritu Som, Brian D Fink, Adam J Rauckhorst, Eric B Taylor, William I Sivitz.

  Glutamine is well recognized as critical to the growth of most cell types. Within mitochondria glutamine is converted to glutamate by glutaminase. Oxaloacetate and glutamate then react to form alpha-ketoglutarate (α-KG) and aspartate catalyzed by glutamic-oxaloacetic transaminase (GOT2) or directly converted to α-KG by glutamate dehydrogenase (GDH). We investigated the role of GOT2 in mediating glutamate metabolism and cell growth in undifferentiated C2C12 cells. CRISPR mediated GOT2 knockout (KO) impaired cell growth, partially overcome by higher concentrations of glutamine. Mitochondrial respiration did not differ between KO and wildtype (WT) cells. Metabolite profiling showed that GOT2KO decreased aspartate by about 50% in KO versus WT cells. In contrast, α-KG increased. Metabolites reflecting the pentose phosphate pathway were significantly increased in KO cells. Metabolic pathway analyses revealed alteration of the TCA cycle, the pentose phosphate pathway, and amino acid metabolism. Glutamine 13C-tracing revealed decreased generation of aspartate, increased ribulose phosphate and evidence for reductive carboxylation of α-KG to isocitrate in KO cells. GDH expression was detected in C2C12 cells but did not differ between WT and GOT2KO mitochondria. GDH is not or barely expressed in adult muscle, however, we observed clear expression in pre-weanling mice. Cytosolic glutamic-oxaloacetic transaminase, GOT1, expression did not differ between GOT2KO and WT cells. In summary, GOT2 is necessary for glutamate flux and generation of downstream metabolites needed for the growth of C2C12 myoblasts. Although respiration did not differ, lack of aspartate and other compounds needed for cell proliferation may have been major factors impairing growth.

Keywords:  Glutamate; Glutamate dehydrogenase; Glutamic oxaloacetic transaminase; Mitochondria; Myoblasts; Skeletal muscle

DOI:  https://doi.org/10.1007/s10863-025-10053-2
Res Sq. 2025 Feb 07. pii: rs.3.rs-5904007. [Epub ahead of print]

The effects of dietary fat on gut microbial composition and function in ovarian cancer.

Mariam M AlHilli, Naseer Sangwan, Alex Myers, Surabhi Tewari, Daniel J Lindner, Gail A M Cresci, Ofer Reizes.

Objectives : The gut microbiome (GM) is pivotal in regulating inflammation, immune responses, and cancer progression. This study investigates the effects of a ketogenic diet (KD) and a high-fat/low-carbohydrate (HF/LC) diet on GM alterations and tumor growth in a syngeneic mouse model of high-grade serous ovarian cancer (EOC). Methods : Thirty female C57BL/6J mice injected with KPCA cells were randomized into KD, HF/LC, and low-fat/high-carbohydrate (LF/HC) diet groups. Tumor growth was monitored with live, in vivo imaging. Stool samples were collected at the time of euthanasia and analyzed by 16SrRNA sequencing and shotgun metagenomic sequencing was performed to identify differential microbial taxonomic composition and metabolic function. Results : Our findings revealed that KD and HF/LC diets significantly accelerated EOC tumor growth compared to the LF/HC diet in a xenograft model. GM diversity was markedly reduced in KD and HF/LC-fed mice, correlating with increased tumor growth, whereas LF/HC-fed mice showed higher GM diversity. Metagenomic analyses identified distinct alterations in microbial taxa including Bacteroides , Lachnospiracae bacterium , Bacterium_D16_50, and Enterococcus faecalis predominantly abundant in HF/LC-fed mice, Dubsiella_newyorkensis predominantly abundant in LF/HC-fed, and KD fed mice showing a higher abundance of Akkermansia and Bacteroides . Functional pathways across diet groups indicated polyamine biosynthesis and fatty acid oxidation pathways were enriched in HF/LC-fed mice. Conclusions These results highlight the intricate relationship between diet, the gut microbiome, and tumor metabolism. The potential role of dietary interventions in cancer prevention and treatment warrants further investigation.

DOI: https://doi.org/10.21203/rs.3.rs-5904007/v1
J Proteome Res. 2025 Feb 19.

Gemcitabine Alters Phosphatidylcholine Metabolism in Mouse Pancreatic Tumors.

Nav Raj Phulara, Chiaki Tsuge Ishida, Peter John Espenshade, Herana Kamal Seneviratne.

  Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest diseases, despite advancements in elucidating tumor biology and developing novel therapeutics. Importantly, lipids, such as phospholipids, are crucial for the survival and proliferation of tumor cells. However, the impact of chemotherapeutic drugs on phospholipid metabolism in PDAC remains poorly understood. Gemcitabine (a nucleoside analogue) is a first-line drug in PDAC treatment, but its clinical effectiveness is limited by multiple factors. Herein, we employed matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) and proteomics approaches to investigate gemcitabine-induced lipid metabolism alterations in mouse pancreatic tumors following gemcitabine treatment (n = 3, control tumors; n = 3, gemcitabine-treated tumors). From MALDI MSI experiments, we observed elevated levels of several phosphatidylcholines (PCs), PC(30:0), PC(32:3), PC(34:2), PC(36:1), and PC(36:2), in gemcitabine-treated tumor tissues compared to the control. In addition, proteomics data revealed the differential abundance of several phospholipid-binding proteins in response to gemcitabine treatments. Furthermore, several endoplasmic reticulum stress-related proteins exhibited high expression in gemcitabine-treated tumor tissues. Altogether, our MALDI MSI and proteomics data provide important insights into alterations in PC metabolism in pancreatic tumors in response to gemcitabine treatment. Importantly, targeting the altered PC metabolism during gemcitabine therapy might help combat pancreatic cancer.

Keywords:  MALDI mass spectrometry imaging; gemcitabine; lipid metabolism; phosphatidylcholine; proteomics

DOI:  https://doi.org/10.1021/acs.jproteome.4c00839
Nat Commun. 2025 Feb 20. 16(1): 1792

Ketogenic diet suppresses colorectal cancer through the gut microbiome long chain fatty acid stearate.

Mina Tsenkova, Madita Brauer, Vitaly Igorevich Pozdeev, Marat Kasakin, Susheel Bhanu Busi, Maryse Schmoetten, Dean Cheung, Marianne Meyers, Fabien Rodriguez, Anthoula Gaigneaux, Eric Koncina, Cedric Gilson, Lisa Schlicker, Diran Herebian, Martine Schmitz, Laura de Nies, Ertan Mayatepek, Serge Haan, Carine de Beaufort, Thorsten Cramer, Johannes Meiser, Carole L Linster, Paul Wilmes, Elisabeth Letellier.

Colorectal cancer (CRC) patients have been shown to possess an altered gut microbiome. Diet is a well-established modulator of the microbiome, and thus, dietary interventions might have a beneficial effect on CRC. An attenuating effect of the ketogenic diet (KD) on CRC cell growth has been previously observed, however the role of the gut microbiome in driving this effect remains unknown. Here, we describe a reduced colonic tumor burden upon KD consumption in a CRC mouse model with a humanized microbiome. Importantly, we demonstrate a causal relationship through microbiome transplantation into germ-free mice, whereby alterations in the gut microbiota were maintained in the absence of continued selective pressure from the KD. Specifically, we identify a shift toward bacterial species that produce stearic acid in ketogenic conditions, whereas consumers were depleted, resulting in elevated levels of free stearate in the gut lumen. This microbial product demonstrates tumor-suppressing properties by inducing apoptosis in cancer cells and decreasing colonic Th17 immune cell populations. Taken together, the beneficial effects of the KD are mediated through alterations in the gut microbiome, including, among others, increased stearic acid production, which in turn significantly reduces intestinal tumor growth.

DOI: https://doi.org/10.1038/s41467-025-56678-0
Cancer Discov. 2025 Feb 17. OF1-OF15

High Glucose Contribution to the TCA Cycle Is a Feature of Aggressive Non-Small Cell Lung Cancer in Patients.

Ling Cai, Nia G Hammond, Alpaslan Tasdogan, Massar Alsamraae, Chendong Yang, Robert B Cameron, Peiran Quan, Ashley Solmonson, Wen Gu, Panayotis Pachnis, Mayher Kaur, Brianna K Chang, Qin Zhou, Christopher T Hensley, Quyen N Do, Luiza Martins Nascentes Melo, Jessalyn M Ubellacker, Akash Kaushik, Maia G Clare, Isabel N Alcazar, Katarzyna Kurylowicz, Joseph D Marcuccilli, Gabriele Allies, Andrea Kutritz, Joachim Klode, Vijayashree Ramesh, Thomas J Rogers, Aparna D Rao, Hannah E Crentsil, Hong Li, Fang Brister, Phyllis McDaniel, Xiaohong Xu, Bret M Evers, Lauren G Zacharias, Jessica Sudderth, Jian Xu, Thomas P Mathews, Dwight Oliver, John D Minna, John Waters, Sean J Morrison, Kemp H Kernstine, Brandon Faubert, Ralph J DeBerardinis.

SIGNIFICANCE: Intraoperative 13C-glucose infusions in patients with NSCLC show that tumors with high labeling of TCA cycle intermediates progress rapidly, resulting in metastasis and early death. Blocking this pathway suppresses metastasis of human NSCLC cells in mice.

DOI: https://doi.org/10.1158/2159-8290.CD-23-1319
bioRxiv. 2025 Jan 30. pii: 2025.01.27.635108. [Epub ahead of print]

Uridine Metabolism as a Targetable Metabolic Achilles' Heel for chemo-resistant B-ALL.

Yuxuan Liu, Haowen Jiang, Jingjing Liu, Lucille Stuani, Milton Merchant, Astraea Jager, Abhishek Koladiya, Ti-Cheng Chang, Pablo Domizi, Jolanda Sarno, Tim Keyes, Dorra Jedoui, Ao Wang, Jodie Meng, Felix Hartmann, Sean C Bendall, Min Huang, Norman J Lacayo, Kathleen M Sakamoto, Charles G Mullighan, Mignon Loh, Jiyang Yu, Jun Yang, Jiangbin Ye, Kara L Davis.

Relapse continues to limit survival for patients with B-cell acute lymphoblastic leukemia (B-ALL). Previous studies have independently implicated activation of B-cell developmental signaling pathways and increased glucose consumption with chemo-resistance and relapse risk. Here, we connect these observations, demonstrating that B-ALL cells with active signaling, defined by high expression of phosphorylated ribosomal protein S6 ("pS6+ cells"), are metabolically unique and glucose dependent. Isotope tracing and metabolic flux analysis confirm that pS6+ cells are highly glycolytic and notably sensitive to glucose deprivation, relying on glucose for de novo nucleotide synthesis. Uridine, but not purine or pyrimidine, rescues pS6+ cells from glucose deprivation, highlighting uridine is essential for their survival. Active signaling in pS6+ cells drives uridine production through activating phosphorylation of carbamoyl phosphate synthetase (CAD), the enzyme catalyzing the initial steps of uridine synthesis. Inhibition of signaling abolishes glucose dependency and CAD phosphorylation in pS6+ cells. Primary pS6+ cells demonstrate high expression of uridine synthesis proteins, including dihydroorotate dehydrogenase (DHODH), the rate-limiting catalyst of de novo uridine synthesis. Gene expression demonstrates that increased expression of DHODH is associated with relapse and inferior event-free survival after chemotherapy. Further, the majority of B-ALL genomic subtypes demonstrate activity of DHODH. Inhibiting DHODH using BAY2402232 effectively kills pS6+ cells in vitro , with its IC50 correlated with the strength of pS6 signaling across 14 B-ALL cell lines and patient-derived xenografts (PDX). In vivo DHODH inhibition prolongs survival and decreases leukemia burden in pS6+ B-ALL cell line and PDX models. These findings link active signaling to uridine dependency in B-ALL cells and an associated risk of relapse. Targeting uridine synthesis through DHODH inhibition offers a promising therapeutic strategy for chemo-resistant B-ALL as a novel therapeutic approach for resistant disease.

DOI: https://doi.org/10.1101/2025.01.27.635108
Magn Reson Med. 2025 Feb 18.

A data-driven approach for improved quantification of in vivo metabolic conversion rates of hyperpolarized [1-13C]pyruvate.

Yaewon Kim, Tanner M Nickles, Philip M Lee, Robert A Bok, Jeremy W Gordon, Peder E Z Larson, Daniel B Vigneron, Cornelius von Morze, Michael A Ohliger.

   PURPOSE: Accurate quantification of metabolism in hyperpolarized (HP) 13C MRI is essential for clinical applications. However, kinetic model parameters are often confounded by uncertainties in radiofrequency flip angles and other model parameters.
METHODS: A data-driven kinetic fitting approach for HP 13C-pyruvate MRI was proposed that compensates for uncertainties in the B1 + field. We hypothesized that introducing a scaling factor to the flip angle to minimize fit residuals would allow more accurate determination of the pyruvate-to-lactate conversion rate (kPL). Numerical simulations were performed under different conditions (flip angle, kPL, and T1 relaxation), with further testing using HP 13C-pyruvate MRI of rat liver and kidneys.
RESULTS: Simulations showed that the proposed method reduced kPL error from 60% to 1% when the prescribed and actual flip angles differed by 60%. The method also showed robustness to T1 uncertainties, achieving median kPL errors within ±3% even when the assumed T1 was incorrect by up to a factor of 2. In rat studies, better-quality fitting for lactate signals (a 1.4-fold decrease in root mean square error [RMSE] for lactate fit) and tighter kPL distributions (an average of 3.1-fold decrease in kPL standard deviation) were achieved using the proposed method compared with when no correction was applied.
CONCLUSION: The proposed data-driven kinetic fitting approach provided a method to accurately quantify HP 13C-pyruvate metabolism in the presence of B1 + inhomogeneity. This model may also be used to correct for other error sources, such as T1 relaxation and flow, and may prove to be clinically valuable in improving tumor staging or assessing treatment response.

Keywords:  flip angle correction; hyerpolarized C‐13 pyruvate; metabolic conversion analysis; metabolic imaging

DOI:  https://doi.org/10.1002/mrm.30445
Cancer Epidemiol. 2025 Feb 13. pii: S1877-7821(25)00027-X. [Epub ahead of print]95 102768

Associations of dietary fat types (MUFA, PUFA, SFA) and sources (animal, plant) with colorectal cancer risk: A comprehensive systematic review and dose-response meta-analysis of prospective cohort studies.

Mohammadmatin Mahjourian, Javad Anjom-Shoae, Mohammad Amin Mohammadi, Christine Feinle-Bisset, Omid Sadeghi.

   BACKGROUND AND OBJECTIVES: While dietary fat intake has long been implicated as a risk factor for colorectal cancer, evidence from prospective cohort studies remains inconsistent. Moreover, previous meta-analyses examining the link between dietary fat intake and risk of colorectal cancer have not explored the dose-response relationships. Therefore, the current systematic review and meta-analysis was conducted to assess the dose-response associations of intakes of specific types (MUFA, PUFA and SFA) and sources (animal, plant) of dietary fat with the risk of colorectal, colon or rectal cancer.
METHODS: A comprehensive literature search of relevant online databases was performed to detect eligible studies until May 2023, identifying 21 prospective cohort studies with a total sample size of 2311,737 participants. The follow-up periods ranged from 7 to 19.4 years, during which 21,125 cases of colorectal, colon or rectal cancer were recorded.
RESULTS: Comparing extreme intake levels of total fat revealed the summary relative risk (RR) of 1.05 (95 % CI: 0.96-1.15) for colorectal cancer, 0.99 (95 % CI: 0.87-1.11) for colon cancer, and 1.09 (0.95 % CI: 0.93-1.13) for rectal cancer, indicating no significant association. Neither animal nor plant fat intake was associated with the risk of cancers. While no significant findings were also observed for MUFA or PUFA, the highest versus lowest comparison showed that a high intake of SFA was associated with a reduced risk of both colorectal 0.91 (95 % CI: 0.85-0.99) and colon cancer 0.86 (95 % CI: 0.75-0.98). However, in the non-linear dose-response analysis, the inverse association was seen within a certain range (<40 g/day).
CONCLUSIONS: These findings suggest that dietary SFA intake, less than 40 g/day, may have a protective effect against colorectal cancer. Further studies are needed to confirm our findings.

Keywords:  Colorectal cancer; colon cancer; dietary fat; meta-analysis; rectal cancer

DOI:  https://doi.org/10.1016/j.canep.2025.102768
World J Gastrointest Oncol. 2025 Feb 15. 17(2): 101211

Ultra-processed food, obesity, and colon cancer: A systematic review and meta-analysis.

Justin Tin, Henry Lee, Alfonso Gonzalez Trejo, Kevin Tin.

   BACKGROUND: Recently, there has been a significant increase in the consumption of ultra-processed foods worldwide. However, the association between the consumption of ultra-processed food, obesity, and the prevalence of colon cancer remains controversial.
AIM: To find out the association between the consumption of ultra-processed food, obesity, and the prevalence of colon cancer.
METHODS: A comprehensive systematic literature search of PubMed, Scopus, Web of Science, and Google Scholar for grey literature was done for articles published before 8th March 2023. The search was done to retrieve potential peer-reviewed articles that explored the association between the consumption of ultra-processed food, obesity, and the prevalence of colon cancer.
RESULTS: Of the 246 potential articles assessed, 17 met the inclusion criteria. Meta-analysis results demonstrated that high consumption of ultra-processed food is associated with an increased risk of obesity [odds ratio (OR): 1.65; 95%CI: 1.07-2.45; P < 0.05]. Consequently, there is a positive association between obesity and an increased risk of colon cancer (OR 1.48; 95%CI: 0.77-2.87; P > 0.05).
CONCLUSION: Consuming ultra-processed foods increases the risk of obesity and colon cancer.

Keywords:  Colon cancer; Colorectal cancer; Diet; Obesity; Oxidative stress; Population, intervention, comparison, primary outcomes, study design; Preferred Reporting Items for Systematic Review and Meta-Analysis; Ultra-processed; Ultra-processed food

DOI:  https://doi.org/10.4251/wjgo.v17.i2.101211
Exp Hematol Oncol. 2025 Feb 15. 14(1): 15

IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response.

Mingyue Yao, Wenzhong Yan, Yafang Wang, Yu Zhao, Xiaowei Xu, Yujun Chen, Chengcheng Yu, Yingnian Li, Hualiang Jiang, Jie Shen, Jianjun Cheng, Chengying Xie.

   BACKGROUND: Despite initial success with FLT3 inhibitors (FLT3is), outcomes for FLT3-ITD acute myeloid leukemia (AML) patients remain unsatisfactory, underscoring the need for more effective treatment options. Epigenetic modifications, such as histone acetylation, contribute to AML's onset and persistence, advocating the potential for epigenetic therapies. However, the poor specificity of pan-histone deacetylase inhibitors (HDACis) leads to undesirable adverse effects, prompting the need for isoform-specific HDACis. This study aims to explore the antileukemic activities and mechanisms of IHCH9033, a novel class I HDACi, alone or combined with FLT3i in FLT3-ITD AML.
METHODS: The viability of AML cell lines and primary AML cells treated with HDACis alone or in combination with FLT3i was detected by MTT or CCK8 assay. Flow cytometry was utilized to examine cell apoptosis, cell cycle progression and ROS production. RNA sequencing analysis, RT-qPCR, western blotting, and co-immunoprecipitation assays were employed to elucidate the molecule mechanisms. The in vivo anti-leukemia efficacy was tested in xenografted mice models derived from FLT3-ITD cell lines and primary AML patients.
RESULTS: Here, we identified IHCH9033, a novel selective class I HDACi, which exhibited an increased antitumor effect in FLT3-ITD AML through effectively eliminating leukemia burden and overcoming resistance to FLT3i. Mechanically, IHCH9033 selectively inhibited DNA repair in FLT3-ITD AML cells, leading to the accumulation of DNA damage that eventually resulted in cell cycle arrest and apoptosis. Additionally, IHCH9033 induced HSP90 acetylation, FLT3 ubiquitination, and proteasomal degradation of FLT3, thereby inhibiting FLT3 downstream signaling. Notably, IHCH9033 maintained its potency in both FLT3i-resistant AML cell lines and primary-resistant patient samples, and exerted strong synergy with the FLT3i quizartinib, leading to tumor regression in FLT3-ITD/TKD AML xenografts. In patient-derived xenografts, the treatment with IHCH9033, both alone and in combination, led to nearly complete eradication of the AML burden, without significant adverse effects.
CONCLUSIONS: Our study shows that IHCH9033, a novel class I HDACi with a desirable pharmacological profile, is a promising drug candidate for FLT3-ITD AML, and suggests a strategy of combining class I HDACis and FLT3is in AML clinical trials to increase efficacy and overcome resistance, thus potentially providing a curative treatment option.

Keywords:  Acute myeloid leukemia; DNA damage response; Drug resistance; FLT3-ITD mutation; HDAC inhibitor; Synergistic effect

DOI:  https://doi.org/10.1186/s40164-025-00605-y
Cell Metab. 2025 Feb 13. pii: S1550-4131(25)00008-7. [Epub ahead of print]

An organism-level quantitative flux model of energy metabolism in mice.

Bo Yuan, Will Doxsey, Özlem Tok, Young-Yon Kwon, Yanshan Liang, Karen E Inouye, Gökhan S Hotamışlıgil, Sheng Hui.

  Mammalian tissues feed on nutrients in the blood circulation. At the organism level, mammalian energy metabolism is comprised of the oxidation, storage, interconversion, and release of circulating nutrients. Here, by integrating isotope tracer infusion, mass spectrometry, and isotope gas analyzer measurement, we developed a framework to systematically quantify fluxes through these metabolic processes for 10 major circulating energy nutrients in mice, resulting in an organism-level quantitative flux model of energy metabolism. This model revealed in wild-type mice that circulating nutrients have metabolic cycling fluxes dominant to their oxidation fluxes, with distinct partitions between cycling and oxidation for individual circulating nutrients. Applications of this framework in obese mouse models showed extensive elevation of metabolic cycling fluxes in ob/ob mice but not in diet-induced obese mice on a per-animal or per-lean mass basis. Our framework is a valuable tool to reveal new features of energy metabolism in physiological and disease conditions.

Keywords:  energy metabolism; futile cycle; high-fat diet; isotope tracing; metabolic flux analysis; ob/ob; obesity

DOI:  https://doi.org/10.1016/j.cmet.2025.01.008
bioRxiv. 2025 Feb 08. pii: 2025.02.03.635951. [Epub ahead of print]

A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.

Anna S Monzel, Jack Devine, Darshana Kapri, Jose Antonio Enriquez, Caroline Trumpff, Martin Picard.

Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions 1-3 . All mitochondria share general features, but not all mitochondria are created equal 4 .Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes . By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 5 ) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics or proteomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity 6-8 , we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.

DOI: https://doi.org/10.1101/2025.02.03.635951
medRxiv. 2025 Jan 22. pii: 2025.01.21.25320898. [Epub ahead of print]

Time-dependent relationship between urinary biomarkers of nucleic acid oxidation and colorectal cancer risk.

Yingya Zhao, Marina S Nogueira, Ginger L Milne, Yu-Tang Gao, Qiuyin Cai, Qing Lan, Haoyang Yi, Nathaniel Rothman, Xiao-Ou Shu, Wei Zheng, Qingxia Chen, Gong Yang.

PURPOSE: Randomized controlled trials have failed to validate that neutralizing oxidative stress (OxS) through antioxidant supplementation reduces cancer risk. This study aims to prospectively investigate whether the relationship between systemic OxS and colorectal cancer (CRC) risk changes over the course of cancer development.
METHODS: This study utilized a nested case-control design in two Shanghai cohorts for primary analysis and one US cohort for replication analysis. During a median follow-up of 15.1 years in the Shanghai cohorts, 1938 incident CRC cases were identified and matched to one control each. In the US cohort, 285 incident CRC cases were included with two matched controls per case. Systemic OxS was assessed by urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxo-dG]) and RNA oxidation (7,8-dihydro-8-oxo-guanosine [8-oxo-Guo]) using UPLC-MS/MS assays. Multivariable-adjusted odds ratios (ORs) for CRC risk were calculated.
RESULTS: After adjusting for potential confounders, we observed an inversion association between OxS markers and CRC risk in the Shanghai cohorts, which was independently replicated in the US cohort. Moreover, the inverse association was time-dependent, manifesting only for CRC cases diagnosed within 5 years of enrollment. ORs (95% CI) for CRC at the 10th and 90th percentiles of 8-oxo-dG levels, relative to the median, were 1.87 (1.39 to 2.53) and 0.48 (0.37 to 0.63), respectively, demonstrating an approximate 4-fold difference in risk between the two groups, with P for overall association of < 0.001. A similar pattern was observed for 8-oxo-Guo. No significant association was found for CRC diagnosed beyond 5 years of enrollment.
CONCLUSION: This novel finding of an inverse and time-dependent relationship between systemic OxS and CRC risk, if further confirmed, may provide a new perspective for revisiting redox-based chemoprevention.
CONTEXT: Background: Almost all large randomized controlled trials have failed to validate the hypothesis that neutralizing oxidative stress through antioxidant supplementation can lower cancer risk, which has puzzled the public and researchers for decades.Key Findings: A reduced risk for colorectal cancer (CRC) with increasing systemic oxidative stress, measured by two urinary biomarkers of DNA and RNA oxidation, was observed in two large prospective cohort studies in Shanghai, China, and was replicated in an independent cohort in the United States. This association was time-dependent, with the inverse relationship strengthening as the biomarker assessment neared the time of CRC diagnosis.Relevance: Our study, for the first time, suggests an inverse and time-dependent relationship between systemic oxidative stress and CRC development, which, if further confirmed, may provide a new perspective for revisiting redox-based chemoprevention.

DOI: https://doi.org/10.1101/2025.01.21.25320898
Cell Signal. 2025 Feb 13. pii: S0898-6568(25)00065-8. [Epub ahead of print] 111652

STAT1 inhibition promotes oxidative stress to sustain leukemia stem cell maintenance.

Xue Han, Kexin Wang, Songqi Zhu, Weiwei Ma, Binghuo Wu, Cunte Chen, Wenjian Mo, Xiaowei Chen, Ming Zhou, Yumiao Li, Shilin Xu, Caixia Wang, Ruiqing Zhou, Peng Lei, Shunqing Wang.

  New strategy to prevent relapse and drug resistance in acute myeloid leukemia (AML) is urgently to be solved. The connection between those properties and leukemia stem cells (LSCs) in AML remains poorly understood. In this study, we demonstrate that leukemia cells with high signal transducer and activator of transcription 1 (STAT1) expression preserve quiescent properties, in contrast, leukemia cells with low STAT1 expression possess active and vulnerable apoptotic properties in AML model, highlighting the differential impact of STAT1 expression on cellular behavior in acute myeloid leukemia. STAT1 depletion damages the quiescence of LSCs and prolongs the survive of AML mice. By inhibiting STAT1 in leukemia cells, we observe a significant elevation in reactive oxygen species (ROS) levels, rendering the cells more susceptible to the detrimental effects of oxidative stress. The synergistic administration of Fludarabine, a potent STAT1 inhibitor, with conventional chemotherapy regimens, augments the efficacy of chemotherapy drugs against AML cells and the sensitivity of LSCs to chemotherapy. In a word, STAT1, as a switch, enables leukemia cells convertible in ROS high and low states. Inhibition of STAT1 enables leukemia cells more sensitive to chemotherapy, STAT1 as a new target offers a promising strategy in AML treatment.

Keywords:  Acute myeloid leukemia (AML); Leukemia stem cells (LSCs); Oxidative stress; Signal transducer and activator of transcription 1 (STAT1)

DOI:  https://doi.org/10.1016/j.cellsig.2025.111652
Curr Med Sci. 2025 Feb 20.

Partial Regulation of Ketone Metabolism by Hypoxia in H9C2 Cardiomyocytes.

Li-Zhen Chen, Hong-Qing Chen, Xin-Yuan Zhang, Shuang Ling, Jin-Wen Xu.

   OBJECTIVE: Hypoxia plays a critical role in the pathophysiology of cardiomyopathy, myocardial infarction, and heart failure. Promoting ketone metabolism has been shown to be beneficial for myocardial cells under hypoxic conditions. However, the expression and regulatory mechanisms of key enzymes in the ketone pathway under hypoxic conditions are still unclear. This study aimed to investigate the effects of hypoxia on the expression of key enzymes in the ketone metabolic pathway and the underlying regulatory mechanisms involved.
METHODS: H9C2 myocardial cells were cultured for 6 h in an oxygen-glucose-deprived state, and the expression of various genes was detected by quantitative real-time PCR. ELISA and lactate dehydrogenase (LDH) cytotoxicity assay were used to measure CoAs, itaconic acid, and LDH levels, respectively, and the dependence of gene expression on hypoxia-inducible factor-1 alpha (HIF-1α) was evaluated using the inhibitor LW6.
RESULTS: H9C2 cardiomyocytes exhibited increased ketone body metabolism in response to hypoxia. Hypoxia induced the expression of the ketone body enzymes succinyl-CoA:3-oxoacid CoA transferase (SCOT/OXCT1), 3-hydroxybutyrate dehydrogenase 2 (BDH2), and acyl-CoA: cholesterol acyltransferase 1 (ACAT1) in cardiomyocytes, with a concomitant increase in the level of acyl-CoA and a decrease in the level of succinyl-CoA. The HIF-1α inhibitor LW6 could partially reverse the expression of BDH2 and ACAT1, as well as the levels of succinyl-CoA. Interestingly, however, hypoxia-induced SCOT/OXCT1 expression was not regulated by the HIF-1α inhibitor. In addition, hypoxia promoted the expression of inflammatory factors.
CONCLUSION: These data confirm the critical role of ketone metabolism in myocardial hypoxia and help to elucidate the pathophysiology of cardiomyopathy, myocardial infarction and heart failure.

Keywords:  Cardiomyocyte; Gene expression; Hypoxia; Ketone metabolism; Succinyl-CoA

DOI:  https://doi.org/10.1007/s11596-025-00002-w
Sci Rep. 2025 Feb 18. 15(1): 5849

Myocardial metabolic flexibility following ketone infusion demonstrated by hyperpolarized [2-13C]pyruvate MRS in pigs.

Sabrina Kahina Bech, Esben Søvsø Szocska Hansen, Bent Roni Nielsen, Henrik Wiggers, Mads Bisgaard Bengtsen, Christoffer Laustsen, Jack J Miller.

This study aims to investigate the effects of β-3-hydroxybutyrate (β-3-OHB) infusion on myocardial metabolic flexibility using hyperpolarized [2-13C]pyruvate magnetic resonance spectroscopy (MRS) in the pig heart. We hypothesized that β-3-OHB infusion will cause rapid, quantifiable alterations in tricarboxylic acid (TCA) cycle flux as measured non-invasively by 13C MRS and reflect myocardial work. Five female Danish landrace pigs underwent β-3-OHB infusion during a hyperinsulinemic euglycemic clamp (HEC). Cardiac metabolism and hemodynamics were monitored using hyperpolarized [2-13C]pyruvate MRS and cardiac MRI. β-3-OHB infusion during HEC resulted in significant increases in cardiac output over baseline (from 1.9 to 3.8 L/min, p = 0.0011) and heart rate (from 51 to 85 bpm, p = 0.0004). Metabolic analysis showed a shift towards increased lactate production and decreased levels of acetyl-carnitine and glutamate during β-3-OHB infusion. Following the termination of the infusion, a normalization of these metabolic markers was observed. These results demonstrate the profound metabolic adaptability of the myocardium to ketone body utilization. The infusion of Na-β-3-OHB significantly alters both the hemodynamics and metabolism of the porcine heart. The observed increase in cardiac output and metabolic shifts towards lactate production suggest that ketone bodies could potentially enhance cardiac function by providing an efficient-energy substrate that, if provided, is preferentially used. This study provides new insights into the metabolic flexibility of the heart and hints at the potential therapeutic benefits of ketone interventions in heart failure treatment.

DOI: https://doi.org/10.1038/s41598-025-90215-9
bioRxiv. 2025 Jan 28. pii: 2025.01.26.634557. [Epub ahead of print]

Temporal and spatial composition of the tumor microenvironment predicts response to immune checkpoint inhibition.

Noah F Greenwald, Iris Nederlof, Cameron Sowers, Daisy Yi Ding, Seongyeol Park, Alex Kong, Kathleen E Houlahan, Sricharan Reddy Varra, Manon de Graaf, Veerle Geurts, Candace C Liu, Jolene S Ranek, Leonie Voorwerk, Michiel de Maaker, Adam Kagel, Erin McCaffrey, Aziz Khan, Christine Yiwen Yeh, Christine Camacho Fullaway, Zumana Khair, Yunhao Bai, Hadeesha Piyadasa, Tyler Risom, Alea Delmastro, Felix J Hartmann, Lise Mangiante, Cristina Sotomayor-Vivas, Ton N Schumacher, Zhicheng Ma, Marc Bosse, Marc J van de Vijver, Robert Tibshirani, Hugo M Horlings, Christina Curtis, Marleen Kok, Michael Angelo.

Immune checkpoint inhibition (ICI) has fundamentally changed cancer treatment. However, only a minority of patients with metastatic triple negative breast cancer (TNBC) benefit from ICI, and the determinants of response remain largely unknown. To better understand the factors influencing patient outcome, we assembled a longitudinal cohort with tissue from multiple timepoints, including primary tumor, pre-treatment metastatic tumor, and on-treatment metastatic tumor from 117 patients treated with ICI (nivolumab) in the phase II TONIC trial. We used highly multiplexed imaging to quantify the subcellular localization of 37 proteins in each tumor. To extract meaningful information from the imaging data, we developed SpaceCat, a computational pipeline that quantifies features from imaging data such as cell density, cell diversity, spatial structure, and functional marker expression. We applied SpaceCat to 678 images from 294 tumors, generating more than 800 distinct features per tumor. Spatial features were more predictive of patient outcome, including features like the degree of mixing between cancer and immune cells, the diversity of the neighboring immune cells surrounding cancer cells, and the degree of T cell infiltration at the tumor border. Non-spatial features, including the ratio between T cell subsets and cancer cells and PD-L1 levels on myeloid cells, were also associated with patient outcome. Surprisingly, we did not identify robust predictors of response in the primary tumors. In contrast, the metastatic tumors had numerous features which predicted response. Some of these features, such as the cellular diversity at the tumor border, were shared across timepoints, but many of the features, such as T cell infiltration at the tumor border, were predictive of response at only a single timepoint. We trained multivariate models on all of the features in the dataset, finding that we could accurately predict patient outcome from the pre-treatment metastatic tumors, with improved performance using the on-treatment tumors. We validated our findings in matched bulk RNA-seq data, finding the most informative features from the on-treatment samples. Our study highlights the importance of profiling sequential tumor biopsies to understand the evolution of the tumor microenvironment, elucidating the temporal and spatial dynamics underlying patient responses and underscoring the need for further research on the prognostic role of metastatic tissue and its utility in stratifying patients for ICI.

DOI: https://doi.org/10.1101/2025.01.26.634557
Chemosphere. 2025 Feb 18. pii: S0045-6535(25)00155-9. [Epub ahead of print]374 144213

M8OI toxicity is associated with an inhibition of ubiquinone reduction by complex I in the mitochondrial electron transport chain.

Tarek M Abdelghany, Jessica Bosak, Alistair C Leitch, Alex Charlton, Lanyu Fan, Fahad A Aljehani, Omar H Alkhathami, Shireen A Hedya, Satomi Miwa, Agnieszka K Bronowska, Judy Hirst, Matthew C Wright.

  Methylimidazolium ionic liquids (MILs) are solvents used in an increasing variety of industrial applications. Recent studies identified the 8C MIL (M8OI) contaminating the environment, detected exposure in humans and proposed M8OI to be a potential trigger for the autoimmune liver disease primary biliary cholangitis (PBC). To gain a better understanding of any PBC trigger mechanism(s), the interaction of M8OI with mitochondria has been examined. M8OI inhibited oxygen consumption in intact cells and induced cell death (IC50%-10 μM). Results from permeabilized cells indicated M8OI inhibits the mitochondrial electron transport chain at complex I, not complexes II, III or IV. Accordingly, succinate supported mitochondrial oxygen consumption and reduced cell death in the presence of M8OI. M8OI inhibited NADH oxidation by both mitochondrial membranes and purified complex I with IC50% values of 470 μM and 340 μM respectively. Based on direct determinations of M8OI in non-mitochondrial and mitochondrial compartments, toxic M8OI concentrations were estimated to result in mitochondrial concentrations commensurate with complex I inhibition. Mitochondrial accumulation followed by complex I inhibition is therefore a possible molecular initiating event for M8OI-dependent cell death. NADH oxidation by purified complex I in combination with a flavin-site electron acceptor was not inhibited by M8OI, indicating no interaction of M8OI at the NADH-binding active site. Modelling supported M8OI binding to the ubiquinone-binding site. By inhibiting turnover, M8OI also gave rise to increases in complex-I-linked reactive oxygen species. However, inhibitors of oxidative stress did not affect M8OI-mediated cell death. The metabolic consequences of M8OI-mediated complex I inhibition, not increased reactive oxygen species production, are therefore the likely cause of apoptotic cell death. Understanding the effects on complex I and the pathways activated and leading to cell death may be informative regarding mitochondrial stress, cell death and diseases such as PBC.

Keywords:  AR42J-B13; Apoptosis; C8mim; Ionic solvents; Liver progenitor; Mitochondria

DOI:  https://doi.org/10.1016/j.chemosphere.2025.144213
Nature. 2025 Feb 20.

Snapshots of acyl carrier protein shuttling in human fatty acid synthase.

Kollin Schultz, Pedro Costa-Pinheiro, Lauren Gardner, Laura V Pinheiro, Julio Ramirez-Solis, Sarah M Gardner, Kathryn E Wellen, Ronen Marmorstein.

The mammalian fatty acid synthase (FASN) enzyme is a dynamic multienzyme that belongs to the megasynthase family. In mammals, a single gene encodes six catalytically active domains and a flexibly tethered acyl carrier protein (ACP) domain that shuttles intermediates between active sites for fatty acid biosynthesis1. FASN is an essential enzyme in mammalian development through the role that fatty acids have in membrane formation, energy storage, cell signalling and protein modifications. Thus, FASN is a promising target for treatment of a large variety of diseases including cancer, metabolic dysfunction-associated fatty liver disease, and viral and parasite infections2,3. The multi-faceted mechanism of FASN and the dynamic nature of the protein, in particular of the ACP, have made it challenging to understand at the molecular level. Here we report cryo-electron microscopy structures of human FASN in a multitude of conformational states with NADPH and NADP+ plus acetoacetyl-CoA present, including structures with the ACP stalled at the dehydratase (DH) and enoyl-reductase (ER) domains. We show that FASN activity in vitro and de novo lipogenesis in cells is inhibited by mutations at the ACP-DH and ACP-ER interfaces. Together, these studies provide new molecular insights into the dynamic nature of FASN and the ACP shuttling mechanism, with implications for developing improved FASN-targeted therapeutics.

DOI: https://doi.org/10.1038/s41586-025-08587-x
Chembiochem. 2025 Feb 19. e202400935

Mitochondria-Targeted Temozolomide Probe for Overcoming MGMT-Mediated Resistance in Glioblastoma.

Daniel Szames, Shana Kelley.

  Temozolomide (Tmz) is a DNA methylating agent used for the treatment of glioblastoma multiforme (GBM). Resistance to Tmz in GBM is caused by the DNA direct repair enzyme O6-methylguanine DNA methyltransferase (MGMT), which is expressed in ~50% of GBM tumours. It has yet to be confirmed that MGMT acts within mitochondria to repair mitochondrial DNA (mtDNA), and in this report we discuss the development of a novel mitochondria-targeted temozolomide probe (mtTmz) for evading MGMT-mediated resistance. Through conjugation of Tmz to a mitochondria-penetrating peptide (MPP), exclusive mitochondrial localization was achieved, and the probe retained alkylation activity demonstrated by chemical and DNA-based assays. Absence of nuclear DNA damage was assessed by detecting γH2AX foci. mtTmz demonstrated efficient cell killing capabilities independent of MGMT status in GBM cells as determined by cell viability assays. It was determined using a Proteinase K digestion assay that MGMT does not translocate to mitochondria in response to mtTmz treatment, and RT-qPCR analysis demonstrated that mtTmz does not induce MGMT gene expression compared to Tmz. The results reported highlight both the potential of mitochondrial targeting of Tmz and mitochondria as a therapeutic target in MGMT-expressing GBM.

Keywords:  DNA Damage; Glioblastoma; Peptide; Temozolomide; mitochondria

DOI:  https://doi.org/10.1002/cbic.202400935
Nutrition. 2025 Jan 23. pii: S0899-9007(25)00010-3. [Epub ahead of print]133 112692

Impact of time-restricted feeding on glycemic indices, vascular oxidative stress, and inflammation in an obese prediabetes rat model induced by a high-fat diet and sugar drink.

Siti Qusyasyiah Ahmad Suhaimi, Ahmad Khusairi Azemi, Siti Safiah Mokhtar, Anani Aila Mat Zin, Aida Hanum Ghulam Rasool.

   OBJECTIVE: This study aims to investigate the effects of time-restricted feeding (TRF) on glycaemic indices and aortic tissue oxidative stress and inflammation in an obese prediabetes rat model.
METHODS AND PROCEDURES: Male Sprague-Dawley rats were divided into two normal and four obese groups. Obese prediabetes was induced by feeding a high-fat diet and sucrose water (HFSD) for 10 weeks; normal rats were given a standard diet and plain water. For the next 6 weeks, rats were grouped into the normal group (NR), which continued on the standard diet; the normal group was switched to TRF with the standard diet (NR + TRFSD); the prediabetes group (OR) was continued on HFSD; the prediabetes group was switched to TRF of HFSD (OR + TRFHFSD); the prediabetes group was switched to TRF of the standard diet (OR + TRFSD); and the prediabetes group was switched to the standard diet (OR + SD). Rats were then sacrificed, and aortic tissues were isolated and quantified for oxidative stress markers malondialdehyde, antioxidant enzyme superoxide dismutase, and inflammation markers tumor necrosis factor-α, and interleukin 1. Fasting blood glucose (FBG), body weight, Lee's index, serum insulin level, and resistance (Homeostatic Model Assessment of Insulin Resistance) were also measured.
RESULTS: Mean FBG and body weight in obese groups were higher compared to the normal groups after 10 weeks of HFDSD. Both obese-prediabetes groups that underwent TRF had reduced levels of tumor necrosis factor-α, interleukin 1, body weight, Lee's index, FBG, and insulin resistance. Furthermore, obese prediabetes on TRF with SD also reduced levels of lipid peroxidation (malondialdehyde), insulin levels and increased levels of the antioxidant enzyme (superoxide dismutase).
CONCLUSION: TRF reduced weight, improved glycaemic indices, vascular oxidative stress, and inflammation in obese-prediabetic rats.

Keywords:  Glycemic indices; Inflammation; Intermittent fasting; Oxidative stress; Prediabetes; Time-restricted feeding

DOI:  https://doi.org/10.1016/j.nut.2025.112692
Cell Rep. 2025 Feb 19. pii: S2211-1247(25)00098-1. [Epub ahead of print]44(3): 115327

Targeting both the enzymatic and non-enzymatic functions of DHODH as a therapeutic vulnerability in c-Myc-driven cancer.

Qiang Zhang, Kaisa Cui, Yue Kong, Jing Yu, Zhanhao Luo, Xiaoya Yang, Liang Gong, Yanchun Xie, Jiuxiu Lin, Chen Liu, Zongjin Zhang, Yugeng Liu, Bingxin Liu, Dayi Liang, Wanyi Zeng, Zhen He, Ping Lan.

  c-Myc (Myc)-driven cancers exhibit aggressive phenotypes and therapeutic resistance. Here, integrating CRISPR-Cas9 screening, we identify dihydroorotate dehydrogenase (DHODH) as a promising target in Myc-driven cancer. Mechanistically, DHODH interacts with Myc to stabilize it independently of its enzymatic activity, thereby antagonizing SKP2-mediated polyubiquitination and proteasomal degradation. EN4, a Myc transcriptional activity inhibitor, disrupts DHODH-Myc interaction, promoting Myc degradation via SKP2. Additionally, Myc transcriptionally activates DHODH, enhancing pyrimidine biosynthesis and ferroptosis defense, processes dependent on DHODH enzymatic activity. Clinically, DHODH positively correlates with Myc, activating pyrimidine metabolism and ferroptosis defense in Myc-driven cancers. Hyperactivation of the DHODH-Myc axis is linked to colorectal cancer progression and poor prognosis. Therapeutically, combining EN4 with a DHODH enzymatic inhibitor demonstrates potent antitumor efficacy in Myc-driven colorectal cancer. Overall, our findings elucidate the metabolic and non-metabolic roles of DHODH in Myc-driven cancer, underscoring its dual potential as a therapeutic target addressing both enzymatic and non-enzymatic functions.

Keywords:  CP: Cancer; CP: Metabolism; DHODH; EN4; Myc; c-Myc-driven cancer; metabolic and non-metabolic roles; pyrimidine metabolism

DOI:  https://doi.org/10.1016/j.celrep.2025.115327
Nat Methods. 2025 Feb 20.

Genetically encoded biosensor for fluorescence lifetime imaging of PTEN dynamics in the intact brain.

Tomer Kagan, Matan Gabay, Aasha Meenakshisundaram, Yossi Levi, Sharbel Eid, Nikol Malchenko, Maya Maman, Anat Nitzan, Luca Ravotto, Ronen Zaidel-Bar, Britta Johanna Eickholt, Maayan Gal, Tal Laviv.

The phosphatase and tensin homolog (PTEN) is a vital protein that maintains an inhibitory brake for cellular proliferation and growth. Accordingly, PTEN loss-of-function mutations are associated with a broad spectrum of human pathologies. Despite its importance, there is currently no method to directly monitor PTEN activity with cellular specificity within intact biological systems. Here we describe the development of a FRET-based biosensor using PTEN conformation as a proxy for the PTEN activity state, for two-photon fluorescence lifetime imaging microscopy. We identify a point mutation that allows the monitoring of PTEN activity with minimal interference to endogenous PTEN signaling. We demonstrate imaging of PTEN activity in cell lines, intact Caenorhabditis elegans and in the mouse brain. Finally, we develop a red-shifted sensor variant that allows us to identify cell-type-specific PTEN activity in excitatory and inhibitory cortical cells. In summary, our approach enables dynamic imaging of PTEN activity in vivo with unprecedented spatial and temporal resolution.

DOI: https://doi.org/10.1038/s41592-025-02610-9
Oncogene. 2025 Feb 16.

GDP-mannose 4,6-dehydratase is a key driver of MYCN-amplified neuroblastoma core fucosylation and tumorigenesis.

Beibei Zhu, Michelle G Pitts, Michael D Buoncristiani, Lindsay T Bryant, Oscar Lopez-Nunez, Juan P Gurria, Cameron Shedlock, Roberto Ribas, Shannon Keohane, Jinpeng Liu, Chi Wang, Matthew S Gentry, Nathan R Shelman, Derek B Allison, B Mark Evers, Ramon C Sun, Eric J Rellinger.

MYCN-amplification is a genetic hallmark of ~40% of high-risk neuroblastomas (NBs). Altered glycosylation is a common feature of adult cancer progression, but little is known about how genetic signatures such as MYCN-amplification alter glycosylation profiles. Herein, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) revealed increased core fucosylated glycan abundance within neuroblast-rich regions of human MYCN-amplified NB tumors. GDP-mannose 4,6-dehydratase (GMDS) is responsible for the first-committed and rate-limiting step of de novo GDP-fucose synthesis. High GMDS expression was found to be associated with poor patient survival, advanced stage disease, and MYCN-amplification in human NB tumors. Chromatin immunoprecipitation and promoter reporter assays demonstrated that N-MYC directly binds and activates the GMDS promoter in NB cells. When GMDS was blocked through either genetic or pharmacological mechanisms, NBs were found to be dependent upon de novo GDP-fucose production to sustain cell surface and secreted core fucosylated glycan abundance, as well as adherence and motility. Moreover, genetic knockdown of GMDS inhibited tumor formation and progression in vivo. These critical findings identify de novo GDP-fucose production as a novel metabolic vulnerability that may be exploited in designing new treatment strategies for MYCN-amplified NBs.

DOI: https://doi.org/10.1038/s41388-025-03297-0
Discov Oncol. 2025 Feb 17. 16(1): 194

Analysis of fatty acid metabolism in prostate cancer and discovery of a new programmed cell death-associated luminal cell subpopulation.

Yan Zeng, Zhaolin Jiang.

   INTRODUCTION: This study focuses on the role of fatty acid metabolism in prostate cancer, particularly in oncogenic luminal cells associated with programmed cell death under the influence of metabolic reprogramming.
MATERIALS AND METHODS: Prostate cancer was analyzed using single-cell transcriptomics and spatial transcriptomics data. Fatty acid metabolism levels in the tumor microenvironment were quantified by multiple gene set scoring methods, and data were processed using NMF and deconvolution methods to identify different cell populations and their interactions in the tumor microenvironment.
RESULTS: Luminal cells have significantly increased activity in fatty acid metabolism, which is associated with the aggressiveness and metastatic capability of tumors. Luminal cell subpopulations have been found to play a key role in the development of prostate cancer, especially their close association with programmed cell death.
CONCLUSION: This study deepens the understanding of the role of fatty acid metabolism in prostate cancer, identifies fatty acid metabolism-related luminal cell subtypes, and proposes new therapeutic targets, providing new insights into prostate cancer treatment.

Keywords:  Fatty acid metabolism; Luminal cells; Programmed cell death; Prostate cancer; Therapeutic targets; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-025-01982-w
ACS Sens. 2025 Feb 17.

Genetically Encoded Single-Wavelength Sensor with High Specificity for Imaging ATP in Living Cells.

Lu Xiao, Xuexi Wang, Dujuan Liu, Chuang Yan, Xian-En Zhang, Minghai Chen.

  Adenosine 5'-triphosphate (ATP) plays an essential role in regulating many metabolic activities. Therefore, developing tools to directly measure ATP in real time will help us understand its underlying functions. Here, we report an optimized genetically encoded ATP sensor (OAS1.0) with a high specificity for ATP detection. OAS1.0 can be genetically targeted to specific cell types and subcellular compartments to monitor ATP production and consumption. We also used OAS1.0 to visualize metabolic-activity-dependent changes in ATP in normal and tumor cell lines and ATP consumption during the virus-host interaction process. OAS1.0 also worked well with a Ca2+ sensor to concurrently monitor ATP and Ca2+ dynamics in living cells. Thus, OAS1.0 represents a promising tool for ATP imaging under both physiological and pathophysiological conditions.

Keywords:  ATP sensor; genetically encoded; high specificity; living cells; single wavelength

DOI:  https://doi.org/10.1021/acssensors.4c03389