bims-medica 2025-03-09 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–03–09
twenty-six papers selected by
Brett Chrest, Wake Forest University

Deuterium metabolic imaging phenotypes mouse glioblastoma heterogeneity through glucose turnover kinetics.
Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis.
Successful application of dietary ketogenic metabolic therapy in patients with glioblastoma: a clinical study.
Quantification of the inputs and outputs of serine and glycine metabolism in cancer cells.
Defined media reveals the essential role of lipid scavenging to support cancer cell proliferation.
Clinical Translation of Hyperpolarized 13C Metabolic Probes for Glioma Imaging.
NOX4 Suppresses Ferroptosis Through Regulation of the Pentose Phosphate Pathway in Colorectal Cancer.
De Novo Serine Synthesis is a Metabolic Vulnerability that can be Exploited to Overcome Sunitinib Resistance in Advanced Renal Cell Carcinoma.
Purification of Native Acetyl CoA Carboxylase From Mammalian Cells.
Altered Fibroblast Glutamine Metabolism Is Linked to the Severity of Cardiac Dysfunction in DCMA, a Mitochondrial Cardiomyopathy.
Clonal dynamics and somatic evolution of haematopoiesis in mouse.
Combination of dietary fiber and exercise training improves fat loss in mice, but does not ameliorate MASLD more than exercise alone.
Lipid peroxidation and colorectal cancer risk: a time-varying relationship.
Energy Metabolism Profiling of Human Colorectal Tumours.
State-dependent motion of a genetically encoded fluorescent biosensor.
Traditional Maasai Dietary Practices and Their Inapplicability to Modern Carnivore Diets: A Narrative Review.
Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
G protein-coupled oestrogen receptor regulates branched-chain amino acid metabolism through c-Jun N-terminal kinase.
Alternate-day fasting differentially affects body composition, metabolic and immune response to fasting in male rats exposed to early-life adversity: Modulatory role of cafeteria diet.
Maternal and infant diet play a role in acute leukemia development: An expanded systematic review and meta-analysis.
Metformin ablates high fat diet-induced skeletal muscle hypertrophy and elevation of sarcolemmal GLUT4 when feeding is initiated in young adult male mice.
The reciprocal effects of autophagy and the Warburg effect in pancreatic ductal adenocarcinoma: an in vitro study.
The association of dietary fatty acids intake with overall and cause-specific mortality: a prospective cohort study from 1999-2018 cycles of the NHANES.
Lipids, apolipoproteins, carbohydrates, and risk of hematological malignancies.
Mitochondria-enriched hematopoietic stem cells exhibit elevated self-renewal capabilities, thriving within the context of aged bone marrow.
Impact of celastrol on mitochondrial dynamics and proliferation in glioblastoma.

Elife. 2025 Mar 04. pii: RP100570. [Epub ahead of print]13

Deuterium metabolic imaging phenotypes mouse glioblastoma heterogeneity through glucose turnover kinetics.

Rui Vasco Simoes, Rafael Neto Henriques, Jonas L Olesen, Beatriz M Cardoso, Francisca F Fernandes, Mariana A V Monteiro, Sune N Jespersen, Tânia Carvalho, Noam Shemesh.

  Glioblastomas are aggressive brain tumors with dismal prognosis. One of the main bottlenecks for developing more effective therapies for glioblastoma stems from their histologic and molecular heterogeneity, leading to distinct tumor microenvironments and disease phenotypes. Effectively characterizing these features would improve the clinical management of glioblastoma. Glucose flux rates through glycolysis and mitochondrial oxidation have been recently shown to quantitatively depict glioblastoma proliferation in mouse models (GL261 and CT2A tumors) using dynamic glucose-enhanced (DGE) deuterium spectroscopy. However, the spatial features of tumor microenvironment phenotypes remain hitherto unresolved. Here, we develop a DGE Deuterium Metabolic Imaging (DMI) approach for profiling tumor microenvironments through glucose conversion kinetics. Using a multimodal combination of tumor mouse models, novel strategies for spectroscopic imaging and noise attenuation, and histopathological correlations, we show that tumor lactate turnover mirrors phenotype differences between GL261 and CT2A mouse glioblastoma, whereas recycling of the peritumoral glutamate-glutamine pool is a potential marker of invasion capacity in pooled cohorts, linked to secondary brain lesions. These findings were validated by histopathological characterization of each tumor, including cell density and proliferation, peritumoral invasion and distant migration, and immune cell infiltration. Our study bodes well for precision neuro-oncology, highlighting the importance of mapping glucose flux rates to better understand the metabolic heterogeneity of glioblastoma and its links to disease phenotypes.

Keywords:  cancer biology; deuterium metabolic imaging; glioblastoma; glycolysis; kinetic modeling; mitochondrial metabolism; mouse

DOI:  https://doi.org/10.7554/eLife.100570
bioRxiv. 2025 Feb 19. pii: 2025.02.18.638948. [Epub ahead of print]

Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis.

Madeleine L Hart, Kristian Davidsen, Serwah Danquah, Eric Zheng, David Sokolov, Lucas B Sullivan.

  Impaired availability of the amino acid aspartate can be a metabolic constraint of cell proliferation in diverse biological contexts. However, the kinetics of aspartate depletion, and its ramifications on downstream metabolism and cell proliferation, remain poorly understood. Here, we deploy the aspartate biosensor jAspSnFR3 with live cell imaging to resolve temporal relationships between aspartate and cell proliferation from genetic, pharmacological, and nutritional manipulations. In cells with impaired aspartate acquisition from mitochondrial complex I inhibition or constrained uptake in aspartate auxotrophs, we find that the proliferation defects lag changes in aspartate levels and only manifest once aspartate levels fall below a critical threshold, supporting the functional link between aspartate levels and cell proliferation in these contexts. In another context of aspartate synthesis inhibition, impairing succinate dehydrogenase (SDH), we find a more complex metabolic interaction, with initial aspartate depletion followed by a rebound of aspartate levels over time. We find that this aspartate rebound effect results from SDH inhibition disproportionately impairing pyrimidine synthesis by inhibiting aspartate transcarbamoylase (ATCase) through the dual effect of diminishing aspartate substrate availability while accumulating succinate, which functions as a competitive inhibitor of aspartate utilization. Finally, we uncover that the nucleotide imbalance from SDH inhibition causes replication stress and introduces a vulnerability to ATR kinase inhibition. Altogether, these findings identify a mechanistic role for succinate in modulating nucleotide synthesis and demonstrate how cascading metabolic interactions can unfold to impact cell function.

Keywords:  SDH; aspartate; biosensor; cancer; metabolism; metabolomics; proliferation; pyrimidines

DOI:  https://doi.org/10.1101/2025.02.18.638948
Front Nutr. 2024 ;11 1489812

Successful application of dietary ketogenic metabolic therapy in patients with glioblastoma: a clinical study.

Andreas Kiryttopoulos, Athanasios E Evangeliou, Irene Katsanika, Ioannis Boukovinas, Nikolaos Foroglou, Basilios Zountsas, Angeliki Cheva, Vaios Nikolopoulos, Thomas Zaramboukas, Tomas Duraj, Thomas N Seyfried, Martha Spilioti.

   Introduction: Glioblastoma multiforme (GBM) ranks as one of the most aggressive primary malignant tumor affecting the brain. The persistent challenge of treatment failure and high relapse rates in GBM highlights the need for new treatment approaches. Recent research has pivoted toward exploring alternative therapeutic methods, such as the ketogenic diet, for GBM.
Methods: A total of 18 patients with GBM, 8 women and 10 men, aged between 34 and 75 years participated in a prospective study, examining the impact of ketogenic diet on tumor progression. The pool of patients originated from our hospital during the period from January 2016 until July 2021 and were followed until January 2024. As an assessment criterion, we set an optimistic target for adherence to the ketogenic diet beyond 6 months. We considered the therapeutic combination successful if the survival reached at least 3 years.
Results: Among the 18 patients participating in the study, 6 adhered to the ketogenic diet for more than 6 months. Of these patients, one patient passed away 43 months after diagnosis, achieving a survival of 3 years; another passed away at 36 months, narrowly missing the 3-year survival mark; and one is still alive at 33 months post-diagnosis but has yet to reach the 3-year milestone and is, therefore, not included in the final survival rate calculation. The remaining 3 are also still alive, completing 84,43 and 44 months of life, respectively. Consequently, the survival rate among these patients is 4 out of 6, or 66.7%. Of the 12 patients who did not adhere to the diet, only one reached 36 months of survival, while the rest have died in an average time of 15.7 ± 6.7 months, with a 3-year survival rate of 8.3%. Comparing the survival rates of the two groups, we see that the difference is 58.3% (66.7% versus 8.3%) and is statistically significant with p < 0.05 (0.0114) and X2 = 6.409.
Discussion: The outcomes observed in these patients offer promising insights into the potential benefits of the ketogenic diet on the progression of glioblastoma multiforme when compared to those who did not follow the diet consistently.

Keywords:  brain; diet; glioblastoma; ketogenic; metabolic; multiforme; tumor

DOI:  https://doi.org/10.3389/fnut.2024.1489812
Arch Biochem Biophys. 2025 Mar 01. pii: S0003-9861(25)00080-3. [Epub ahead of print] 110367

Quantification of the inputs and outputs of serine and glycine metabolism in cancer cells.

Yuqi Wang, Hao Wu, Xun Hu.

   BACKGROUND: The significance of serine and glycine metabolism in cancer cells is increasingly acknowledged, yet the quantification of their metabolic flux remains incomplete, impeding a comprehensive understanding. This study aimed to quantify the metabolic flux of serine and glycine in cancer cells, focusing on their inputs and outputs, by means of Combinations of C-13 Isotopes Tracing and mathematical delineation, alongside Isotopically Nonstationary Metabolic Flux Analysis.
RESULTS: In HeLa cells, serine uptake, the serine synthesis pathway (SSP), and other sources (e.g., protein degradation) contribute 71.2%, 24.0%, and 5.7%, respectively, to serine inputs. Conversely, glycine inputs stem from uptake (45.6%), conversion from serine (45.1%), and other sources (9.4%). Serine input flux surpasses glycine by 7.3-fold. Serine predominantly directs a major fraction (94.7%) to phospholipid, sphingolipid, and protein synthesis, with only a minor fraction (5.3%) directing towards one-carbon unit and glycine production. Glycine mainly supports protein and nucleotide synthesis (100%), without conversion back to serine. Serine output rate exceeds glycine output rate by 7.3-fold. Serine deprivation substantially mainly impairs output to synthesis of phospholipid and sphingolipid, crucial for cell growth, while other outputs unaffected. AGS cells exhibit comparable serine and glycine flux to HeLa cells, albeit lacking SSP activity. Serine deprivation in AGS cells halts output flux to phospholipid, sphingolipid, protein synthesis, completely inhibiting cell growth.
CONCLUSIONS: By providing quantitative insights into serine and glycine metabolism, this study delineates the association of serine flux to different metabolic pathway with cancer cell growth and offers potential targets for therapeutic intervention, highlighting the importance of serine flux to pathway for the synthesis of phospholipids and sphingolipids in cancer cells growth.

Keywords:  Serine; cancer cell; glycine; isotope tracing; metabolic rates

DOI:  https://doi.org/10.1016/j.abb.2025.110367
bioRxiv. 2025 Feb 17. pii: 2025.02.12.637975. [Epub ahead of print]

Defined media reveals the essential role of lipid scavenging to support cancer cell proliferation.

Oliver J Newsom, Lucas B Sullivan.

Fetal bovine serum (FBS) is a nearly ubiquitous, yet undefined additive in mammalian cell culture media whose functional contributions to promoting cell proliferation remain poorly understood. Efforts to replace serum supplementation in culture media have been hindered by an incomplete understanding of the environmental requirements fulfilled by FBS in culture. Here, we use a combination of live-cell imaging and liquid chromatography-mass spectrometry to elucidate the role of serum in supporting proliferation. We show that serum provides consumed factors that enable proliferation and demonstrate that the serum metal and lipid components are crucial to sustaining proliferation in culture. Importantly, despite access to a wide range of lipid classes, albumin-bound lipids are the primary species consumed during cancer cell proliferation. Furthermore, we find that combinations of the additive ITS, containing necessary metals, and albumin-associated lipid classes are sufficient to replace FBS in culture media. We show that serum-free media enables sensitive quantification of lipid consumption dynamics during cell proliferation, which indicate that fatty acids (FA) are consumed through a mass-action mechanism, with minimal competition from other lipid classes. Finally, we find that pharmacologic disruption of FA activation and incorporation into the cellular lipidome reduces uptake from the environment and impairs cell proliferation. This work therefore identifies metabolic contributions of serum in cell culture settings and provides a framework for building cell culture systems that sustain cell proliferation without the variable and undefined contributions of FBS.

DOI: https://doi.org/10.1101/2025.02.12.637975
AJNR Am J Neuroradiol. 2025 Mar 05. pii: ajnr.A8726. [Epub ahead of print]

Clinical Translation of Hyperpolarized 13C Metabolic Probes for Glioma Imaging.

Adam W Autry, Yaewon Kim, Duy Dang, Hsin-Yu Chen, James B Slater, Robert A Bok, Duan Xu, Janine M Lupo, Jeremy W Gordon, Peder E Z Larson, Daniel B Vigneron, Yan Li, Susan M Chang.

Hyperpolarized carbon-13 (HP-13C) MRI enables the real-time measurement of dynamic metabolism by utilizing molecular probes whose magnetization has been transiently enhanced via dynamic nuclear polarization of 13C labels. Based on pre-clinical and clinical investigations demonstrating Warburg-related metabolic dysfunction and tricarboxylic acid (TCA)-cycle alterations in gliomas, HP13C techniques appear very promising for overcoming conventional challenges to evaluating tumor burden and extent, early therapeutic response and progression among patients non-invasively. This article surveys the multi-faceted translational development of HP-13C MRI in the context of glioma imaging, while emphasizing innovation concerning the pharmacy production of HP probes - [1-13C]/[2-13C]-pyruvate and [1-13C,5-12C]-alpha-ketoglutarate - that serve as non-radioactive metabolic contrast agents. Borrowing from practical experience, we present specific probe indications for isocitrate dehydrogenase (IDH)-wildtype glioblastomas and IDH-mutant gliomas together with example data to show the targeted, pathway-dependent function of these agents and their utility. Additional information pertaining to HP-13C hardware, acquisition and post-processing techniques provides an overview of the imaging methodology as it is currently performed at a leading institution. Considering the developing markers for progressive disease in glioblastomas and rapidly advancing capability, this unique imaging technology appears poised for translational impact following further evaluation.ABBREVIATIONS: 2-HG = D-2-hydroxyglutarate; α-KG = alpha-ketoglutarate; CSI = chemical shift imaging; d-DNP = dissolution-dynamic nuclear polarization; EPI = echo-planar imaging; EPSI = echo-planar spectroscopic imaging; IDHm = isocitrate dehydrogenasemutant; IR-SPGR = inversion recovery-prepared fast spoiled gradient-recalled (imaging); LrGGs = lower-grade gliomas; NMR = nuclear magnetic resonance; OGC = oxoglutarate carrier; PHIP = parahydrogen-induced polarization; SNR = signal-to-noise ratio; TCA cycle = tricarboxylic acid cycle; WHO = World Health Organization.

DOI: https://doi.org/10.3174/ajnr.A8726
Curr Med Sci. 2025 Mar 03.

NOX4 Suppresses Ferroptosis Through Regulation of the Pentose Phosphate Pathway in Colorectal Cancer.

Jing Zhu, Chao Jiang, Fan Wang, Ming-Yue Tao, Hai-Xiao Wang, Yuan Sun, Hong-Xia Hui.

   OBJECTIVE: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are known as major sources of reactive oxygen species (ROS), yet their role in regulating cellular antioxidative metabolism and ferroptosis is unclear. This study assessed the expression and clinical relevance of NOXs across pan-cancer and investigated the role of NOX4 in colorectal cancer progression METHODS: We analyzed transcriptomic and survival data from The Cancer Genome Atlas (TCGA) for NOXs across 22 types of solid tumors. A CRISPR library targeting NOXs was developed for potential therapeutic target screening in colorectal cancer cells (CRCs). Techniques such as CRISPR-knockout cell lines, 1,2-13C-glucose tracing, PI staining, BrdU assays, and coimmunoprecipitation were employed to elucidate the function of NOX4 in CRCs.
RESULTS: NOX4 emerged as a key therapeutic target for colorectal cancer from TCGA data. CRISPR screening highlighted its essential role in CRC survival, with functional experiments confirming that NOX4 upregulation promotes cell survival and proliferation. The interaction of NOX4 with glucose‑6‑phosphate dehydrogenase (G6PD) was found to enhance the pentose phosphate pathway (PPP), facilitating ROS clearance and protecting CRCs against ferroptosis.
CONCLUSIONS: This study identified NOX4 as a novel ferroptosis suppressor and a therapeutic target for the treatment of colorectal cancer. The findings suggest that a coupling between NADPH oxidase enzyme NOX4 and the PPP regulates ferroptosis and reveal an accompanying metabolic vulnerability for therapeutic targeting in colorectal cancer.

Keywords:  Colorectal cancer; Ferroptosis; Oxidative stress; Pentose phosphate pathway

DOI:  https://doi.org/10.1007/s11596-025-00013-7
Cancer Res. 2025 Mar 03.

De Novo Serine Synthesis is a Metabolic Vulnerability that can be Exploited to Overcome Sunitinib Resistance in Advanced Renal Cell Carcinoma.

Manon Teisseire, Umakant Sahu, Julien Parola, Meng-Chen Tsai, Valérie Vial, Jérôme Durivault, Renaud Grépin, Yann Cormerais, Clément Molina, Arthur Gouraud, Gilles Pagès, Issam Ben-Sahra, Sandy Giuliano.

Sunitinib is an oral tyrosine kinase inhibitor used in treating advanced renal cell carcinoma (RCC) that exhibits significant efficacy but faces resistance in 30% of patients. Identifying the molecular mechanisms underlying resistance could enable the development of strategies to enhance sunitinib sensitivity. Here, we showed that sunitinib induces a metabolic shift leading to increased serine synthesis in RCC cells. Activation of the GCN2-ATF4 stress response pathway was identified as the mechanistic link between sunitinib treatment and elevated serine production. The increased serine biosynthesis supported nucleotide synthesis and sustained cell proliferation, migration, and invasion following sunitinib treatment. Inhibiting key enzymes in the serine synthesis pathway, such as PHGDH and PSAT1, enhanced the sensitivity of resistant cells to sunitinib. Beyond RCC, similar activation of serine synthesis following sunitinib treatment occurred in a variety of other cancer types, suggesting a shared adaptive response to sunitinib therapy. Together, this study identifies the de novo serine synthesis pathway as a potential target to overcome sunitinib resistance, offering insights into therapeutic strategies applicable across diverse cancer contexts.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1393
Bio Protoc. 2025 Feb 20. 15(4): e5221

Purification of Native Acetyl CoA Carboxylase From Mammalian Cells.

Yaxue Sun, Jiachen Li, Lianmei Zhao, Hongtao Zhu.

  Fatty acid (FA) biosynthesis is a crucial cellular process that converts nutrients into metabolic intermediates necessary for membrane biosynthesis, energy storage, and the production of signaling molecules. Acetyl-CoA carboxylase (ACACA) plays a pivotal catalytic role in both fatty acid synthesis and oxidation. This cytosolic enzyme catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, which represents the first and rate-limiting step in de novo fatty acid biosynthesis. In this study, we developed a rapid and effective purification scheme for separating human ACACA without any exogenous affinity tags, providing researchers with a novel method to obtain human ACACA in its native form. Key features • Detailed protocol for the purification of native ACACA. • ACACA is biotinylated in mammalian cells. Graphical overview.

Keywords:  ACACA; Biotinylated; Endogenous; Fatty acids (FAs); Tumors

DOI:  https://doi.org/10.21769/BioProtoc.5221
J Inherit Metab Dis. 2025 Mar;48(2): e70018

Altered Fibroblast Glutamine Metabolism Is Linked to the Severity of Cardiac Dysfunction in DCMA, a Mitochondrial Cardiomyopathy.

Melissa A King, Katherine C Heger, Marija Drikic, Ayush Mandwal, Aneal Khan, David S Sinasac, Keir Pittman, Edward L Huttlin, Steven C Greenway, Ian A Lewis.

  The dilated cardiomyopathy with ataxia (DCMA) syndrome is a rare mitochondrial disorder caused by mutations in the poorly understood DNAJC19 gene. Cardiac involvement in DCMA ranges from mild conduction abnormalities to early severe myocardial dysfunction. Although evidence suggests that DCMA is linked to abnormalities in mitochondrial function, the molecular underpinnings of this condition are unclear, and there is no way to predict which patients will develop life-threatening disease. To address this, we developed a metabolic flux assay for assessing the metabolic function of mitochondria in fibroblasts derived from DCMA patients. Using this approach, we discovered that DCMA fibroblasts have elevated glutamine uptake, increased glutamate and ammonium secretion, and elevated lactate production. Moreover, we observed that these cellular perturbations were closely correlated with cardiac dysfunction in a blinded cohort of patient cell lines. These findings suggest that glutamine catabolism is abnormal in DCMA and may serve as a predictor of clinical progression.

Keywords:  3‐methylglutaconic aciduria; DCMA; dilated cardiomyopathy; glutamine; metabolism

DOI:  https://doi.org/10.1002/jimd.70018
Nature. 2025 Mar 05.

Clonal dynamics and somatic evolution of haematopoiesis in mouse.

Chiraag D Kapadia, Nicholas Williams, Kevin J Dawson, Caroline Watson, Matthew J Yousefzadeh, Duy Le, Kudzai Nyamondo, Sreeya Kodavali, Alex Cagan, Sarah Waldvogel, Xiaoyan Zhang, Josephine De La Fuente, Daniel Leongamornlert, Emily Mitchell, Marcus A Florez, Krzysztof Sosnowski, Rogelio Aguilar, Alejandra Martell, Anna Guzman, David Harrison, Laura J Niedernhofer, Katherine Y King, Peter J Campbell, Jamie Blundell, Margaret A Goodell, Jyoti Nangalia.

Haematopoietic stem cells maintain blood production throughout life1. Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of the haematopoietic stem cell pool during murine ageing. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse stem cells and progenitors accrue approximately 45 somatic mutations per year, a rate only approximately threefold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns show that stem and multipotent progenitor cell pools are established during embryogenesis, after which they independently self-renew in parallel over life, evenly contributing to differentiated progenitors and peripheral blood. The stem cell pool grows steadily over the mouse lifespan to about 70,000 cells, self-renewing about every 6 weeks. Aged mice did not display the profound loss of clonal diversity characteristic of human haematopoietic ageing. However, targeted sequencing showed small, expanded clones in the context of murine ageing, which were larger and more numerous following haematological perturbations, exhibiting a selection landscape similar to humans. Our data illustrate both conserved features of population dynamics of blood and distinct patterns of age-associated somatic evolution in the short-lived mouse.

DOI: https://doi.org/10.1038/s41586-025-08625-8
Am J Physiol Gastrointest Liver Physiol. 2025 Mar 04.

Combination of dietary fiber and exercise training improves fat loss in mice, but does not ameliorate MASLD more than exercise alone.

Artemiy Kovynev, Mikołaj M Charchuta, Amina Begtašević, Quinten R Ducarmon, Patrick C N Rensen, Milena Schönke.

  Background: Lifestyle interventions, such as diet and exercise, are currently the main therapies against metabolic dysfunction-associated steatotic liver disease (MASLD). However, not much is known about the combined impact of fiber and exercise on the modulation of gut-liver axis and MASLD amelioration. Here, we studied the impact of the combination of exercise training and a fiber-rich diet on the amelioration of MASLD. Methods: Male APOE*3-Leiden.CETP mice were fed a high-fat high-cholesterol diet with or without the addition of fiber (10% inulin) and exercise trained on a treadmill, or remained sedentary. Results: Exercise training and fiber supplementation reduced fat mass gain and lowered plasma glucose levels. Only the combination treatment, however, induced fat loss, and decreased plasma triglyceride and cholesterol levels compared to sedentary control mice. Exercise training with and without the addition of fiber had a similar ameliorating effect on the MASLD score. Only exercise without fiber decreased the hepatic expression of inflammatory markers. Fiber diet was mainly responsible for remodeling the gut microbial composition, with an increase in the relative abundance of the short-chain fatty acid (SCFA)-producing genera Anaerostipes and Muribaculaceae, while, surprisingly, exercise training alone and with fiber resulted in the highest increase of SCFA production. Conclusion: Overall, the combination of exercise training and dietary fiber decreases fat mass and improves glucose and lipid homeostasis, but does not have an additional synergistic positive effect on liver health compared to exercise training alone.

Keywords:  MASLD; dietary fiber; exercise; gut microbiota; mouse model

DOI:  https://doi.org/10.1152/ajpgi.00317.2024
medRxiv. 2025 Feb 20. pii: 2025.02.16.25322362. [Epub ahead of print]

Lipid peroxidation and colorectal cancer risk: a time-varying relationship.

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

Importance: We recently observed an inverse and time-dependent association between systemic oxidative stress (OxS), measured by urinary biomarkers of nucleic acid oxidation, and colorectal cancer (CRC) risk. Further investigations into other types of OxS markers are warranted.
Objective: To extend the investigation into systemic lipid peroxidation and CRC risk.
Design Setting and Participants: Utilizing a nested case-control design, this study's primary analysis was performed in two large prospective cohorts in Shanghai, China, and replicated in an independent cohort in the US.
Exposures: Systemic lipid peroxidation was assessed by urinary F 2 -isoprostanes (F 2 -IsoPs) using UPLC-MS/MS assays.
Main Outcomes and Measures: During 15.1-year follow-up in the Shanghai cohorts, 1938 incident CRC cases were identified and matched to one control each through incidence-density sampling. In the US cohort, 285 incident CRC cases were included, each matched to two controls. Odds ratios (ORs) for CRC were calculated using multivariable conditional logistic regression models.
Results: Elevated levels of urinary 5-F 2t -IsoP (5-iPF 2α -VI), a major isomer of F 2 -IsoPs induced solely by free radicals, were associated with reduced risk of CRC in the Shanghai cohorts. This finding was replicated in the US cohort. Moreover, this inverse association was time-dependent, manifesting only in the later years of cancer development. Multivariable-adjusted ORs (95% CI) for CRC diagnosed within 5 years of enrollment at the 10th and 90th percentiles of 5-F 2t -IsoP levels, relative to the median, were 1.57 (1.26-1.96) and 0.61 (0.42-0.89), respectively, indicating a 2.2-fold difference in risk between the two groups. A stronger association was observed when using the composite index of DNA, RNA and lipid OxS markers, showing a 3.9-fold difference in risk between the two groups. No significant association was found for CRC diagnosed beyond 5 years of enrollment.
Conclusions: This study provides new evidence that systemic OxS is inversely and time-dependently associated with CRC risk in humans.
Key Points: Question: Is the time-dependent relationship between oxidative stress and tumorigenesis observed at the cellular level in experimental models also present at the systemic level in a population-based setting?Findings: Elevated systemic lipid peroxidation, measured by urinary F 2 -isoprostanes, was associated with a reduced risk of colorectal cancer (CRC) in two large prospective cohort studies in Shanghai, China, which was replicated in an independent cohort in the United States. This association varied over time, showing a stronger effect as cancer advanced. Meaning: This study provides new evidence that systemic oxidative stress is inversely and time-dependently associated with CRC risk in humans.

DOI: https://doi.org/10.1101/2025.02.16.25322362
J Cell Mol Med. 2025 Mar;29(5): e70462

Energy Metabolism Profiling of Human Colorectal Tumours.

Leenu Reinsalu, Sten Miller, Giuseppe Leonardo Auditano, Marju Puurand, Rafael Moreno-Sanchez, Emma Saavedra, Vahur Valvere, Tuuli Käämbre.

  Colorectal cancer (CRC) is a significant global health burden, and its early detection is crucial. Novel diagnostic and prognostic methods are required for improving patient treatment, survival and quality of life. One promising approach is the analysis and understanding of the metabolic reprogramming undergone by cancer cells. Here, by analysing the changes in transcript and protein contents, activities, pathway flux and energy metabolite ratios in post-operative CRC tumours, in comparison to adjacent healthy tissue, the energy metabolism was characterised at the molecular and functional levels. Greater expression of glucose transporter 1 and lactate dehydrogenase A (LDH), together with increased protein content and activity of LDH in tumours, suggested a higher glycolytic capability. Hexokinase transcripts, protein and activity were similar, whereas monocarboxylate transport transcripts and protein contents were lower in tumours. The creatine kinase transcripts and the adenylate kinase protein contents were lower in tumours, suggesting a functional decrease in the CRC energy transfer pathway. Notwithstanding this, oxidative phosphorylation was fully functional and exhibited higher catalytic efficiency (Vmax/KmADP) in tumours, whereas the cellular energy charge was slightly lower in tumours. Remarkably, higher OxPhos catalytic efficiency correlated with advancing CRC clinical stage. The data revealed that CRC tumours exhibit a hybrid energy metabolism phenotype where both glycolysis and oxidative phosphorylation are highly active.

Keywords:  colorectal cancer; energy metabolism; glycolysis; oxidative phosphorylation

DOI:  https://doi.org/10.1111/jcmm.70462
Proc Natl Acad Sci U S A. 2025 Mar 11. 122(10): e2426324122

State-dependent motion of a genetically encoded fluorescent biosensor.

Paul C Rosen, Samantha M Horwitz, Daniel J Brooks, Erica Kim, Joseph A Ambarian, Lidia Waidmann, Katherine M Davis, Gary Yellen.

  Genetically encoded biosensors can measure biochemical properties such as small-molecule concentrations with single-cell resolution, even in vivo. Despite their utility, these sensors are "black boxes": Very little is known about the structures of their low- and high-fluorescence states or what features are required to transition between them. We used LiLac, a lactate biosensor with a quantitative fluorescence-lifetime readout, as a model system to address these questions. X-ray crystal structures and engineered high-affinity metal bridges demonstrate that LiLac exhibits a large interdomain twist motion that pulls the fluorescent protein away from a "sealed," high-lifetime state in the absence of lactate to a "cracked," low-lifetime state in its presence. Understanding the structures and dynamics of LiLac will help to think about and engineer other fluorescent biosensors.

Keywords:  genetically encoded fluorescent biosensor; metabolite biosensor; protein conformational change

DOI:  https://doi.org/10.1073/pnas.2426324122
Cureus. 2025 Feb;17(2): e78448

Traditional Maasai Dietary Practices and Their Inapplicability to Modern Carnivore Diets: A Narrative Review.

David M Goldman, Thomas J Waterfall, Matthew Nagra.

  The traditional dietary practices of the Maasai people frequently are cited to support meat-based diets in industrialized populations, owing to the historically low prevalence of cardiovascular disease among this nomadic pastoralist group. However, such comparisons typically neglect the multifaceted interplay of genetic, environmental, and lifestyle factors that underpin Maasai health outcomes. This narrative review critically examines the socio-ecological context of the Maasai, highlighting their unique genetic adaptations for cholesterol metabolism, high physical activity levels, intermittent fasting, calorie restriction, and high-altitude living. It also addresses the confounding effects of infectious diseases and a reduced life expectancy, which shape their cardiovascular risk profile. Significant differences in the dietary composition and context exist between the traditional Maasai diet and modern meat-based dietary patterns, rendering generalizations problematic. This review emphasizes the importance of population-specific factors and underscores the limitations of extrapolating health benefits attributed to the traditional Maasai diet to other populations who do not share these factors.

Keywords:  carnivore diet; diet and cardiovascular health; dietary generalizability; maasai diet; meat-based diet; pastoralist nutrition

DOI:  https://doi.org/10.7759/cureus.78448
Nature. 2025 Mar 05.

Structure of mitochondrial pyruvate carrier and its inhibition mechanism.

Zheng He, Jianxiu Zhang, Yan Xu, Eve J Fine, Carl-Mikael Suomivuori, Ron O Dror, Liang Feng.

The mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate-a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation-into the mitochondrial matrix1-5. It thus serves as a pivotal metabolic gatekeeper and has fundamental roles in cellular metabolism. Moreover, MPC is a key target for drugs aimed at managing diabetes, non-alcoholic steatohepatitis and neurodegenerative diseases4-6. However, despite MPC's critical roles in both physiology and medicine, the molecular mechanisms underlying its transport function and how it is inhibited by drugs have remained largely unclear. Here our structural findings on human MPC define the architecture of this vital transporter, delineate its substrate-binding site and translocation pathway, and reveal its major conformational states. Furthermore, we explain the binding and inhibition mechanisms of MPC inhibitors. Our findings provide the molecular basis for understanding MPC's function and pave the way for the development of more-effective therapeutic reagents that target MPC.

DOI: https://doi.org/10.1038/s41586-025-08667-y
FEBS Lett. 2025 Mar 06.

G protein-coupled oestrogen receptor regulates branched-chain amino acid metabolism through c-Jun N-terminal kinase.

Anshu Gupta, Prasad Govind Shinde, Sachin Jorvekar, Akash Suresh Humane, Mythri Chandrasekaran, Roshan M Borkar, Sudhagar Selvaraju.

  Branched-chain amino acids (BCAA) are essential requirements for overall protein turnover, signalling and energy balance, and dysregulation of their metabolic pathway has been associated with many pathophysiological events. Despite the importance of BCAA in human health, our understanding of their metabolic regulation is limited. Here, we present evidence that G protein-coupled oestrogen receptor (GPER) activation inhibits the key BCAA metabolic regulatory enzyme branched-chain α-keto acid dehydrogenase complex (BCKDH) by phosphorylating S293. Inhibition of BCKDH results in leucine, isoleucine and valine accumulation in cells. Interestingly, GPER did not alter the levels of the kinase BCKDK and the phosphatase PPM1K, which regulate BCKDH activity, but activated MAPK signalling. Using gene silencing, we identified that JNK intercedes GPER-mediated BCKDH inhibition. Together, our results demonstrate that GPER inhibits BCAA metabolism through JNK signalling.

Keywords:  G protein‐coupled oestrogen receptor; branched‐chain amino acids; branched‐chain α‐keto acid dehydrogenase complex; branched‐chain α‐keto acid dehydrogenase kinase; c‐Jun N‐terminal kinase

DOI:  https://doi.org/10.1002/1873-3468.70030
PLoS One. 2025 ;20(3): e0313103

Alternate-day fasting differentially affects body composition, metabolic and immune response to fasting in male rats exposed to early-life adversity: Modulatory role of cafeteria diet.

Sara C Sagae, Edson D R Paz, Bárbara Zanardini, Ana Claudia Amaral, Gabriela A Bronczek, Patrícia Koehler-Santos, Jarbas R de Oliveira, Celso R Franci, Márcio V F Donadio, Parker J Holman, Charlis Raineki.

The increased risk for obesity and metabolic disorders following early-life adversity is aggravated by poor diet (e.g., cafeteria diet). Alternate-day fasting (ADF) is a dietary regimen shown to improve immune and metabolic dysfunction related to obesity. Here, we evaluate if ADF can ameliorate the negative effects of early-life adversity and/or cafeteria diet on biological, immune and metabolic parameters. At weaning, animals reared under normal or adverse conditions (i.e., low bedding) were fed either standard chow or cafeteria diets ad libitum or subjected to an ADF regimen. In adulthood, we measured 24-hour fasted cholesterol, triglycerides, cytokines, oxidative stress markers, and body composition parameters including perigonadal, retroperitoneal, and brown fat pad weight. Animals exposed to early-life adversity respond differently to cafeteria diet and ADF. Adverse reared animals fed chow diet in the ADF regimen showed the largest reduction in body weight and perigonadal and retroperitoneal fat pad weight, the smallest increase in corticosterone levels, and the largest increase in TNF-α levels. However, the differential effects of the ADF regimen on body, perigonadal and retroperitoneal fat weight observed in adversely reared animals fed chow diet compared to controls were not present if the adversely reared animals were fed cafeteria diet in the ADF regimen. Furthermore, adversely reared animals fed cafeteria diet in the ADF regimen showed high IL-1β and IL-6 levels. Together, the data suggest that the altered vulnerability to metabolic and immune dysfunction following early-life adversity is not just due to the type of diet but also how the diet is consumed.

DOI: https://doi.org/10.1371/journal.pone.0313103
Clin Nutr ESPEN. 2025 Feb 27. pii: S2405-4577(25)00086-5. [Epub ahead of print]66 515-522

Maternal and infant diet play a role in acute leukemia development: An expanded systematic review and meta-analysis.

M Karen Flores-García, Gisela Flores-Collado, Ángel Mérida-Ortega, Rodrigo Ugalde-Resano, Alejandra González-Rocha, Edgar Denova-Gutiérrez, Paloma Muñoz-Aguirre, Marta Zapata-Tarrés, Lizbeth López-Carrillo.

   BACKGROUND: The most common subtypes of acute leukemia (AL) are acute lymphoid leukemia (ALL), and acute myeloid leukemia (AML). Among those less than 15 years old, ALL is the most common subtype. It has recently been proposed that diet may play an important role in the development of AL. This review expands on the existing systematic reviews and meta-analyses published on infant and maternal diet in relation to AL.
METHODS: An electronic search was carried out in four databases (Pubmed/Medline Lilacs, Scopus and Web of Science), through April 2022. Observational epidemiological studies that reported the association between AL (ALL and/or AML) and the food consumed by children (<18 years), their mother or both were included. Fixed effects models were used for meta-analysis and heterogeneity between studies was assessed using the Q statistic test and I2 estimation. The risk of bias was assessed using the Newcastle-Ottawa scale.
RESULTS: A total of 15 studies were included (1 cohort and 14 case-control), of which 9 exclusively evaluated the maternal diet, 4 child diet, and 2 that evaluated both. Our results showed that children's consumption of processed meat was positively associated with AL (OR = 1.72; 95 % CI 1.08, 2.72), whereas the consumption of vegetables was found to be inversely associated with AL (OR = 0.61; 95 % CI % 0.39, 0.92). Furthermore, maternal fruit consumption was inversely associated with ALL (OR = 0.71; 95 % CI 0.59-0.83), while coffee consumption was positively associated with AL (OR = 1.20; 95 % CI 1.00, 1.44) and ALL (OR = 1.31; 95 % CI: 1.10, 1.56).
CONCLUSIONS: Our results support that maternal and early infant diet play a role in the development of AL.

Keywords:  Child diet; Childhood leukemia; Maternal diet; Review

DOI:  https://doi.org/10.1016/j.clnesp.2025.02.024
Connect Tissue Res. 2025 Mar 07. 1-15

Metformin ablates high fat diet-induced skeletal muscle hypertrophy and elevation of sarcolemmal GLUT4 when feeding is initiated in young adult male mice.

John M Lawler, Khaled Y Kamal, Rachel E Botchlett, Shih Lung Woo, Honggui Li, Jeff M Hord, James D Fluckey, Chaodong Wu.

  A high-fat diet (HFD) and metabolic disease can impair insulin signaling in skeletal muscle, including a reduction in IRS-1 and GLUT-4 at the cell membrane. Other sarcolemmal proteins (e.g. caveolin-3, nNOS) within the dystrophin-glycoprotein complex (DGC) are partially lost with Type II diabetes. Thus, we hypothesized that a HFD would cause a significant loss of sarcolemmal DGC proteins and GLUT4, and the anti-diabetic drug metformin would mitigate the disruption of the DGC and preserve sarcolemmal GLUT4 on the soleus muscle. Eight-week-old mice were fed a high-fat diet for 12 weeks. After 8 weeks, one-half of the HFD mice received metformin for the remaining 4 weeks. HFD caused a marked increase in soleus muscle mass and fiber cross-sectional area and elevated sarcolemmal GLUT4, even though systemic insulin resistance was greater. HFD-induced muscle hypertrophy and elevated membrane GLUT4 were unexpectedly attenuated by metformin. In addition, IRS-1 positive staining was not reduced by HFD but rather enhanced in the metformin mice fed a high-fat diet. Sarcolemmal staining of dystrophin and caveolin-3 was reduced by HFD but not in the metformin group, while nNOS intensity was unaffected by HFD and metformin. These findings suggest that skeletal muscles in young adult mice can compensate for a high-fat diet and insulin resistance, with a minor disruption of the DGC, by maintaining cell membrane nNOS and IRS-1 and elevating GLUT4. We postulate that a window of compensatory GLUT4 and nNOS signaling allows calorically dense food to enhance skeletal muscle fiber size when introduced in adolescence.

Keywords:  GLUT4; High‑fat diet; insulin resistance; metformin; nNOS

DOI:  https://doi.org/10.1080/03008207.2025.2471853
Med Oncol. 2025 Feb 28. 42(4): 86

The reciprocal effects of autophagy and the Warburg effect in pancreatic ductal adenocarcinoma: an in vitro study.

Bita Azizzadeh, Maryam Majidinia, Ali Gheysarzadeh.

  Autophagy and the Warburg effect are two common pathways in pancreatic ductal adenocarcinoma (PDAC). To date, the reciprocal effects of these pathways have not yet been elucidated. Therefore, this study was designed to investigate the relationship between these factors in vitro and may provide therapeutic targets in the future. The Mia-Paca-2 and AsPc-1 cell lines were cultured under normal conditions. To achieve autophagy, starvation was induced by Hank's balanced salt solution (HBSS), whereas autophagy was inhibited by 3-methyladenine (3-MA). The Warburg effect is mimicked by lactic acid, and the Warburg effect is inhibited by oxamate, the main inhibitor of lactate dehydrogenase. Cell viability was checked through the MTT assay method. Autophagy was checked via evaluation of Beclin-1 via western blotting. The amount of lactic acid was also measured with a lactate dehydrogenase (LDH) assay kit. The cells were incubated with different concentrations of 3-MA, lactic acid and oxamate. The viability of AsPc-1 cells decreased, and the IC50 values were 1195 µM, 23.06 mM and 8.617 mM for 3-MA, lactic acid and oxamate, respectively. Similarly, the IC50 values of Mia-Paca-2 were 873.9 µM, 35.9 mM and 26.74 mM for 3-MA, lactic acid and oxamate, respectively. Our data revealed that starvation increased the expression of the autophagy-related protein Beclin-1 (P value < 0.05); however, 3-MA significantly reduced its expression (P value < 0.05). In addition, lactic acid alone did not affect the expression level of Beclin-1 (P value > 0.05), but oxamate treatment increased its expression (P value < 0.05). We also showed that starvation reduced lactic acid levels, but an autophagy inhibitor, 3MA, significantly increased lactic acid production (P value < 0.05). Our findings showed that lactic acid alone has no significant effect on autophagy and that oxamate induces autophagy, possibly because of caloric restriction. On the other hand, autophagy inhibits lactic acid production, whereas the inhibition of autophagy leads to increased lactic acid production.

Keywords:  Autophagy; Lactic acid; Pancreatic ductal adenocarcinoma (PDAC); Warburg effect

DOI:  https://doi.org/10.1007/s12032-025-02631-6
Front Nutr. 2025 ;12 1468513

The association of dietary fatty acids intake with overall and cause-specific mortality: a prospective cohort study from 1999-2018 cycles of the NHANES.

Zhaoxiang Zhang, Lei Ding, Yali Liang, Hu Yang, Yu Zhu.

   Background: Existing studies have evaluated the association of dietary fatty acids with mortality. However, the findings remained contentious. Our aimed to investigate the association of total dietary fat and each type of fatty acids with overall and cause-specific mortality.
Methods: We conducted a population-based prospective cohort study derived from the U.S. NHANES from 1999 to 2018. Baseline dietary information was assessed utilizing two 24-h dietary recalls. The death status was followed up to December 31, 2019. Hazard ratio (HR) was calculated by Cox regression and competing risk model. The effects of isocaloric replacement saturated fatty acids (SFAs) with monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) were estimated using the leave-one-out method.
Results: A total of 49,884 U.S. adults were included. 7,347 deaths, including 2,288 and 1,652 deaths from cardio-cerebrovascular disease (CCVD) and cancer, arose during 494,277 person-years. The intake of SFAs was positively associated with an increased risk of overall mortality, with extreme-quintile HR of 1.10 (95% CI: 1.02-1.19, Ptrend  = 0.013); whereas an inverse association of PUFAs intake with overall mortality was observed, with extreme-quintile HR of 0.87 (95% CI: 0.81-0.94, Ptrend  = 0.001). Greater intake of PUFAs was associated with a lower risk of CCVD-and cancer-specific mortality at borderline statistical significance. The isocaloric substitutions of 5% energy from MUFAs and PUFAs for SFAs was associated with 13 and 12% lower risk of overall mortality.
Conclusion: Greater intake of SFAs was positively associated with mortality, while greater intake of PUFAs was negatively associated with mortality. Reducing SFA by increasing MUFAs and PUFAs was an attractive strategy to lower mortality.

Keywords:  monounsaturated fatty acids; mortality; polyunsaturated fatty acids; saturated fatty acids; substitution effect

DOI:  https://doi.org/10.3389/fnut.2025.1468513
Eur J Epidemiol. 2025 Mar 04.

Lipids, apolipoproteins, carbohydrates, and risk of hematological malignancies.

Qianwei Liu, Dang Wei, Niklas Hammar, Yanping Yang, Maria Feychting, Zhe Zhang, Göran Walldius, Karin E Smedby, Fang Fang.

  Previous studies have investigated the role of metabolic factors in risk of hematological malignancies with contradicting findings. Existing studies are generally limited by potential concern of reverse causality and confounding by inflammation. Therefore, we aimed to investigate the associations of glucose, lipid, and apolipoprotein biomarkers with the risk of hematological malignancy. We performed a study of over 560,000 individuals of the Swedish AMORIS cohort, with measurements of biomarkers for carbohydrate, lipid, and apolipoprotein metabolism during 1985-1996 and follow-up until 2020. We conducted a prospective cohort study and used Cox models to investigate the association of nine different metabolic biomarkers (glucose, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), LDL-C/HDL-C, triglyceride (TG), apolipoprotein B (ApoB), apolipoprotein A-I (ApoA I), and ApoB/ApoA-I) with risk of hematological malignancy, after excluding the first five years of follow-up and adjustment for inflammatory biomarkers. We observed a decreased risk of hematological malignancy associated with one SD increase of TC (HR 0.93; 95% CI 0.91-0.96), LDL-C (HR 0.94; 95% CI 0.91-0.97), HDL-C (HR 0.92; 95% CI 0.86-0.99), and ApoA-I (HR 0.96; 95% CI 0.93-0.996). Our study highlights a decreased risk of hematological malignancy associated with a higher level of TC, LDL-C, HDL-C, and ApoA-I.

Keywords:  Apolipoproteins; Cohort study; Hematological malignancy; Lipids; Metabolism

DOI:  https://doi.org/10.1007/s10654-025-01207-y
Nat Aging. 2025 Mar 06.

Mitochondria-enriched hematopoietic stem cells exhibit elevated self-renewal capabilities, thriving within the context of aged bone marrow.

Haruhito Totani, Takayoshi Matsumura, Rui Yokomori, Terumasa Umemoto, Yuji Takihara, Chong Yang, Lee Hui Chua, Atsushi Watanabe, Takaomi Sanda, Toshio Suda.

The aging of hematopoietic stem cells (HSCs) substantially alters their characteristics. Mitochondria, essential for cellular metabolism, play a crucial role, and their dysfunction is a hallmark of aging-induced changes. The impact of mitochondrial mass on aged HSCs remains incompletely understood. Here we demonstrate that HSCs with high mitochondrial mass during aging are not merely cells that have accumulated damaged mitochondria and become exhausted. In addition, these HSCs retain a high regenerative capacity and remain in the aging bone marrow. Furthermore, we identified GPR183 as a distinct marker characterizing aged HSCs through single-cell analysis. HSCs marked by GPR183 were also enriched in aged HSCs with high mitochondrial mass, possessing a high capacity of self-renewal. These insights deepen understanding of HSC aging and provide additional perspectives on the assessment of aged HSCs, underscoring the importance of mitochondrial dynamics in aging.

DOI: https://doi.org/10.1038/s43587-025-00828-y
BMC Cancer. 2025 Mar 06. 25(1): 412

Impact of celastrol on mitochondrial dynamics and proliferation in glioblastoma.

Lei Liang, Wenying Lv, Gang Cheng, Mou Gao, Junzhao Sun, Ning Liu, Hanbo Zhang, Baorui Guo, Jiayu Liu, Yanteng Li, Shengqiang Xie, Jiangting Wang, Junru Hei, Jianning Zhang.

   BACKGROUND: Targeting mitochondrial dynamics offers promising strategies for treating glioblastoma multiforme. Celastrol has demonstrated therapeutic effects on various cancers, but its impact on mitochondrial dynamics in glioblastoma multiforme remains largely unknown. We studied the effects of Celastrol on mitochondrial dynamics, redox homeostasis, and the proliferation.
METHODS: Mito-Tracker Green staining was conducted on U251, LN229, and U87-MG cells to evaluate the effects of Celastrol on mitochondrial dynamics. The Western blot analysis quantified the expression levels of mitochondrial dynamin, antioxidant enzymes, and cell cycle-related proteins. JC-1 staining was performed to discern mitochondrial membrane potential. Mitochondrial reactive oxygen species were identified using MitoSOX. The proliferative capacity of cells was assessed using Cell Counting Kit-8 analysis, and colony formation assays. Survival analysis was employed to evaluate the therapeutic efficacy of Celastrol in C57BL/6J mice with glioblastoma.
RESULTS: Our findings suggest that Celastrol (1 and 1.5 µM) promotes mitochondrial fission by downregulating the expression of mitofusin-1. A decrease in mitochondrial membrane potential at 1 and 1.5 µM indicates that Celastrol impaired mitochondrial function. Concurrently, an increase in mitochondrial reactive oxygen species and impaired upregulation of antioxidant enzymes were noted at 1.5 µM, indicating that Celastrol led to an imbalance in mitochondrial redox homeostasis. At both 1 and 1.5 µM, cell proliferation was inhibited, which may be related to the decreased expression levels of Cyclin-dependent kinase 1 and Cyclin B1. Celastrol extended the survival of GBM-afflicted mice.
CONCLUSION: Celastrol promotes mitochondrial fission in glioblastoma multiforme cells by reducing mitofusin-1 expression, accompanying mitochondrial dysfunction, lower mitochondrial membrane potential, heightened oxidative stress, and decreased Cyclin-dependent kinase 1 and Cyclin B1 levels. This indicates that Celastrol possesses potential for repurposing as an agent targeting mitochondrial dynamics in glioblastoma multiforme, warranting further investigation.

Keywords:  CDK1 protein; Celastrol; Drug repurposing; Glioblastoma; Mitochondrial dynamics; Oxidative stress

DOI:  https://doi.org/10.1186/s12885-025-13733-9