bims-medica 2025-12-14 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–12–14
24 papers selected by
Brett Chrest, Wake Forest University

Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses.
Ketogenesis is Dispensable for the Metabolic Adaptations to Caloric Restriction.
Enhanced lipid metabolism serves as a metabolic vulnerability to polyunsaturated fatty acids in glioblastoma.
The sour regulation of metabolism: acidity challenges tumor cells while fueling their metabolic survival.
Metabolic costs and trade-offs of hypermetabolism in human motor neurons with ATP synthase deficiency.
Potent synergy of DHODH and SREBP inhibition in acute myeloid leukemia via disruption of cholesterol and lipid metabolism.
Three mammalian VDAC isoforms distinctly regulate mitochondrial function and proteome to maintain cell metabolism.
Catabolic rewiring in cancer impacts dietary interventions.
Carbohydrate mouth-rinsing does not rescue simulated time trial performance in trained endurance cyclists following a 5-day ketogenic diet.
Brain glucose extraction is fixed at 10% despite twofold variability in resting cerebral blood flow in healthy humans.
Comparative analysis of metabolic and functional cardiac alterations in diet- and genetically induced mouse models of cardiac dysfunction.
Rapid mitochondrial repolarization upon reperfusion after cardiac ischemia.
A step-by-step guide to performing cancer metabolism research using custom-made media.
Effect of 8-Hour Time-Restricted Eating (16/8 TRE) on Glucose Metabolism and Lipid Profile in Adults: A Systematic Review and Meta-Analysis.
Efficacy of ketogenic metabolic therapy as an adjuvant to the current standard of care in the treatment of glioblastoma: A systematic review of clinical trials.
Predicting the toxicity-efficacy ratio of venetoclax in real-world patients.
Imaging mitochondrial membrane potential via concentration-dependent fluorescence lifetime changes.
Proteostasis Stress Drives Stem Cell Aging, Clonal Hematopoiesis and Leukemia.
Bidirectional Mendelian Randomization and Multi-Omics Uncover Causal Serum Metabolites and Neuro-Related Mechanistic Pathways in Acute Myeloid Leukemia.
Lactate accumulates in the cerebrospinal fluid after prolonged exercise.
CRTC2 Promotes AML Progression and Mediates Mitochondrially-Driven Venetoclax Resistance.
Mitochondrial Metabolomics Reveals the Mechanism of SCCP Induced Energy Metabolism Inhibition.
Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.
CPX-351 and the Frontier of Nanoparticle-Based Therapeutics in Acute Myeloid Leukemia.

Nat Metab. 2025 Dec 09.

Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses.

Brandon M Oswald, Lisa M DeCamp, Joseph Longo, Michael S Dahabieh, Nicholas Bunda, Benjamin K Johnson, McLane J Watson, Shixin Ma, Samuel E J Preston, Ryan D Sheldon, Michael P Vincent, Abigail E Ellis, Molly T Soper-Hopper, Christine Isaguirre, Dahlya Kamarudin, Hui Shen, Kelsey S Williams, Peter A Crawford, Susan Kaech, H Josh Jang, Evan C Lien, Connie M Krawczyk, Russell G Jones.

Reducing calorie intake through dietary restriction (DR) slows tumour growth in mammals, yet the underlying mechanisms are poorly defined. Here, we show that DR enhances anti-tumour immunity by optimizing CD8+ T cell function within the tumour microenvironment (TME). Using syngeneic xenograft tumour models, we found that DR induces a profound reprogramming of CD8+ T cell fate in the TME, favouring the expansion of effector T cell subsets with enhanced metabolic capacity and cytotoxic potential, while limiting the accumulation of terminally exhausted T cells. This metabolic reprogramming is driven by enhanced ketone body oxidation, particularly β-hydroxybutyrate (βOHB), which is elevated in both the circulation and tumour tissues of DR-fed mice. βOHB fuels T cell oxidative metabolism under DR, increasing mitochondrial membrane potential and tricarboxylic acid cycle-dependent pathways critical for T cell effector function, including acetyl-CoA production. By contrast, T cells deficient for ketone body oxidation exhibit reduced mitochondrial function, increased exhaustion and fail to control tumour growth under DR conditions. Importantly, DR synergizes with anti-PD1 immunotherapy, further augmenting anti-tumour T cell responses and limiting tumour progression. Our findings reveal that T cell metabolic reprogramming is central to the anti-tumour effects of DR, highlighting nutritional control of CD8+ T cell fate as a key driver of anti-tumour immunity.

DOI: https://doi.org/10.1038/s42255-025-01415-6
Aging Cell. 2025 Dec 10. e70318

Ketogenesis is Dispensable for the Metabolic Adaptations to Caloric Restriction.

Chung-Yang Yeh, Alexis L Borgelt, Brynn J Vogt, Alyssa A Clark, Ted T Wong, Isaac Grunow, Michelle M Sonsalla, Reji Babygirija, Yang Liu, Michaela E Trautman, Mariah F Calubag, Bailey A Knopf, Fan Xiao, Dudley W Lamming.

  Caloric restriction (CR) extends the health and lifespan of diverse species. When fed once daily, CR-treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketone bodies, we investigated the role of ketogenesis in CR using mice with whole-body ablation of Hmgcs2, the rate-limiting enzyme producing the main ketone body β-hydroxybutyrate (βHB). Here, we report that Hmgcs2 is largely dispensable for many metabolic benefits of CR, including CR-driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex-specific effects of Hmgcs2 on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remained robust in mice lacking Hmgcs2. To gain insight into why the deletion of Hmgcs2 does not disrupt CR, we measured fasting βHB levels as mice initiated a CR diet. Surprisingly, as mice adapt to CR, they no longer engage in high levels of ketogenesis during the daily fast. Our work suggests that the metabolic benefits of long-term CR are not mediated by ketogenesis.

Keywords:  BHB; caloric restriction; dietary restriction; ketogenesis; ketones; metabolic health; metabolism

DOI:  https://doi.org/10.1111/acel.70318
JCI Insight. 2025 Dec 09. pii: e191465. [Epub ahead of print]

Enhanced lipid metabolism serves as a metabolic vulnerability to polyunsaturated fatty acids in glioblastoma.

Shiva Kant, Yi Zhao, Pravin Kesarwani, Kumari Alka, Jacob F Oyeniyi, Ghulam Mohammad, Nadia Ashrafi, Stewart F Graham, C Ryan Miller, Prakash Chinnaiyan.

  Enhanced lipid metabolism, which involves the active import, storage, and utilization of fatty acids from the tumor microenvironment, plays a contributory role in malignant glioma transformation; thereby, serving as an important gain of function. In this work, through studies initially designed to understand and reconcile possible mechanisms underlying the anti-tumor activity of a high-fat ketogenic diet, we discovered that this phenotype of enhanced lipid metabolism observed in glioblastoma may also serve as a metabolic vulnerability to diet modification. Specifically, exogenous polyunsaturated fatty acids (PUFA) demonstrate the unique ability of short-circuiting lipid homeostasis in glioblastoma cells. This leads to lipolysis-mediated lipid droplet breakdown, an accumulation of intracellular free fatty acids, and lipid peroxidation-mediated cytotoxicity, which was potentiated when combined with radiation therapy. Leveraging this data, we formulated a PUFA-rich modified diet that does not require carbohydrate restriction, which would likely improve long-term adherence when compared to a ketogenic diet. The modified PUFA-rich diet demonstrated both anti-tumor activity and potent synergy when combined with radiation therapy in mouse glioblastoma models. Collectively, this work offers both a mechanistic understanding and a potentially translatable approach of targeting this metabolic phenotype in glioblastoma through diet modification and/or nutritional supplementation that may be readily integrated into clinical practice.

Keywords:  Brain cancer; Metabolism; Metabolomics; Neuroscience; Oncology; Radiation therapy

DOI:  https://doi.org/10.1172/jci.insight.191465
Cancer Res. 2025 Dec 11.

The sour regulation of metabolism: acidity challenges tumor cells while fueling their metabolic survival.

Bruna Martins Garcia, Patricia Altea-Manzano.

The tumor microenvironment imposes diverse metabolic challenges to cancer cells. Overcoming these challenges is essential for survival, proliferation, and dissemination. However, how cancer cells cope with the harsh environment and how the different coexisting stresses affect the tumor in vivo is unknown. Recently, Groessl, Kalis and colleagues published their findings in Science showing that acidosis outweighs all other stresses and plays a major role in the adaptation to them. Mechanistically, acidosis inhibits the ERK-DRP1 pathway, resulting in mitochondria elongation, which triggers a metabolic shift from glycolysis to oxidative phosphorylation. These findings highlight the plasticity of cancer cell mitochondria and refute the previous belief that cancer mitochondria are inherently dysfunctional. Indeed, inhibition of mitochondrial fusion or oxidative phosphorylation in acidic tumors is sufficient to promote cell death. Thus, enhancing respiration under acidosis comes to light as an essential metabolic adaptation to cancer survival and proliferation and targeting how cancer cells adapt to acidosis emerges as a new avenue for therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5633
Commun Biol. 2025 Dec 11. 8(1): 1759

Metabolic costs and trade-offs of hypermetabolism in human motor neurons with ATP synthase deficiency.

Rubén Torregrosa-Muñumer, Jeremi Turkia, Rumeysa Ermiş, Jouni Kvist, Sandra Harjuhaahto, Jana Pennonen, Ville Hietakangas, Emil Ylikallio, Henna Tyynismaa.

Hypermetabolism, a futile cycle of energy production and consumption, has been proposed as an adaptative response to deficiencies in mitochondrial oxidative phosphorylation. However, the cellular costs of hypermetabolism remain largely unknown. Here we studied the consequences of hypermetabolism in human motor neurons harboring a heteroplasmic mutation in MT-ATP6, which impairs ATP synthase assembly. Respirometry, metabolomics, and proteomics analyses of the motor neurons showed that elevated ATP production rates were accompanied with increased demand for acetyl-Coenzyme A (acetyl-CoA) and depleted pantothenate (vitamin B5), and the proteome was remodeled to support the metabolic adaptation. Mitochondrial membrane potential and coupling efficiency remained stable, and the therapeutic agent avanafil did not affect metabolite levels. However, a redistribution of acetyl-CoA usage resulted in metabolic trade-offs, including reduced histone acetylation and altered maintenance of the neurotransmitter acetylcholine, revealing potential vulnerabilities in motor neurons. These findings advance the understanding of cellular metabolic consequences imposed by hypermetabolic conditions.

DOI: https://doi.org/10.1038/s42003-025-09149-7
Haematologica. 2025 Dec 11.

Potent synergy of DHODH and SREBP inhibition in acute myeloid leukemia via disruption of cholesterol and lipid metabolism.

Shanna M Hogeling, Dominique Sternadt, Nikita La Rose, Marjan Geugien, Diego Pereira-Martins, Fiona A J Van den Heuvel, Anna Kuchnio, Christine E Pietsch, Ulrike Philippar, Gerwin Huls, Jan Jacob Schuringa.

Acute myeloid leukemia (AML) remains difficult to cure, in part related to strong genetic and functional heterogeneity between and within individual patients. Metabolic reprogramming is emerging as an important feature of AML cells, allowing to explore alternative treatment strategies. Here, we describe a novel DHODH inhibitor, JNJ-74856665, that showed strong efficacy in a subset of AML samples. In a multi-omics approach, by combining label-free quantitative proteome data with drug sensitivity data in bone marrow stromal cocultures in a large cohort of primary AML patient samples we identified that sensitivity to DHODH inhibition (DHODHi) is linked to cholesterol and lipid metabolism. DHODHi resulted in an accumulation of cholesterol, mitochondrial ROS and lipid peroxidation. LC-MS/MS-based lipidomics studies revealed that DHODHi resulted in a strong increase in polyunsaturated fatty acids (PUFAs) and triglycerides (TGs), which are the primary lipid species stored in lipid droplets (LDs). We hypothesized that this might be the consequence of increased ROS and lipid peroxidation levels, prompting the cell to detoxify such toxic lipid species by storing them in LDs. Indeed, we could observed a marked increase in LD formation upon DHODHi. The transcriptional regulator SREBF2, known to control cholesterol and lipid metabolism, was upregulated in DHODHi sensitive AMLs, and a strong synergy was observed between combination of both DHODHi and the SREBP inhibitor dipyridamole. Our data indicate that combined DHODH and SREBP inhibition is of interest to explore further as a therapeutic target option in AML.

DOI: https://doi.org/10.3324/haematol.2025.287918
J Biol Chem. 2025 Dec 05. pii: S0021-9258(25)02861-3. [Epub ahead of print] 111009

Three mammalian VDAC isoforms distinctly regulate mitochondrial function and proteome to maintain cell metabolism.

Megha Rajendran, William M Rosencrans, Nina A Bautista, Wendy Fitzgerald, Diana Huynh, Bethel G Beyene, Baiyi Quan, Jennifer D Petersen, Julie Hwang, Tsui-Fen Chou, Sergey M Bezrukov, Tatiana K Rostovtseva.

  The Voltage Dependent Anion Channel (VDAC) is the most ubiquitous protein in the mitochondrial outer membrane. This channel facilitates the flux of water-soluble metabolites and ions like calcium across the mitochondrial outer membrane. Beyond this canonical role, VDAC has been implicated, through interactions with protein partners, in several cellular processes such as apoptosis, calcium signaling, and lipid metabolism. There are three VDAC isoforms in mammalian cells, VDAC1, VDAC2, and VDAC3, with varying tissue-specific expression profiles. From a biophysical standpoint, all three isoforms conduct metabolites and ions with similar efficiency. However, isoform knockouts (KOs) in mice lead to distinct phenotypes, which may be due to differences in VDAC isoform interactions with partner proteins. To understand the functional role of each VDAC isoform within a single cell type, we created functional KOs of each isoform in HeLa cells and performed a comparative study of their metabolic activity and proteomics. We found that each isoform KO alters the proteome differently, with VDAC3 KO dramatically downregulating key members of the electron transport chain (ETC) while shifting the mitochondria into a glutamine-dependent state. Importantly, this unexpected dependence of mitochondrial function on the VDAC3 isoform is not compensated for by the more ubiquitously expressed VDAC1 and VDAC2 isoforms. In contrast, VDAC2 KO did not affect respiration but upregulated ETC components and decreased key enzymes in the glutamine metabolic pathway. VDAC1 KO specifically reduced glycolytic activity linked to decreased hexokinase localization to mitochondria. These results reveal non-redundant roles of VDAC isoforms in cancer cell metabolic adaptability.

Keywords:  CRISPR/Cas9 gene knockout; metabolic regulation; mitochondrial respiratory chain complex; proteomics; voltage-dependent anion channel

DOI:  https://doi.org/10.1016/j.jbc.2025.111009
Commun Biol. 2025 Dec 08.

Catabolic rewiring in cancer impacts dietary interventions.

Christos Chinopoulos.

Tumors exhibit metabolic fuel requirements resembling those of embryonic and other highly proliferative tissues, a similarity that can be exploited to combat neoplasia. However, several challenges limit the efficacy of dietary modifications in cancer therapy. This review explores how cancer cells acquire and catabolize macromolecules to harness energy and assesses the feasibility of influencing these pathways through dietary changes. Although dietary interventions modulate the energetic substrate supply to tumors only to a limited extent, they offer significant ancillary benefits by imposing hormonal states that burden cancer metabolism, enhancing immune responses, and reducing inflammation. Integrating dietary considerations into the standard of care for cancer patients represents a promising adjunct to traditional treatments, despite their dampened impact on nutrient availability for tumor energy metabolism.

DOI: https://doi.org/10.1038/s42003-025-09333-9
J Int Soc Sports Nutr. 2025 Dec 31. 22(1): 2598232

Carbohydrate mouth-rinsing does not rescue simulated time trial performance in trained endurance cyclists following a 5-day ketogenic diet.

Guy Guppy, James Brouner, Owen Spendiff.

   BACKGROUND: Carbohydrate mouth rinsing (CHO-MR) during periods of fasting or low muscle glycogen availability could provide a more pronounced ergogenic effect compared to fed and high muscle glycogen conditions. However, there is little evidence investigating the efficacy of CHO-MR during periods of low muscle glycogen induced by ketogenic diets. Therefore, this study aimed to investigate the impact of CHO-MR vs. a placebo (PLA-MR) on cycling time trial performance in trained endurance cyclists following their habitual diet (HD) or a 5-day ketogenic diet (KD).
METHODS: Eight participants completed baseline testing and four trial conditions. For each trial, participants adhered to either their HD or a KD for 5 consecutive days. During the first 4 days of each dietary phase, they tracked daily nutrition; additionally, they recorded morning fasting blood glucose and β-hydroxybutyrate (βHB) levels for the 4 days preceding and the morning of each trial. Each trial comprised a 33.6 km simulated time trial in which rinsing was performed for ten seconds at 7 km intervals.
RESULTS: The 5-day KD significantly increased the time to completion (TTC) compared to HD (p < .001). Although no significant differences in TTC were detected between HD + CHO-MR and KD + CHO-MR (p = .670), CHO-MR did not restore KD performance to within 2% of HD conditions (±158 s; 4.8%). While a significant main effect for diet on morning fasted blood [βHB] (p = .001) was observed on day 5, it was not significantly associated with exercise time (r (14) = -.442, p = .086). Post-exercise blood [glucose] was significantly higher in the HD + CHO-MR and HD + PLA-MR conditions compared to the KD + CHO-MR (p = .038 & p = .021), and KD + PLA-MR (p = .011 and p = .003) conditions, respectively.
CONCLUSION: The data indicate that repeated 6.4% CHO-MR during endurance cycling is insufficient to overcome performance impairments induced via a 5-day ketogenic diet. This suggests that peripheral substrate availability may constrain the hepatic glucose output in response to central nervous system cues. Further research is required to elucidate how peripheral glycogen stores, central neural drive, and ergogenic interventions interact under low-carbohydrate conditions.

Keywords:  Ketogenic diet; carbohydrate; cycling; endurance; low-carbohydrate; mouth-rinse

DOI:  https://doi.org/10.1080/15502783.2025.2598232
J Cereb Blood Flow Metab. 2025 Dec 07. 271678X251400247

Brain glucose extraction is fixed at 10% despite twofold variability in resting cerebral blood flow in healthy humans.

Jennifer S Duffy, Hannah G Caldwell, Ryan L Hoiland, Connor A Howe, Kurt J Smith, Anthony R Bain, David B MacLeod, Philip N Ainslie, Travis D Gibbons.

  In the resting, non-stimulated brain, metabolic demands are met exclusively by the delivery and extraction of glucose and oxygen at an ~6:1 ratio. Amongst healthy people at rest, there is marked variability in resting global cerebral blood flow (CBF) yet remarkably stable concentrations of circulating glucose and oxygen. Thus, we would expect interindividual variability in resting CBF to be inversely related to oxygen and glucose extraction, maintaining oxidative glucose metabolism. Herein, we investigated the fundamental relationship between CBF and substrate extraction in 75 healthy adults (27.3 ± 4.8 years) with resting measures of CBF and cross-brain concentrations of oxygen and glucose. We observed that the marked interindividual variability in CBF (<500 to >1200 mL/min) is inversely related to oxygen extraction (R2 = 0.85, p = 0.005) but not glucose extraction (R2 = 0.30, p = 0.273). The metabolic rates of oxygen and glucose (CMRO2 and CMRglc) are both directly correlated with CBF. However, there was a 1.6-fold greater slope for CMRglc-CBF, compared to CMRO2-CBF (p = 0.040). These findings indicate that the resting brain extracts more oxygen when delivery is low, maintaining stable CMRO2 and ATP production. Despite glucose being the primary oxidized substrate, the brain's ability to adjust its extraction is limited, making CMRglc more dependent on delivery.

Keywords:  Cerebral metabolism; aerobic glycolysis; arteriovenous; cerebral blood flow; glucose extraction; oxygen extraction

DOI:  https://doi.org/10.1177/0271678X251400247
FEBS J. 2025 Dec 12.

Comparative analysis of metabolic and functional cardiac alterations in diet- and genetically induced mouse models of cardiac dysfunction.

Christiane Ott, Patricia Baumgarten, Thorsten Henning, Daniela Weber, Iwona Wallach, Jana Grune, Ulrich Kintscher, Hermann-Georg Holzhütter, Tilman Grune, Nikolaus Berndt.

  Cardiac metabolism is highly adaptive, and distinct maladaptive remodeling processes may contribute to the development of cardiac dysfunction. Here, we compared the metabolic, structural, and functional adaptations of two murine models: C57BL/6J mice fed a high-fat, carbohydrate-free diet and New Zealand Obese mice maintained on a standard diet. Cardiac function was assessed by echocardiography, plasma metabolite profiles were analyzed, and cardiac proteomes were quantified by mass spectrometry. Proteomic data were computationally integrated into a kinetic model of cardiac central metabolism (CARDIOKIN1) to predict changes in substrate utilization and ATP production capacities under physiological nutrient conditions. Diet-induced metabolic stress led to cardiac dysfunction with preserved ejection fraction, characterized by mitochondrial dysfunction, impaired ATP production, inflammation, and reduced cardiac mass. Conversely, genetically induced obesity resulted in cardiac impairment with reduced ejection fraction associated with mild fibrosis, maintained ATP production, and substrate switching favoring fatty acid utilization. Proteomic and computational analyses revealed a coordinated downregulation of metabolic networks involved in oxidative phosphorylation, substrate transport, and energy production in both models, but with distinct profiles of metabolic inflexibility and mitochondrial efficiency. This study provides insights of how dietary versus genetic metabolic stress reprograms cardiac metabolism and structure, offering mechanistic insights into the diverse pathways leading to cardiac dysfunction. These insights may guide future strategies for metabolic intervention in heart failure subtypes.

Keywords:  cardiac dysfunction; cardiac metabolism; genetically induced obesity; high‐fat diet; metabolic adaptation

DOI:  https://doi.org/10.1111/febs.70362
Nat Cardiovasc Res. 2025 Dec 11.

Rapid mitochondrial repolarization upon reperfusion after cardiac ischemia.

Abigail V Giles, Raul Covian, Hiran A Prag, Nils Burger, Bertrand Lucotte, Chak Shun Yu, Junhui Sun, Elizabeth Murphy, Thomas Krieg, Michael P Murphy, Robert S Balaban.

The mitochondrial membrane potential (ΔΨm) drives oxidative phosphorylation and alterations contribute to cardiac pathologies, but real-time assessment of ΔΨm has not been possible. Here we describe noninvasive measurements using mitochondrial heme bL and bH absorbances, which rapidly respond to ΔΨm. Multi-wavelength absorbance spectroscopy enabled their continuous monitoring in isolated mitochondria and the perfused heart. Calibration of heme b absorbance in isolated mitochondria revealed that reduced heme bL relative to total reduced heme b (fbL = bL/(bL + bH)) exhibits a sigmoidal relationship with ΔΨm. Extrapolating this relationship to the heart enabled estimation of ΔΨm as 166 ± 18 mV (n = 25, mean ± s.d.). We used this approach to assess how ΔΨm changes during ischemia-reperfusion injury, an unknown limiting the understanding of ischemia-reperfusion injury. In perfused hearts, ΔΨm declined during ischemia and rapidly reestablished upon reperfusion, supported by oxidation of the succinate accumulated during ischemia. These findings expand our understanding of ischemia-reperfusion injury.

DOI: https://doi.org/10.1038/s44161-025-00752-9
Life Sci Alliance. 2026 Feb;pii: e202503529. [Epub ahead of print]9(2):

A step-by-step guide to performing cancer metabolism research using custom-made media.

Sophie Seifert, Francisco Yanqui-Rivera, Tim Kühn, Lena Elise Høyland, Toman Borteçen, Bella Agranovich, Lara Elea Eckhardt, Martin Herdt, Alessa Henneberg, Verena Panitz, Faisal Hayat, Marie Migaud, Gernot Poschet, Ifat Abramovich, Eyal Gottlieb, Jeroen Krijgsveld, Mathias Ziegler, Mirja Tamara Prentzell, Christiane A Opitz.

The preparation of custom-made media offers precise control over nutrient composition, enabling detailed studies of cellular metabolism. We demonstrate how self-made media formulations enable diverse assay designs and readouts to assess cancer metabolism. Self-made media can be used in Seahorse assays to measure mitochondrial respiration under defined conditions. In nutrient deprivation experiments, amino acid or vitamin removal can uncover how cancer cells adapt to metabolic stress. Using labeled amino acids enables analysis of nascent protein synthesis and translational regulation, while stable-isotope tracing reveals metabolic fluxes through key pathways. This guide presents a suite of metabolic assays using custom-made media, covering experimental design, the selection of controls, sample preparation, data acquisition, and interpretation. The accompanying online media calculator "Media Minds" streamlines the creation of custom media formulations, ensuring accuracy and reproducibility.

DOI: https://doi.org/10.26508/lsa.202503529
Nutr Rev. 2025 Dec 06. pii: nuaf206. [Epub ahead of print]

Effect of 8-Hour Time-Restricted Eating (16/8 TRE) on Glucose Metabolism and Lipid Profile in Adults: A Systematic Review and Meta-Analysis.

Po-San Wong, Kewen Wan, Zihan Dai, Angus Pak-Hung Yu, Stephen Heung-Sang Wong, Eric Tsz-Chun Poon.

   CONTEXT: A dietary regimen that includes a fasting period of 16 hours coupled with a daily time-restricted eating (TRE) period of 8 hours (16/8 TRE) is gaining popularity; however, its effect on glycolipid metabolic markers remains unclear.
OBJECTIVE: In this systematic review and meta-analysis of reported studies we aimed to examine the effects on glycolipid metabolism of the 16/8 TRE dietary regimen compared with a control diet in adult study participants.
DATA SOURCES: We searched the PubMed, MEDLINE, Cochrane Library, Scopus, and Web of Science databases for relevant articles published from database inception until January 15, 2025.
DATA EXTRACTION: We extracted publication details, including data on study participant characteristics, intervention durations, and outcomes.
DATA ANALYSIS: All analyses were conducted using a random-effects model with the standardized mean difference (SMD). Subgroup analyses were performed for physical activity (PA) level, participant sex, and intervention duration.
RESULTS: In total, 23 randomized controlled trials (RCTs)with a total of 1280 participants were included in this analysis. The 16/8 TRE intervention resulted in a slight reduction in levels of fasting glucose (SMD, -0.25; 95% CI, -0.42 to -0.08; P = .004), homeostasis model assessment for insulin resistance (HOMA-IR) (SMD, -0.16; 95% CI, -0.29 to -0.02; P = .03), and insulin levels (SMD, -0.22; 95% CI, -0.43 to -0.01; P = .04). Regarding lipid profiles, 16/8 TRE had a modest effect on high-density lipoprotein cholesterol (HDL-C) (SMD, 0.15; 95% CI: 0.01-0.29; P = .04). No significant effects were found for other markers compared to the control diet. Subgroup analysis suggested the presence of sex differences in triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-C), with significant improvements in TGs (SMD, -0.52; 95% CI, -1.04 to -0.01; P = .05), and LDL-C (SMD, -0.41; 95% CI, -0.75 to -0.07; P = .02) found in studies with only male participants. Additionally, participants with higher PA levels demonstrated greater improvements in LDL-C (SMD, -0.43; 95% CI, -0.74 to -0.12; P = .007). Studies with durations exceeding 6 months showed a significant improvement in HbA1c (SMD, -0.31; 95% CI, -0.56 to -0.05; P = .02).
CONCLUSION: Study participants who followed the 16/8 TRE showed an overall improvement in fasting glucose, HOMA-IR, insulin, and HDL-C levels compared to participants who followed the control diet. However, the effects of the 16/8 TRE in individuals were likely to have been moderated by participant sex, PA level, and intervention duration.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration No. CRD42025645789.

Keywords:  intermittent fasting; meta-analysis; metabolic health; time-restricted eating

DOI:  https://doi.org/10.1093/nutrit/nuaf206
Med Oncol. 2025 Dec 11. 43(1): 49

Efficacy of ketogenic metabolic therapy as an adjuvant to the current standard of care in the treatment of glioblastoma: A systematic review of clinical trials.

Emily McKerill, Joecelyn Kirani Tan, Chethana Krishna Rao, Christian A Linares, Soirindhri Banerjee, Rukhshana Dina Rabbani, Sola Adeleke, Aruni Ghose, Stergios Boussios.

  Glioblastoma is a diffuse, heterogenous tumour with a poor prognosis as current therapeutic options have limited efficacy. As a result, research aims to explore new treatment options which exploit the hallmarks of cancer. This review aimed to understand the breadth of research considering ketogenic metabolic therapy (KMT) as an adjuvant to standard therapy. KMT aims to improve overall survival by exploiting the metabolic reprogramming exclusive to neoplastic cells. Preclinical trials show benefits in KMT when used alongside radiotherapy, through increasing anti-tumour effects compared to controls. Literature searches conducted over three databases, in line with PRISMA guidelines, collated studies relevant to KMT and glioblastoma. Six prospective studies and one retrospective study met the inclusion criteria for this review. Data regarding participants, interventions and survival were extracted. Studies included used small numbers of participants, as many aimed to assess the feasibility of larger-scale trials, which increases errors and bias of results. Furthermore, direct comparison between trials was limited due to study heterogeneity, as each trial used differing parameters and diet compositions. As a result, no definitive conclusions could be made. Future studies should use larger cohorts with standardised parameters so results are representative, and comparisons can be made to evaluate efficacy.

Keywords:  Adjuvant; Brain tumour; Efficacy; Glioblastoma; Ketogenic metabolic therapy

DOI:  https://doi.org/10.1007/s12032-025-03165-7
Ann Hematol. 2025 Dec 11.

Predicting the toxicity-efficacy ratio of venetoclax in real-world patients.

Loïc Osanno, Lucy Brocque, Laurent Bourguignon, Carla Delpech, Laure Farnault, Julien Colle, Pauline Roche, Jacques Chiaroni, Caroline Izard, Régis Costello, Mathilde Dacos, Caroline Solas, Chems Djezzar, Joseph Ciccolini, Thomas Cluzeau, Geoffroy Venton, Raphaëlle Fanciullino.

  This study investigates the pharmacokinetic variability and exposure-response relationships of Venetoclax (VEN) in adult patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. The study was conducted in a real-world clinical setting and included 48 patients who were treated with VEN in combination with azacytidine. We found significant inter-individual variability of 68% and intra-individual variability of 39% in plasma VEN concentrations. In addition, higher VEN concentrations were associated with better hematological responses. Median overall survival for the entire cohort was 17.8 months, with 1- and 2-year survival rates of 51% and 36.4%, respectively. A comparison of the 14-day VEN and 28-day VEN protocols showed that patients benefited from longer treatment durations, which resulted in more courses being administered. Plasma concentrations in the 14-day VEN protocol were higher than in the 28-day VEN protocol (2330 + 1675 ng/mL vs. 1503 + 966 ng/mL, respectively) without an increase in toxicities. The optimal protocol would be 400 mg/14d if we consider survival as a function of the 1818ng/mL cutoff. These results highlight the importance of considering therapeutic drug monitoring (TDM) as a strategy to optimize treatment outcomes by balancing efficacy and safety.

Keywords:  Acute myeloid leukemia; Hematological toxicity; Pharmacokinetic variability; Therapeutic drug monitoring; Venetoclax

DOI:  https://doi.org/10.1007/s00277-025-06531-7
Nat Commun. 2025 Dec 12. 16(1): 11088

Imaging mitochondrial membrane potential via concentration-dependent fluorescence lifetime changes.

Dilizhatai Saimi, Luc Reymond, Tursunjan Aziz, Xuan Shen, Ziying Luo, Shuaibo Pi, Yitong Liu, Song Fu, Shuangjin Ding, Anming Meng, Liangyi Chen, Hui Jiang, Zhixing Chen.

Mitochondria are central to cellular metabolism. Various fluorescence tools have been developed for imaging the mitochondrial environment. Yet, new reporters and imaging methods for directly reading the mitochondrial status are needed for high spatial-temporal resolution imaging. Here, we introduce PK Mito Deep Red (PKMDR), a low-phototoxicity mitochondrial probe for time-lapse imaging, whose fluorescence lifetime serves as a sensitive indicator of mitochondrial membrane potential (Δψm). The positively charged PKMDR accumulates within mitochondria under a higher Δψm, leading to concentration-induced quenching and a measurable decrease in fluorescence lifetime. Since mitochondrial respiration primarily regulates Δψm, PKMDR's fluorescence lifetime effectively reports on the status of oxidative phosphorylation. Using PKMDR with fluorescence lifetime imaging microscopy (FLIM), we visualize heterogeneous Δψm across individual cells, organoids, and tissues over time. This method reliably reveals the heterogeneity between metabolically active peripheral mitochondria and relatively inactive perinuclear mitochondria in various cell types. Overall, PKMDR-FLIM is a robust tool for directly visualizing Δψm with high spatiotemporal resolution.

DOI: https://doi.org/10.1038/s41467-025-66042-x
bioRxiv. 2025 Dec 01. pii: 2025.11.27.690982. [Epub ahead of print]

Proteostasis Stress Drives Stem Cell Aging, Clonal Hematopoiesis and Leukemia.

Fanny J Zhou, Michelle K Le, Helen C Wang, Wei Yang, Huan-You Wang, Arukshita Tiwari, Xinjian Cen, Mary Jean Sunshine, Jeffrey A Magee, Robert A J Signer.

Aging is the primary risk factor for clonal hematopoiesis and the development of hematologic malignancies ( 1-5 ), yet the selective pressures that shape stem cell behavior and clonal expansion during aging remain poorly defined. Here, we identify proteostasis stress as a central driver of hematopoietic stem cell (HSC) aging and clonal evolution. We show that Heat shock factor 1 (Hsf1) is activated in aging HSCs to preserve proteostasis and sustain self-renewal. However, this physiological, age-associated adaptive mechanism is co-opted by pre-leukemic Dnmt3a -mutant HSCs to resist proteostasis and inflammatory stress required to fuel clonal expansion during aging. In the context of co-occurring Dnmt3a and Nras mutations, which are frequently observed in human acute myeloid leukemia (AML) ( 6-13 ), mutant HSCs and progenitors exhibit heightened dependence on Hsf1 for expansion, malignant transformation and disease progression. Loss of Hsf1 , or disruption of proteostasis, impairs expansion of mutant progenitors, delays leukemia onset, and prolongs survival. Together, these findings reveal proteostasis as a key constraint in the aging hematopoietic system that imposes a selective bottleneck. Hsf1 activation enables both physiological adaptation in aging stem cells and pathological clonal outgrowth in pre-leukemic and leukemic states, establishing proteostasis control as a pivotal mechanism linking stem cell aging to clonal hematopoiesis and malignancy.

DOI: https://doi.org/10.1101/2025.11.27.690982
Int J Mol Sci. 2025 Nov 22. pii: 11307. [Epub ahead of print]26(23):

Bidirectional Mendelian Randomization and Multi-Omics Uncover Causal Serum Metabolites and Neuro-Related Mechanistic Pathways in Acute Myeloid Leukemia.

Haohan Ye, Yuanheng Liu, Jun Tang, Xiaoli Li.

  Acute myeloid leukemia (AML) is a lethal clonal hematopoietic malignancy. Several reports have shown that serum metabolite alterations have been implicated in AML, but the causal relationship and underlying biological mechanisms remain unclear. We performed bidirectional Mendelian randomization (MR) to evaluate the association between 486 serum metabolites and AML. The analytical approaches used to minimize research bias included the inverse variance weighting (IVW), MR-Egger and weighted median (WM) methods. Sensitivity analyses were performed using Cochran's Q Test, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and Leave-one-out (LOO) analysis. Metabolic pathway analysis was conducted using the MetaboAnalyst 6.0 platform. We utilized RNA-seq data to explore the potential genes and mechanisms underlying the regulation of AML occurrence by serum metabolites. We identified 23 serum metabolites (13 known and 10 unknown) significantly associated with AML. Sensitivity analyses further validated the robustness of these associations. No evidence of reverse causality was detected by reverse MR analysis. The core pathways were histidine metabolism and fructose/mannose metabolism. Transcriptomic integration revealed 39 overlapping genes (differentially expressed genes vs. metabolite-associated genes) as key mediators, enriched in neuroactive ligand signaling, synaptic vesicle cycle, and GABAergic synapse (KEGG), plus synapse assembly and calmodulin binding and neuron-to-neuron synapse (GO). This study establishes causal links between specific serum metabolites and AML, revealing neuro-related mechanistic pathways. These findings provide novel biomarkers and therapeutic targets for AML precision medicine.

Keywords:  acute myeloid leukemia; mendelian randomization; metabolic pathways; serum metabolites; transcriptome

DOI:  https://doi.org/10.3390/ijms262311307
J Cereb Blood Flow Metab. 2025 Dec 07. 271678X251399006

Lactate accumulates in the cerebrospinal fluid after prolonged exercise.

Jennifer S Duffy, Justin A Monteleone, Jay Mjr Carr, Connor A Howe, Jodie Koep, Jordan D Bird, Tenasia D Monaghan, Lillian M Brewster, Andrew R Steele, Kate N Thomas, David MacLeod, Philip N Ainslie, Travis D Gibbons.

  The resting brain is fuelled by glucose with a small release of lactate. During exercise, the brain switches to extracting lactate from blood and this increases brain carbohydrate uptake in great excess to that of oxygen. The fate of this excess carbohydrate uptake is unknown. Studies investigating the fate of brain carbohydrate uptake use brief periods of brain activation and so it is possible that the dissociation between brain glucose and oxygen metabolism is temporal and not material. In 13 healthy humans, we induced sustained increases in brain carbohydrate uptake via 2 h of mixed-intensity cycling exercise and hypothesized that lactate accumulation in the cerebrospinal fluid would account for some of this excess carbohydrate uptake. Exercise shifted the brain from releasing to extracting lactate (p = 0.034), causing an excess uptake of 14.3 ± 3.7 mmol of carbohydrate over 2 h of exercise. Although CSF glucose remained perfectly stable (3.0 ± 0.2 vs 3.0 ± 0.1 mmol/L; p = 1.0), CSF lactate concentration doubled (1.1 ± 0.05 vs 2.2 ± 0.3 mmol/L; p < 0.0001) and was correlated to cerebral lactate uptake (r = 0.68, p = 0.015). This accumulation of lactate in CSF represents a 15% increase in carbohydrate-based ATP availability, but accounts for only 6% of the unexplained carbohydrate extracted by the brain during exercise.

Keywords:  Brain; carbohydrate; cerebrospinal fluid; exercise; lactate; metabolism

DOI:  https://doi.org/10.1177/0271678X251399006
FASEB J. 2025 Dec 15. 39(23): e71316

CRTC2 Promotes AML Progression and Mediates Mitochondrially-Driven Venetoclax Resistance.

Xiaomei Liang, Yilu Zheng, Bangxue Jiang, Yuling Huang, Jing Tang, Haimei Deng, Chenxing Zhang, Minyi Zhao, Dongjun Lin.

  Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the malignant proliferation of myeloid progenitor cells. Although the introduction of the B-cell lymphoma-2 (BCL-2) inhibitor Venetoclax (VEN) has significantly improved patient outcomes and established it as a first-line treatment, high rates of drug resistance and relapse remain major clinical challenges. We integrated RUNX3 chromatin immunoprecipitation sequencing (ChIP-seq) data with the GAPIA2 database to identify CRTC2 as a key candidate gene. Subsequently, we employed qRT-PCR to compare CRTC2 expression levels between donors and AML patients. The role of CRTC2 in apoptosis was further validated through knockdown and overexpression experiments in various cell lines. To investigate the impact of CRTC2 on AML progression, we established a cell line-derived xenograft (CDX) model. The proportion of human CD45-positive (hCD45+) cells in the bone marrow and liver was assessed, and histological examination was conducted using HE staining, along with peripheral blood smear analysis. In addressing VEN resistance, we analyzed CRTC2 expression patterns in clinical samples and explored the synergistic therapeutic effect of a CRTC2 inhibitor in combination with VEN. To further elucidate the underlying molecular mechanisms, we performed mitochondrial function assays and analyzed mitochondrial translation-related proteins. Clinical analyses have demonstrated that elevated expression levels of CRTC2, a downstream target of RUNX3, are significantly correlated with poor prognosis in patients with AML. Functional experiments have shown that CRTC2 plays a role in disease progression by modulating apoptosis in AML cells. The knockdown of CRTC2 was observed to delay disease progression in CDX mouse models. Additional investigations revealed a positive correlation between CRTC2 expression and resistance to VEN in AML cells, with CRTC2 inhibition synergistically enhancing VEN's cytotoxic effects. Mechanistic studies suggest that increased mitochondrial activity contributes to VEN resistance, thereby identifying a potential molecular target for overcoming drug resistance. CRTC2 is a key regulator in AML, with high expression levels promoting disease progression and resistance to VEN. Inhibiting CRTC2 reduces mitochondrial translation and energy reserves, increasing AML cell sensitivity to VEN. These results highlight CRTC2 as a promising therapeutic target and suggest a new strategy to overcome VEN resistance.

Keywords:  CRTC2; acute myeloid leukemia; drug resistance; mitochondrial translation

DOI:  https://doi.org/10.1096/fj.202503054R
Environ Sci Technol. 2025 Dec 11.

Mitochondrial Metabolomics Reveals the Mechanism of SCCP Induced Energy Metabolism Inhibition.

Chenhao Huang, Shuangshuang Chen, Lin Cheng, Chengcheng Shi, Rong Cao, Li Wang, Yuan Gao, Ying Yu, Ningbo Geng, Jiping Chen.

  Short-chain chlorinated paraffins (SCCPs) disturb cellular energy metabolism in vitro, but their subcellular toxicity mechanisms are incompletely understood. This study employed mitochondrial metabolomics integrated with phenotypic assays to investigate the subcellular mechanisms of SCCP-induced energy metabolism inhibition. Exposure to SCCPs (0-100 μg/L) caused profound downregulation of ATP. Seahorse respirometry analyses revealed the dose-dependent inhibition of oxidative phosphorylation and compensatory upregulation of glycolysis. Mitochondrial ultrastructural damage (swelling and cristae loss) and dissipation of mitochondrial membrane potential confirmed mitochondria as the primary targets of SCCPs. Mitochondrial metabolomics demonstrated that the suppression of the TCA cycle (depleted citrate, oxaloacetate) and OXPHOS (reduced NAD+, ATP/ADP; inhibited Complex V activity) is responsible for the downregulation of ATP. The conversion from phosphatidylcholines to lysophosphatidylcholines further verified mitochondrial membrane damage. Perturbations in nucleotide metabolism reflected impaired synthesis pathways for DNA/RNA. Critically, medium-chain chlorinated paraffins (MCCPs), proposed as SCCP substitutes, induced qualitatively similar mitochondrial damage (respiration inhibition, cristae disruption, and ΔΨm loss), challenging the presumed safety of MCCPs as alternatives. This study revealed the key mechanisms of SCCP induced energy metabolism inhibition at the subcellular level, underscoring the need for careful reconsideration of MCCP usage.

Keywords:  ATP Inhibition; SCCPs; Seahorse respirometry; mitochondrial dysfunction; mitochondrial metabolomics; oxidative phosphorylation (OXPHOS)

DOI:  https://doi.org/10.1021/acs.est.5c12098
Trends Biochem Sci. 2025 Dec 05. pii: S0968-0004(25)00266-X. [Epub ahead of print]

Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.

Denis Lacabanne, Jonathan J Ruprecht, Maximilian Sichrovsky, Lucy R Forrest, Vanessa Leone, Sotiria Tavoulari, Edmund R S Kunji.

  The mitochondrial pyruvate carrier (MPC), of the SLC54 family of solute carriers, has a critical role in eukaryotic energy metabolism by transporting pyruvate, the end-product of glycolysis, into the mitochondrial matrix. Recently, structures of the human MPC1/MPC2 and MPC1L/MPC2 heterodimers in the outward-open, occluded, and inward-open states have been determined by cryo-electron microscopy (cryo-EM) and by AlphaFold modeling. In this review we discuss the membrane orientation, substrate binding site properties, and structural features of the alternating access mechanism of the carrier, as well as the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state. These structural studies will support drug development efforts for the treatment of diabetes mellitus, neurodegeneration, metabolic dysfunction-associated steatotic liver disease (MASLD), and some types of cancers.

Keywords:  alternating access transport mechanism; membrane protein structure; mitochondrion; solute carrier family SLC54; structure-based drug design; sugar and energy metabolism

DOI:  https://doi.org/10.1016/j.tibs.2025.11.002
Int J Mol Sci. 2025 Nov 30. pii: 11628. [Epub ahead of print]26(23):

CPX-351 and the Frontier of Nanoparticle-Based Therapeutics in Acute Myeloid Leukemia.

Ioannis Konstantinidis, Sophia Tsokkou, Antonios Keramas, Eleni Gavriilaki, Georgios Delis, Theodora Papamitsou.

  Acute myeloid leukemia (AML) continues to carry a dismal prognosis in older adults and those with secondary or high-risk disease, where conventional 7 + 3 chemotherapy has long delivered complete remission rates below 40% and median overall survival often under 6 months. CPX-351 (Vyxeos), a liposomal co-encapsulation of cytarabine and daunorubicin at a fixed synergistic 5:1 molar ratio, was designed to overcome the pharmacokinetic mismatch that undermines the traditional regimen. This review critically examines the preclinical rationale and clinical evidence for CPX-351, with particular attention to whether its nanoparticle platform truly represents a breakthrough or merely an incremental refinement of decades-old cytotoxics. Across phase I-III trials and real-world cohorts, CPX-351 consistently outperformed standard 7 + 3 in its approved populations of newly diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC) in patients aged 60-75 years. In the pivotal phase III study (n = 309), CPX-351 improved median overall survival from 5.95 to 9.56 months (HR 0.69, 95% CI 0.52-0.90; p = 0.005) and raised the complete remission rate from 33.3% to 47.7%, while facilitating allogeneic transplantation in 34% as opposed to 25% of patients. A five-year follow-up sustained the separation in survival curves, and post-hoc analyses of responders showed median overall survival exceeding 25 months with CPX-351 versus approximately 10 months with 7 + 3 (HR 0.49). Real-world series have reported composite remission rates of 53-60%, measurable residual disease negativity in up to 65% of responders, and median overall survival of 12-20 months, depending on transplant utilization. Despite these gains, the absolute survival benefit remains modest, prolonged cytopenias are universal, and outcomes in TP53-mutated or younger adverse-risk patients are still poor, raising legitimate questions about cost-effectiveness and generalizability. Nonetheless, CPX-351 stands as the first clinically validated example of ratiometric nanomedicine in oncology, proving that reformulating established drugs can yield meaningful progress where novel agents have often failed.

Keywords:  AML-MRC; CPX-351; MRD negativity; acute myeloid leukemia (AML); cytarabine; daunorubicin; liposomal drug delivery; nanoparticle therapeutics; therapy-related AML; translational oncology

DOI:  https://doi.org/10.3390/ijms262311628