bims-medica 2025-02-02 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

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

Comprehensive Overview of Ketone Bodies in Cancer Metabolism: Mechanisms and Application.
A genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells.
Critical Review of Ketogenic Diet Throughout the Cancer Continuum for Neuroglioma: Insights from a Medical Nutrition Therapy (MNT) Perspective.
Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival.
The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives.
Fluorescence lifetime imaging microscopy for metabolic analysis of LDHB inhibition in triple negative breast cancer.
Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.
Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells.
Ketogenic diet with oxyresveratrol and zinc inhibits glioblastoma and restores memory function and motor coordination.
Alteration of Lipid Metabolism in Hypoxic Cancer Cells.
Sex-related changes in lactate dehydrogenase A expression differently impact the immune response in melanoma.
Nicotinamide mononucleotide restores impaired metabolism, endothelial cell proliferation and angiogenesis in old sedentary male mice.
Invasive lobular carcinoma integrated multi-omics analysis reveals silencing of Arginosuccinate synthase and upregulation of nucleotide biosynthesis in tamoxifen resistance.
Endurance training and pyruvate dehydrogenase kinase 4 (PDK4) inhibition combination is superior to each one alone in attenuating hyperketonemia/ketoacidosis in diabetic rats.
Sex differences in the metabolism of glucose and fatty acids by adipose tissue and skeletal muscle in humans.
Subcellular mitochondrial heterogeneity enables opposing metabolic demands.
NADH Reductive Stress and Its Correlation with Disease Severity in Leigh Syndrome: A Pilot Study Using Patient Fibroblasts and a Mouse Model.
Effective eradication of acute myeloid leukemia stem cells with FLT3-directed antibody-drug conjugates.
The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity.
A human metabolic map of pharmacological perturbations reveals drug modes of action.
Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability.
Concurrent inhibition of p300/CBP and FLT3 enhances cytotoxicity and overcomes resistance in acute myeloid leukemia.
The association between dietary creatine intake and cancer in U.S. adults: insights from NHANES 2007-2018.
Flux measurements of the tricarboxylic acid cycle in the tumors of mice.
Glutamine and cancer: metabolism, immune microenvironment, and therapeutic targets.
Stochasticity in dietary restriction-mediated lifespan outcomes in Drosophila.
Olaparib-induced hyperglycemia in ovarian cancer patients - a case series analysis of a three-month therapy with a consideration of BMI.

Biomedicines. 2025 Jan 16. pii: 210. [Epub ahead of print]13(1):

Comprehensive Overview of Ketone Bodies in Cancer Metabolism: Mechanisms and Application.

Ziyuan Liang, Lixian Deng, Xiaoying Zhou, Zhe Zhang, Weilin Zhao.

  Reprogramming energy metabolism is pivotal to tumor development. Ketone bodies (KBs), which are generated during lipid metabolism, are fundamental bioactive molecules that can be modulated to satisfy the escalating metabolic needs of cancer cells. At present, a burgeoning body of research is concentrating on the metabolism of KBs within tumors, investigating their roles as signaling mediators, drivers of post-translational modifications, and regulators of inflammation and oxidative stress. The ketogenic diet (KD) may enhance the sensitivity of various cancers to standard therapies, such as chemotherapy and radiotherapy, by exploiting the reprogrammed metabolism of cancer cells and shifting the metabolic state from glucose reliance to KB utilization, rendering it a promising candidate for adjunct cancer therapy. Nonetheless, numerous questions remain regarding the expression of key metabolic genes across different tumors, the regulation of their activities, and the impact of individual KBs on various tumor types. Further investigation is imperative to resolve the conflicting data concerning KB synthesis and functionality within tumors. This review aims to encapsulate the intricate roles of KBs in cancer metabolism, elucidating a comprehensive grasp of their mechanisms and highlighting emerging clinical applications, thereby setting the stage for future investigations into their therapeutic potential.

Keywords:  ketogenic diet; ketone bodies; metabolism; therapeutic approach; tumor

DOI:  https://doi.org/10.3390/biomedicines13010210
Cell Chem Biol. 2025 Jan 21. pii: S2451-9456(25)00002-9. [Epub ahead of print]

A genetically encoded fluorescent biosensor for visualization of acetyl-CoA in live cells.

Joseph J Smith, Taylor R Valentino, Austin H Ablicki, Riddhidev Banerjee, Adam R Colligan, Debra M Eckert, Gabrielle A Desjardins, Katharine L Diehl.

  Acetyl-coenzyme A is a central metabolite that participates in many cellular pathways. Evidence suggests that acetyl-CoA metabolism is highly compartmentalized in mammalian cells. Yet methods to measure acetyl-CoA in living cells are lacking. Herein, we engineered an acetyl-CoA biosensor from the bacterial protein PanZ and circularly permuted green fluorescent protein (cpGFP). The sensor, "PancACe," has a maximum change of ∼2-fold and a response range of ∼10 μM-2 mM acetyl-CoA. We demonstrated that the sensor has a greater than 7-fold selectivity over coenzyme A, butyryl-CoA, malonyl-CoA, and succinyl-CoA, and a 2.3-fold selectivity over propionyl-CoA. We expressed the sensor in E. coli and showed that it enables detection of rapid changes in acetyl-CoA levels. By localizing the sensor to either the cytoplasm, nucleus, or mitochondria in human cells, we showed that it enables subcellular detection of changes in acetyl-CoA levels, the magnitudes of which agreed with an orthogonal PicoProbe assay.

Keywords:  acetyl-CoA; biosensor; coenzyme A; metabolism; metabolite; protein engineering

DOI:  https://doi.org/10.1016/j.chembiol.2025.01.002
Curr Nutr Rep. 2025 Jan 30. 14(1): 24

Critical Review of Ketogenic Diet Throughout the Cancer Continuum for Neuroglioma: Insights from a Medical Nutrition Therapy (MNT) Perspective.

Kristina D Thomopoulos-Titomihelakis, Hillary Sach, Rayna McCann, Qianhui Zhang, Sydney Kurnit, Genesis Codoni De Juan, Amanda Rushing.

  PURPOSE OF REVIEW: A Ketogenic diet (KD; a diet comprised of 75% fat, 20% protein and 5% carbohydrates) has gained much popularity in recent years, especially regarding neurogliomas (or "gliomas"). This review critically assesses literature on the application of KD throughout the cancer continuum from a Medical Nutrition Therapy (MNT) perspective. RECENT FINDINGS: 2021 revised classification standards for Central Nervous System (CNS) tumors are available. Despite research on KD and CNS tumors increasing, the role and benefits of MNT to augment side effects of traditional treatment and KD throughout the cancer continuum remain unclear. Glioma cancer survivors may benefit from a KD. It is a challenging, yet feasible non-pharmacological adjuvant approach. More research is needed regarding KD for prevention and post-treatment of glioma. Standard guidelines regarding macronutrient composition of KD for glioma are warranted. The need and benefits of nutritional guidance provided by a Registered Dietitian Nutritionist (RD or RDNs) during adherence to KD are understated.

Keywords:  Cancer survivorship; Glioma; Intermittent fasting; Ketogenic diet; Medical nutrition therapy; Neuroglioma

DOI:  https://doi.org/10.1007/s13668-025-00609-4
Cell Commun Signal. 2025 Jan 25. 23(1): 47

Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival.

Monika Komza, Jesminara Khatun, Jesse D Gelles, Andrew P Trotta, Ioana Abraham-Enachescu, Juan Henao, Ahmed Elsaadi, Andriana G Kotini, Cara Clementelli, JoAnn Arandela, Sebastian El Ghaity-Beckley, Agneesh Barua, Yiyang Chen, Mirela Berisa, Bridget K Marcellino, Eirini P Papapetrou, Masha V Poyurovsky, Jerry Edward Chipuk.

  One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.

Keywords:  Adaptations; Bioenergetics; Cancer; Chemotherapy; Glucose; Leukemia; Metabolism; Mitochondria; Oncogenes; Stem cells

DOI:  https://doi.org/10.1186/s12964-025-02044-y
Int J Mol Sci. 2024 Dec 26. pii: 92. [Epub ahead of print]26(1):

The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives.

Amer Ahmed, Giorgia Natalia Iaconisi, Daria Di Molfetta, Vincenzo Coppola, Antonello Caponio, Ansu Singh, Aasia Bibi, Loredana Capobianco, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte.

  Cancer cells undergo remarkable metabolic changes to meet their high energetic and biosynthetic demands. The Warburg effect is the most well-characterized metabolic alteration, driving cancer cells to catabolize glucose through aerobic glycolysis to promote proliferation. Another prominent metabolic hallmark of cancer cells is their increased reliance on glutamine to replenish tricarboxylic acid (TCA) cycle intermediates essential for ATP production, aspartate and fatty acid synthesis, and maintaining redox homeostasis. In this context, mitochondria, which are primarily used to maintain energy homeostasis and support balanced biosynthesis in normal cells, become central organelles for fulfilling the heightened biosynthetic and energetic demands of proliferating cancer cells. Mitochondrial coordination and metabolite exchange with other cellular compartments are crucial. The human SLC25 mitochondrial carrier family, comprising 53 members, plays a pivotal role in transporting TCA intermediates, amino acids, vitamins, nucleotides, and cofactors across the inner mitochondrial membrane, thereby facilitating this cross-talk. Numerous studies have demonstrated that mitochondrial carriers are altered in cancer cells, actively contributing to tumorigenesis. This review comprehensively discusses the role of SLC25 carriers in cancer pathogenesis and metabolic reprogramming based on current experimental evidence. It also highlights the research gaps that need to be addressed in future studies. Understanding the involvement of these carriers in tumorigenesis may provide valuable novel targets for drug development.

Keywords:  cancer; metabolic reprogramming; metabolism; mitochondria; mitochondrial carriers

DOI:  https://doi.org/10.3390/ijms26010092
bioRxiv. 2025 Jan 18. pii: 2025.01.13.632864. [Epub ahead of print]

Fluorescence lifetime imaging microscopy for metabolic analysis of LDHB inhibition in triple negative breast cancer.

A Galloway, B Ter Hofstede, Alex J Walsh.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with no targeted treatments currently available. TNBC cells participate in metabolic symbiosis, a process that optimizes tumor growth by balancing metabolic processes between glycolysis and oxidative phosphorylation through increased activity by the enzyme lactate dehydrogenase B (LDHB). Metabolic symbiosis allows oxidative cancer cells to function at a similar rate as glycolytic cancer cells, increasing overall metabolic activity and proliferation. Here, fluorescence lifetime imaging microscopy (FLIM) is used to analyze the metabolism of TNBC cells with inhibition of LDHB using a multiphoton microscope to measure the fluorescent lifetimes of two metabolic coenzymes, NAD(P)H and FAD. LDHB is inhibited via an indole derivative known as AXKO-0046 in varying concentrations. Understanding how TNBC cell metabolism changes due to LDHB inhibition will provide further insight into metabolic symbiosis and potential new TNBC treatment options.

DOI: https://doi.org/10.1101/2025.01.13.632864
Sci Adv. 2025 Jan 31. 11(5): eads0535

Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.

Eric D Queathem, Zahra Moazzami, David B Stagg, Alisa B Nelson, Kyle Fulghum, Abdirahman Hayir, Alisha Seay, Jacob R Gillingham, D André d'Avignon, Xianlin Han, Hai-Bin Ruan, Peter A Crawford, Patrycja Puchalska.

Ketogenesis is a dynamic metabolic conduit supporting hepatic fat oxidation particularly when carbohydrates are in short supply. Ketone bodies may be recycled into anabolic substrates, but a physiological role for this process has not been identified. Here, we use mass spectrometry-based 13C-isotope tracing and shotgun lipidomics to establish a link between hepatic ketogenesis and lipid anabolism. Unexpectedly, mouse liver and primary hepatocytes consumed ketone bodies to support fatty acid biosynthesis via both de novo lipogenesis (DNL) and polyunsaturated fatty acid (PUFA) elongation. While an acetoacetate intermediate was not absolutely required for ketone bodies to source DNL, PUFA elongation required activation of acetoacetate by cytosolic acetoacetyl-coenzyme A synthetase (AACS). Moreover, AACS deficiency diminished free and esterified PUFAs in hepatocytes, while ketogenic insufficiency depleted PUFAs and increased liver triacylglycerols. These findings suggest that hepatic ketogenesis influences PUFA metabolism, representing a molecular mechanism through which ketone bodies could influence systemic physiology and chronic diseases.

DOI: https://doi.org/10.1126/sciadv.ads0535
Cell Mol Biol Lett. 2025 Jan 09. 30(1): 3

Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells.

Adhish S Walvekar, Marc Warmoes, Dean Cheung, Tim Sikora, Najmesadat Seyedkatouli, Gemma Gomez-Giro, Sebastian Perrone, Lisa Dengler, François Unger, Bruno F R Santos, Floriane Gavotto, Xiangyi Dong, Julia Becker-Kettern, Yong-Jun Kwon, Christian Jäger, Jens C Schwamborn, Nicole J Van Bergen, John Christodoulou, Carole L Linster.

   BACKGROUND: Metabolism is error prone. For instance, the reduced forms of the central metabolic cofactors nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH), can be converted into redox-inactive products, NADHX and NADPHX, through enzymatically catalyzed or spontaneous hydration. The metabolite repair enzymes NAXD and NAXE convert these damaged compounds back to the functional NAD(P)H cofactors. Pathogenic loss-of-function variants in NAXE and NAXD lead to development of the neurometabolic disorders progressive, early-onset encephalopathy with brain edema and/or leukoencephalopathy (PEBEL)1 and PEBEL2, respectively.
METHODS: To gain insights into the molecular disease mechanisms, we investigated the metabolic impact of NAXD deficiency in human cell models. Control and NAXD-deficient cells were cultivated under different conditions, followed by cell viability and mitochondrial function assays as well as metabolomic analyses without or with stable isotope labeling. Enzymatic assays with purified recombinant proteins were performed to confirm molecular mechanisms suggested by the cell culture experiments.
RESULTS: HAP1 NAXD knockout (NAXDko) cells showed growth impairment specifically in a basal medium containing galactose instead of glucose. Surprisingly, the galactose-grown NAXDko cells displayed only subtle signs of mitochondrial impairment, whereas metabolomic analyses revealed a strong inhibition of the cytosolic, de novo serine synthesis pathway in those cells as well as in NAXD patient-derived fibroblasts. We identified inhibition of 3-phosphoglycerate dehydrogenase as the root cause for this metabolic perturbation. The NAD precursor nicotinamide riboside (NR) and inosine exerted beneficial effects on HAP1 cell viability under galactose stress, with more pronounced effects in NAXDko cells. Metabolomic profiling in supplemented cells indicated that NR and inosine act via different mechanisms that at least partially involve the serine synthesis pathway.
CONCLUSIONS: Taken together, our study identifies a metabolic vulnerability in NAXD-deficient cells that can be targeted by small molecules such as NR or inosine, opening perspectives in the search for mechanism-based therapeutic interventions in PEBEL disorders.

Keywords:  3-Phosphoglycerate dehydrogenase; Inborn errors of metabolism; Inosine; Metabolite damage and repair; NAD(P)H hydration; NAXD; Nicotinamide riboside; Serine biosynthesis

DOI:  https://doi.org/10.1186/s11658-024-00681-8
Oncol Res. 2025 ;33(2): 381-395

Ketogenic diet with oxyresveratrol and zinc inhibits glioblastoma and restores memory function and motor coordination.

Tanvi Vijay Gujaran, Vignesh Balaji Easwaran, Runali Sankhe, Pugazhandhi Bakthavatchalam, Herman Sunil Dsouza, K Sreedhara Ranganath Pai.

   Background: To date, there is no effective cure for the highly malignant brain tumor glioblastoma (GBM). GBM is the most common, aggressive central nervous system tumor (CNS). It commonly originates in glial cells such as microglia, oligodendroglia, astrocytes, or subpopulations of cancer stem cells (CSCs). Glucose plays an important role in the, which energy metabolism of normal and cancer cells, but cancer cells exhibit an increased demand for glucose is required for their differentiation and proliferation. The main aim of this study is to explore the anti-cancer efficacy of the ketogenic diet against GBM. Also, this research focuses on the identification of the catalytic action of zinc in epigenetic modulators such as oxyresveratrol and ensures the combinatorial effect in the treatment of GBM.
Method: In this study, we have evaluated various parameters to understand the therapeutic efficacy of the treatment groups through in vivo experiments against aggressive brain tumors. Intracerebroventricular experiments were performed to induce the tumor in the animals and estimate the tumor burden and proliferative index. Followed by the Morris water maze, an open field test, and rota rod was performed to evaluate the memory and motor coordination. To understand the glucose, and ketone level modification before and after treatment, the level of glucose and ketone was analyzed. Moreover, the zinc level is assessed using flame atomic absorption spectroscopy.
Results: The results suggested that the ketogenic diet has an anti-cancer efficacy against C6-induced GBM cell lines. Also, it exerts a synergistic effect with the epigenetic modulator, oxyresveratrol, and zinc against GBM cell lines. Moreover, the treatment groups improved memory and motor coordination and modified the glucose and ketone levels to reduce the tumor burden and Ki-67 proliferative index.
Conclusion: This study revealed the therapeutic effect of the ketogenic diet along with its combination such as oxyresveratrol and zinc against the C6-induced GBM in the Wistar rats. Also, it improved memory and motor coordination and reduced tumor growth. It also modified the glucose and ketone levels in the tumor-induced animal and supported to diminish the tumor burden.

Keywords:  Glioblastoma (GBM); Ketogenic diet (KD); Oxyresveratrol; Warburg effect; Zinc

DOI:  https://doi.org/10.32604/or.2024.049538
Chem Biomed Imaging. 2025 Jan 27. 3(1): 25-34

Alteration of Lipid Metabolism in Hypoxic Cancer Cells.

Gil A Gonzalez, Ezinne U Osuji, Natalie C Fiur, Matthew G Clark, Seohee Ma, Laura L Lukov, Chi Zhang.

Due to uncontrolled cell proliferation and disrupted vascularization, many cancer cells in solid tumors have limited oxygen supply. The hypoxic microenvironments of tumors lead to metabolic reprogramming of cancer cells, contributing to therapy resistance and metastasis. To identify better targets for the effective removal of hypoxia-adaptive cancer cells, it is crucial to understand how cancer cells alter their metabolism in hypoxic conditions. Here, we studied lipid metabolic changes in cancer cells under hypoxia using coherent Raman scattering (CRS) microscopy. We discovered the accumulation of lipid droplets (LDs) in the endoplasmic reticulum (ER) in hypoxia. Time-lapse CRS microscopy revealed the release of old LDs and the reaccumulated LDs in the ER during hypoxia exposure. Additionally, we explored the impact of carbon sources on LD formation and found that MIA PaCa2 cells preferred fatty acid uptake for LD formation, while glucose was essential to alleviate lipotoxicity. Hyperspectral-stimulated Raman scattering (SRS) microscopy revealed a reduction in cholesteryl ester content and a decrease in lipid saturation levels of LDs in hypoxic MIA PaCa2 cancer cells. This alteration in LD content is linked to reduced efficacy of treatments targeting cholesteryl ester formation. This study unveils important lipid metabolic changes in hypoxic cancer cells, providing insights that could lead to better treatment strategies for hypoxia-resistant cancer cells.

DOI: https://doi.org/10.1021/cbmi.4c00050
FEBS J. 2025 Jan 31.

Sex-related changes in lactate dehydrogenase A expression differently impact the immune response in melanoma.

Marta Iozzo, Giuseppina Comito, Luigi Ippolito, Giada Sandrini, Elisa Pardella, Erica Pranzini, Mariaelena Capone, Gabriele Madonna, Paolo Antonio Ascierto, Paola Chiarugi, Elisa Giannoni.

  Melanoma is more aggressive in male patients than female ones and this is associated with sexual dimorphism in immune responses. Taking into consideration the impact tumour metabolic alterations in affecting the immune landscape, we aimed to investigate the effect of the sex-dependent metabolic profile of melanoma in re-shaping immune composition. Melanoma is characterised by Warburg metabolism, and secreted lactate has emerged as a key driver in the establishment of an immunosuppressive environment. Here, we identified lactate dehydrogenase A (LDH-A) as a crucial player in modulating sex-related differences in melanoma immune responses, both in vitro and in patient-derived specimens. LDH-A is associated with higher lactate secretion in male melanoma cells, which leads to a significant enrichment in pro-tumoural regulatory T cells (Treg) with a concurrent decrease in the number and activity of anti-tumour CD8+ T cells. Remarkably, pharmacological and genetic impairment of LDH-A in male melanoma cells normalises Treg and CD8+ infiltration. In keeping with this, in vivo pharmacological targeting of LDH-A in melanoma-bearing male mice impairs tumour growth and lung colonisation, with a concomitant modulation of Treg and CD8+ T cells infiltration. Taken together, our findings highlight the sex-related differences promoted by LDH-A in immune reshaping in melanoma, and suggest that therapeutic targeting of LDH-A could be leveraged as an effective strategy to abolish the sex-gap in melanoma progression.

Keywords:  CD8+; Treg; lactate; melanoma; sex

DOI:  https://doi.org/10.1111/febs.17423
iScience. 2025 Jan 17. 28(1): 111656

Nicotinamide mononucleotide restores impaired metabolism, endothelial cell proliferation and angiogenesis in old sedentary male mice.

Kevin Kiesworo, Thomas Agius, Michael R Macarthur, Martine Lambelet, Arnaud Lyon, Jing Zhang, Guillermo Turiel, Zheng Fan, Sènan d'Almeida, Korkut Uygun, Heidi Yeh, Sébastien Déglise, Katrien de Bock, Sarah J Mitchell, Alejandro Ocampo, Florent Allagnat, Alban Longchamp.

  Aging is accompanied by a decline in neovascularization potential and increased susceptibility to ischemic injury. Here, we confirm the age-related impaired neovascularization following ischemic leg injury and impaired angiogenesis. The age-related deficits in angiogenesis arose primarily from diminished EC proliferation capacity, but not migration or VEGF sensitivity. Aged EC harvested from the mouse skeletal muscle displayed a pro-angiogenic gene expression phenotype, along with considerable changes in metabolic genes. Metabolomics analysis and 13C glucose tracing revealed impaired ATP production and blockade in glycolysis and TCA cycle in late passage HUVECs, which occurred at nicotinamide adenine dinucleotide (NAD⁺)-dependent steps, along with NAD+ depletion. Supplementation with nicotinamide mononucleotide (NMN), a precursor of NAD⁺, enhances late-passage EC proliferation and sprouting angiogenesis from aged mice aortas. Taken together, our study illustrates the importance of NAD+-dependent metabolism in the maintenance of EC proliferation capacity with age, and the therapeutic potential of NAD precursors.

Keywords:  Cellular physiology; Metabolomics

DOI:  https://doi.org/10.1016/j.isci.2024.111656
bioRxiv. 2025 Jan 17. pii: 2025.01.16.633236. [Epub ahead of print]

Invasive lobular carcinoma integrated multi-omics analysis reveals silencing of Arginosuccinate synthase and upregulation of nucleotide biosynthesis in tamoxifen resistance.

Annapurna Gupta, Fouad Choueiry, Jesse Reardon, Nikhil Pramod, Anagh Kulkarni, Eswar Shankar, Steven T Sizemore, Daniel G Stover, Jiangjiang Zhu, Bhuvaneswari Ramaswamy, Sarmila Majumder.

Invasive Lobular Carcinoma (ILC), a distinct subtype of breast cancer is hallmarked by E-Cadherin loss, slow proliferation, and strong hormone receptor positivity. ILC faces significant challenges in clinical management due to advanced stage at diagnosis, late recurrence, and development of resistance to endocrine therapy - a cornerstone of ILC treatment. To elucidate the mechanisms underlying endocrine resistance in ILC, ILC cell lines (MDA-MB-134-VI, SUM44PE) were generated to be resistant to tamoxifen, a selective estrogen receptor modulator. The tamoxifen-resistant (TAMR) cells exhibit a 2-fold increase tamoxifen IC 50 relative to parental cells. Metabolomics and RNA-sequencing revealed deregulation of alanine, aspartate, and glutamate metabolism, purine metabolism, and arginine and proline metabolism in TAMR cells. Among the fifteen commonly dysregulated genes in these pathways, low ASS1 expression was identified in the TAMR cells and was significantly correlated with poor outcome in ILC patients, specifically in the context of endocrine therapy. Our study reveals methylation mediated silencing of ASS1 in TAMR cells as a likely mechanism of downregulation. Demethylation restored ASS1 expression and correspondingly reduced tamoxifen IC 50 toward parental levels. Nucleic acid biosynthesis is augmented in TAMR cells, evidenced by increase in nucleotide intermediates. Both TAMR cell lines demonstrated increased expression of several nucleic acid biosynthesis enzymes, including PAICS, PRPS1, ADSS2, CAD, and DHODH . Furthermore, CAD, the key multifunctional protein of de novo pyrimidine biosynthesis pathway is differentially activated in TAMR cells. Treating TAMR cell with Decitabine, a demethylating agent, or Farudodstat, a pyrimidine biosynthesis inhibitor, markedly augmented efficacy of tamoxifen. Collectively, our study unveils ASS1 downregulation as a novel mechanism underlying acquired tamoxifen resistance in ILC and establishes a metabolic link between ASS1 and nucleic acid biosynthesis. Restoring ASS1 expression or inhibiting pyrimidine biosynthesis restored tamoxifen sensitivity. ASS1 could be a potential biomarker and therapeutic target in tamoxifen resistant ILC patients, warranting further investigation.

DOI: https://doi.org/10.1101/2025.01.16.633236
Iran J Basic Med Sci. 2025 ;28(1): 80-86

Endurance training and pyruvate dehydrogenase kinase 4 (PDK4) inhibition combination is superior to each one alone in attenuating hyperketonemia/ketoacidosis in diabetic rats.

Hamed Rezaeinasab, Abdolhamid Habibi, Ramin Rezaei, Aref Basereh, Salva Reverentia Yurista, Kayvan Khoramipour.

   Objectives: While ketone bodies are not the main heart fuel, exercise may increase their uptake. Objectives: This study aimed to investigate the effect of 6-week endurance training and Pyruvate dehydrogenase kinase 4 )PDK4( inhibition on ketone bodies metabolism in the heart of diabetic rats with emphasis on the role of Peroxisome proliferator-activated receptor-gamma coactivator PGC-1alpha (PGC-1α).
Materials and Methods: Sixty male Wistar rats were divided into eight groups: healthy control group (CONT), endurance training group (TRA), diabetic group (DM), DM + EX group, Dichloroacetate (DCA) group, DM + DCA group, TRA + DCA group, and DM + TRA + DCA group. Diabetes was induced using streptozotocin (STZ). The animals in training groups ran on the treadmill for six weeks (30-50 min running at 20-30 m/min). After the training period, molecular markers for mitochondrial biogenesis and ketone metabolism were assessed in the heart. Circulating ß-hydroxybutyrate (ßOHB) and Acetylacetonate (AcAc) levels were also measured.
Results: Our results showed that 6-week endurance training increased the cardiac expression of PGC-1α, 3-oxoacid CoA-transferase 1 (OXCT1), and Acetyl-CoA Acetyltransferase 1 (ACAT1) and reduced beta-hydroxybutyrate dehydrogenase1 (BDH1) expression (P≤0.05). In addition, exercise and DCA usage significantly decreased PDK4 gene expression, ßOHB, and AcAc blood levels (P≤0.05). Furthermore, the combination of 6-week endurance training and DCA supplementation led to more reduction in PDFK4 gene expression, ßOHB, and AcAc blood levels.
Conclusion: Six-week endurance training and DCA supplementation could safely improve ketone body metabolism in the heart, ultimately reducing hyperketonemia/ketoacidosis in diabetic rats.

Keywords:  Dietary supplements; Endurance training; Gene expression; Ketone bodies; Ketosis; Pyruvate dehydrogenase - kinase 4

DOI:  https://doi.org/10.22038/ijbms.2024.79864.17305
Physiol Rev. 2025 Jan 27.

Sex differences in the metabolism of glucose and fatty acids by adipose tissue and skeletal muscle in humans.

Damla N Costa, Sylvia Santosa, Michael D Jensen.

  Adult males and females have markedly different body composition, energy expenditure, and have different degrees of risk for metabolic diseases. A major aspect of metabolic regulation involves the appropriate storage and disposal of glucose and fatty acids. The use of sophisticated calorimetry, tracer, and imaging techniques have provided insight into the complex metabolism of these substrates showing that the regulation of these processes varies tremendously throughout the day, from the overnight fasting condition to meal ingestion, to the effects of physical activity. The sexual dimorphism in substrate metabolism is most readily observed in how fatty acids are stored and mobilized. The objective of this review is to provide a comprehensive and critical summary of the reported sex-differences in the mobilization, oxidation and storage of fat and carbohydrate in adipose tissue and skeletal muscle. We will describe how adipose tissue lipolysis differs between sexes, and how this varies between fed, fasted and exercise conditions. We will also review what is known about endogenous and exogenous fatty acid storage in adipose tissue and muscle, as well as how oxidation compares between men and women in response to exercise. What has been learned about the cellular level regulation of these processes will be described. Although glucose metabolism exhibits fewer differences between men and women, we will also review the existing knowledge on this topic.

Keywords:  exercise; fatty acids; glucose; metabolism; sex differences

DOI:  https://doi.org/10.1152/physrev.00008.2024
Trends Endocrinol Metab. 2025 Jan 28. pii: S1043-2760(25)00003-7. [Epub ahead of print]

Subcellular mitochondrial heterogeneity enables opposing metabolic demands.

Brandon Chen, Yatrik M Shah, Costas A Lyssiotis.

  Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell. They demonstrate that subcellular mitochondrial heterogeneity enables metabolic compartmentalization to permit concurrent oxidative ATP production and reductive proline biosynthesis.

Keywords:  metabolic compartmentalization; mitochondria dynamics; mitochondrial ultrastructure; organelle communication; proline metabolism

DOI:  https://doi.org/10.1016/j.tem.2025.01.003
Biomolecules. 2024 Dec 31. pii: 38. [Epub ahead of print]15(1):

NADH Reductive Stress and Its Correlation with Disease Severity in Leigh Syndrome: A Pilot Study Using Patient Fibroblasts and a Mouse Model.

Tamaki Ishima, Natsuka Kimura, Mizuki Kobayashi, Chika Watanabe, Eriko F Jimbo, Ryosuke Kobayashi, Takuro Horii, Izuho Hatada, Kei Murayama, Akira Ohtake, Ryozo Nagai, Hitoshi Osaka, Kenichi Aizawa.

  Nicotinamide adenine dinucleotide (NAD) is a critical cofactor in mitochondrial energy production. The NADH/NAD+ ratio, reflecting the balance between NADH (reduced) and NAD+ (oxidized), is a key marker for the severity of mitochondrial diseases. We recently developed a streamlined LC-MS/MS method for the precise measurement of NADH and NAD+. Utilizing this technique, we quantified NADH and NAD+ levels in fibroblasts derived from pediatric patients and in a Leigh syndrome mouse model in which mitochondrial respiratory chain complex I subunit Ndufs4 is knocked out (KO). In patient-derived fibroblasts, NAD+ levels did not differ significantly from those of healthy controls (p = 0.79); however, NADH levels were significantly elevated (p = 0.04), indicating increased NADH reductive stress. This increase, observed despite comparable total NAD(H) levels between the groups, was attributed to elevated NADH levels. Similarly, in the mouse model, NADH levels were significantly increased in the KO group (p = 0.002), further suggesting that NADH elevation drives reductive stress. This precise method for NADH measurement is expected to outperform conventional assays, such as those for lactate, providing a simpler and more reliable means of assessing disease progression.

Keywords:  LC-MS/MS; Leigh syndrome; NADH; Ndufs4-KO mice; mitochondrial diseases; reductive stress

DOI:  https://doi.org/10.3390/biom15010038
Leukemia. 2025 Jan 27.

Effective eradication of acute myeloid leukemia stem cells with FLT3-directed antibody-drug conjugates.

Marina Able, Marc-André Kasper, Binje Vick, Jonathan Schwach, Xiang Gao, Saskia Schmitt, Belay Tizazu, Amrei Fischer, Sarah Künzl, Marit Leilich, Isabelle Mai, Philipp Ochtrop, Andreas Stengl, Mark A R de Geus, Michael von Bergwelt-Baildon, Dominik Schumacher, Jonas Helma, Christian P R Hackenberger, Katharina S Götze, Irmela Jeremias, Heinrich Leonhardt, Michaela Feuring, Karsten Spiekermann.

Refractory disease and relapse are major challenges in acute myeloid leukemia (AML) therapy attributed to survival of leukemic stem cells (LSC). To target LSCs, antibody-drug conjugates (ADCs) provide an elegant solution, combining the specificity of antibodies with highly potent payloads. We aimed to investigate if FLT3-20D9h3-ADCs delivering either the DNA-alkylator duocarmycin (DUBA) or the microtubule-toxin monomethyl auristatin F (MMAF) can eradicate quiescent LSCs. We show here that DUBA more potently kills cell-cycle arrested AML cells compared to microtubule-targeting auristatins. Due to limited stability of 20D9h3-DUBA ADC in vivo, we analyzed both ADCs in advanced in vitro stem cell assays. 20D9h3-DUBA successfully eliminated leukemic progenitors in vitro in colony-forming unit and long-term culture initiating cell assays, both in patient cells and in patient-derived xenograft (PDX) cells. Further, it completely prevented engraftment of AML PDX leukemia-initiating cells in NSG mice. 20D9h3-MMAF had a similar effect in engraftment assays, but a less prominent effect in colony assays. Both ADCs did not affect healthy stem and progenitor cells at comparable doses providing the rationale for FLT3 as therapeutic LSC target. Collectively, we show that FLT3-directed ADCs with DUBA or MMAF have potent activity against AML LSCs and represent promising candidates for further clinical development.

DOI: https://doi.org/10.1038/s41375-024-02510-5
Cell Rep. 2025 Jan 24. pii: S2211-1247(24)01580-8. [Epub ahead of print]44(2): 115229

The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity.

DUTRENEO Study Investigators

  Tumors are complex ecosystems of interacting cell types. The concept of cancer hallmarks distills this complexity into underlying principles that govern tumor growth. Here, we explore the spatial distribution of cancer hallmarks across 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. We show that hallmark activity is spatially organized, with the cancer compartment contributing to the activity of seven out of 13 hallmarks, while the tumor microenvironment (TME) contributes to the activity of the rest. Additionally, we discover that genomic distance between tumor subclones correlates with differences in hallmark activity, even leading to clone-hallmark specialization. Finally, we demonstrate interdependent relationships between hallmarks at the junctions of TME and cancer compartments and how they relate to sensitivity to different neoadjuvant treatments in 33 bladder cancer patients from the DUTRENEO trial. In conclusion, our findings may improve our understanding of tumor ecology and help identify new drug biomarkers.

Keywords:  CP: cancer; cancer hallmarks; drug sensitivity; ecosystem; intratumoral heterogeneity; spatial transcriptomics; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2024.115229
Nat Biotechnol. 2025 Jan 28.

A human metabolic map of pharmacological perturbations reveals drug modes of action.

Laurentz Schuhknecht, Karin Ortmayr, Jürgen Jänes, Martina Bläsi, Eleni Panoussis, Sebastian Bors, Terézia Dorčáková, Tobias Fuhrer, Pedro Beltrao, Mattia Zampieri.

Understanding a small molecule's mode of action (MoA) is essential to guide the selection, optimization and clinical development of lead compounds. In this study, we used high-throughput non-targeted metabolomics to profile changes in 2,269 putative metabolites induced by 1,520 drugs in A549 lung cancer cells. Although only 26% of the drugs inhibited cell growth, 86% caused intracellular metabolic changes, which were largely conserved in two additional cancer cell lines. By testing more than 3.4 million drug-metabolite dependencies, we generated a lookup table of drug interference with metabolism, enabling high-throughput characterization of compounds across drug therapeutic classes in a single-pass screen. The identified metabolic changes revealed previously unknown effects of drugs, expanding their MoA annotations and potential therapeutic applications. We confirmed metabolome-based predictions for four new glucocorticoid receptor agonists, two unconventional 3-hydroxy-3-methylglutaryl-CoA (HMGCR) inhibitors and two dihydroorotate dehydrogenase (DHODH) inhibitors. Furthermore, we demonstrated that metabolome profiling complements other phenotypic and molecular profiling technologies, opening opportunities to increase the efficiency, scale and accuracy of preclinical drug discovery.

DOI: https://doi.org/10.1038/s41587-024-02524-5
Life Metab. 2025 Feb;4(1): loae040

Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability.

Yik-Lam Cho, Hayden Weng Siong Tan, Jicheng Yang, Basil Zheng Mian Kuah, Nicole Si Ying Lim, Naiyang Fu, Boon-Huat Bay, Shuo-Chien Ling, Han-Ming Shen.

  Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the pentose phosphate pathway (PPP) in glycolysis. Glucose metabolism is closely implicated in the regulation of mitophagy, a selective form of autophagy for the degradation of damaged mitochondria. The PPP and its key enzymes such as G6PD possess important metabolic functions, including biosynthesis and maintenance of intracellular redox balance, while their implication in mitophagy is largely unknown. Here, via a whole-genome CRISPR-Cas9 screening, we identified that G6PD regulates PINK1 (phosphatase and tensin homolog [PTEN]-induced kinase 1)-Parkin-mediated mitophagy. The function of G6PD in mitophagy was verified via multiple approaches. G6PD deletion significantly inhibited mitophagy, which can be rescued by G6PD reconstitution. Intriguingly, while the catalytic activity of G6PD is required, the known PPP functions per se are not involved in mitophagy regulation. Importantly, we found a portion of G6PD localized at mitochondria where it interacts with PINK1. G6PD deletion resulted in an impairment in PINK1 stabilization and subsequent inhibition of ubiquitin phosphorylation, a key starting point of mitophagy. Finally, we found that G6PD deletion resulted in lower cell viability upon mitochondrial depolarization, indicating the physiological function of G6PD-mediated mitophagy in response to mitochondrial stress. In summary, our study reveals a novel role of G6PD as a key positive regulator in mitophagy, which bridges several important cellular processes, namely glucose metabolism, redox homeostasis, and mitochondrial quality control.

Keywords:  G6PD; NADPH; PINK1; PPP; ROS; mitophagy

DOI:  https://doi.org/10.1093/lifemeta/loae040
Acta Pharmacol Sin. 2025 Jan 30.

Concurrent inhibition of p300/CBP and FLT3 enhances cytotoxicity and overcomes resistance in acute myeloid leukemia.

Yu-Jun Chen, Yu Zhao, Ming-Yue Yao, Ya-Fang Wang, Ming Ma, Cheng-Cheng Yu, Hua-Liang Jiang, Wu Wei, Jie Shen, Xiao-Wei Xu, Cheng-Ying Xie.

  FMS-like tyrosine kinase-3 (FLT3), a class 3 receptor tyrosine kinase, can be activated by mutations of internal tandem duplication (FLT3-ITD) or point mutations in the tyrosine kinase domain (FLT3-TKD), leading to constitutive activation of downstream signaling cascades, including the JAK/STAT5, PI3K/AKT/mTOR and RAS/MAPK pathways, which promote the progression of leukemic cells. Despite the initial promise of FLT3 inhibitors, the discouraging outcomes in the treatment of FLT3-ITD-positive acute myeloid leukemia (AML) promote the pursuit of more potent and enduring therapeutic approaches. The histone acetyltransferase complex comprising the E1A binding protein P300 and its paralog CREB-binding protein (p300/CBP) is a promising therapeutic target, but the development of effective p300/CBP inhibitors faces challenges due to inherent resistance and low efficacy, often exacerbated by the absence of reliable clinical biomarkers for patient stratification. In this study we investigated the role of p300/CBP in FLT3-ITD AML and evaluated the therapeutic potential of targeting p300/CBP alone or in combination with FLT3 inhibitors. We showed that high expression of p300 was significantly associated with poor prognosis in AML patients and positively correlated with FLT3 expression. We unveiled that the p300/CBP inhibitors A485 or CCS1477 dose-dependently downregulated FLT3 transcription via abrogation of histone acetylation in FLT3-ITD AML cells; in contrast, the FLT3 inhibitor quizartinib reduced the level of H3K27Ac. Concurrent inhibition of p300/CBP and FLT3 enhanced the suppression of FLT3 signaling and H3K27 acetylation, concomitantly reducing the phosphorylation of STAT5, AKT, ERK and the expression of c-Myc, thereby leading to synergistic antileukemic effects both in vitro and in vivo. Moreover, we found that p300/CBP-associated transcripts were highly expressed in quizartinib-resistant AML cells with FLT3-TKD mutation. Targeting p300/CBP with A485 or CCS1477 retained the efficacy of quizartinib, suggesting marked synergy when combined with p300/CBP inhibitors in quizartinib-resistant AML models, as well as primary FLT3-ITD+ AML samples. These results demonstrate a potential therapeutic strategy of combining p300/CBP and FLT3 inhibitors to treat FLT3-ITD and FLT3-TKD AML.

Keywords:  FLT3; acute myeloid leukemia; combination strategy; p300/CBP; quizartinib resistance

DOI:  https://doi.org/10.1038/s41401-025-01479-w
Front Nutr. 2024 ;11 1460057

The association between dietary creatine intake and cancer in U.S. adults: insights from NHANES 2007-2018.

Junhui Jiang, Hu Zhao, Jiong Chen, Junhao Du, Weixiang Ni, Baohua Zheng, Junhong Wu, Chunhong Xiao.

   Background: Creatine has anti-inflammatory, antioxidant, and immunomodulatory effects. However, its impact on tumors remains uncertain.
Methods: This study used data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018 to investigate the relationship between dietary creatine intake and cancer in American adults. A total of 25,879 participants aged 20 years and older were included, and their medical information, dietary creatine intake, and covariates were collected. Multiple logistic regression models were used to assess the relationships between age, dietary creatine intake, and cancer risk. Restricted cubic spline (RCS) analysis explored the nonlinear relationships between dietary creatine intake, age, and cancer prevalence.
Results: RCS analysis revealed a linear, negative association between dietary creatine intake and cancer risk. For each standard deviation (SD) increase in dietary creatine intake, cancer risk decreased by 5% (adjusted odds ratio (OR) = 0.95, 95% CI: 0.91-0.99, p = 0.025). This negative association was strongest among males (adjusted OR = 0.93, 95% CI: 0.88-0.99, p = 0.021) and overweight participants (adjusted OR = 0.92, 95% CI: 0.84-0.99, p = 0.044). Interaction results indicated specific age group effects. Further analysis showed that higher dietary creatine intake was significantly inversely associated with cancer risk among older adults (adjusted OR = 0.86, 95% CI: 0.77-0.97, p = 0.014). RCS analysis revealed a linear, positive correlation between age and cancer risk. For each SD increase in age, cancer risk increased by 3.27 times (adjusted OR = 3.27, 95% CI: 3.07-3.48, p < 0.001).
Conclusion: These findings suggest that higher dietary creatine intake may reduce cancer risk in a nationally representative adult population. Further prospective studies are needed to clarify the relationship between dietary creatine intake and cancer risk.

Keywords:  NHANES; age; cancer; creatine; nutrition

DOI:  https://doi.org/10.3389/fnut.2024.1460057
Life Metab. 2023 Jun;2(3): load020

Flux measurements of the tricarboxylic acid cycle in the tumors of mice.

Shiyu Liu, Jason W Locasale.

DOI: https://doi.org/10.1093/lifemeta/load020
Cell Commun Signal. 2025 Jan 24. 23(1): 45

Glutamine and cancer: metabolism, immune microenvironment, and therapeutic targets.

Ding Nan, Weiping Yao, Luanluan Huang, Ruiqi Liu, Xiaoyan Chen, Wenjie Xia, Hailong Sheng, Haibo Zhang, Xiaodong Liang, Yanwei Lu.

  Glutamine is the most abundant amino acid in human serum, and it can provide carbon and nitrogen for biosynthesis, which is crucial for proliferating cells. Moreover, it is widely known that glutamine metabolism is reprogrammed in cancer cells. Many cancer cells undergo metabolic reprogramming targeting glutamine, increasing its uptake to meet their rapid proliferation demands. An increasing amount of study is being done on the particular glutamine metabolic pathways in cancer cells.Further investigation into the function of glutamine in immune cells is warranted given the critical role these cells play in the fight against cancer. Immune cells use glutamine for a variety of biological purposes, including the growth, differentiation, and destruction of cancer cells. With the encouraging results of cancer immunotherapy in recent years, more investigation into the impact of glutamine metabolism on immune cell function in the cancer microenvironment could lead to the discovery of new targets and therapeutic approaches.Oral supplementation with glutamine also enhances the immune capabilities of cancer patients, improves the sensitivity to chemotherapy and radiotherapy, and improves prognosis. The unique metabolism of glutamine in cancer cells, its function in various immune cells, the impact of inhibitors of glutamine metabolism, and the therapeutic use of glutamine supplements are all covered in detail in this article.

Keywords:  Cancer; Glutaminase inhibitors; Glutamine antimetabolites; Glutamine metabolism; Immune cells

DOI:  https://doi.org/10.1186/s12964-024-02018-6
Geroscience. 2025 Jan 31.

Stochasticity in dietary restriction-mediated lifespan outcomes in Drosophila.

Olivia L Mosley, Joel A Villa, Advaitha Kamalakkannan, Eliyashaib James, Jessica M Hoffman, Yang Lyu.

  Dietary restriction (DR) is widely considered to be one of the most potent approaches to extend healthy lifespan across various species, yet it has become increasingly apparent that DR-mediated longevity is influenced by biological and non-biological factors. We propose that current priorities in the field should include understanding the relative contributions of these factors to elucidate the mechanisms underlying the beneficial effects of DR. Our work conducted in two laboratories represents an attempt to unify DR protocols in Drosophila and to investigate the stochastic effects of DR. Across 64 pairs of survival data (DR/ad libitum, or AL), we find that DR does not universally extend lifespan. Specifically, we observed that DR conferred a significant lifespan extension in only 26.7% (17/64) of pairs. Our pooled data show that the overall lifespan difference between DR and AL groups is statistically significant, but the median lifespan increase under DR (7.1%) is small. The effects of DR were overshadowed by stochastic factors and genotype. Future research efforts directed toward gaining a comprehensive understanding of DR-dependent mechanisms should focus on unraveling the interactions between genetic and environmental factors. This is essential for developing personalized healthspan-extending interventions and optimizing dietary recommendations for individual genetic profiles.

Keywords:   Drosophila ; Dietary restriction; Health; Longevity; Stochasticity; Variation

DOI:  https://doi.org/10.1007/s11357-025-01537-5
Pharmacol Rep. 2025 Jan 29.

Olaparib-induced hyperglycemia in ovarian cancer patients - a case series analysis of a three-month therapy with a consideration of BMI.

Joanna Stanisławiak-Rudowicz, Edyta Szałek, Barbara Więckowska, Edmund Grześkowiak, Radosław Mądry.

   BACKGROUND: Olaparib is a relatively new poly(ADP-ribose) polymerase inhibitor (PARPi) administered to ovarian cancer (OC) patients with a complete or partial response to first-line chemotherapy. One of the metabolic side effects of olaparib is the disruption of glucose homeostasis, often resulting in hyperglycemia The study was a retrospective analysis of olaparib-induced hyperglycemia in OC patients with initial normoglycemia following the first, second, and third month of olaparib treatment METHODS: The study involved 32 OC patients, classified into three groups according to their Body Mass Index (BMI): normal BMI (BMI 18.5-24.9 kg/m2; n = 13), overweight (BMI 25-29.9 kg/m2; n = 13), and obese (BMI ≥ 30 kg/m2; n = 6). The fasting glucose (FG) concentration was evaluated after the first, second, and third cycle of olaparib treatment (a cycle is the equivalent of 28 days of treatment). The severity of the observed hyperglycemia was assessed using the Common Terminology Criteria for Adverse Events (CTCAE v5.0).
RESULTS: A significant increase in glycemia was observed after the first and second cycles of olaparib treatment in the group with normal BMI and after the third cycle in overweight and obese patients. There were no significant differences in glucose levels among the groups following the first, the second, and the third cycle. Grade 1 hyperglycemia with impaired fasting glucose levels (5.6-6.9 mmol/l) was found in 15 patients (normal BMI: n = 4, overweight: n = 9, and obesity: n = 2), while glycemia typical of diabetes (≥ 7.0 mmol/l) was observed in one obese patient.
CONCLUSIONS: Regardless of the weight of OC patients, it is essential to control glycemia during olaparib treatment.

Keywords:  Adverse effects; BMI; Hyperglycemia; Olaparib

DOI:  https://doi.org/10.1007/s43440-025-00702-z