bims-medica 2025-03-30 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–03–30
nineteen papers selected by
Brett Chrest, Wake Forest University

Safety, Feasibility, and Effectiveness of Ketogenic Diet in Pediatric Patients With Brain Tumors: A Systematic Review.
Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats.
A human brain map of mitochondrial respiratory capacity and diversity.
Low dose Taxol causes mitochondrial dysfunction in actively respiring cancer cells.
The mutual effects of stearoyl-CoA desaturase and cancer-associated fibroblasts: A focus on cancer biology.
Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement.
Protocol for spatial metabolomics and isotope tracing in the mouse brain.
A leigh syndrome mutation perturbs long-range energy coupling in respiratory complex I.
Fatty Acid Metabolism Provides an Essential Survival Signal in OxPhos and BCR DLBCL Cells.
Mitochondrial respiration defects in lymphoblast cell lines from patients with Dravet syndrome.
Concurrent inhibition of FLT3 and sphingosine kinase-1 triggers synergistic cytotoxicity in midostaurin resistant FLT3-ITD positive acute myeloid leukemia cells via blocking FLT3/STAT5A signaling to induce apoptosis.
Pyruvate kinase modulates the link between β-cell fructose metabolism and insulin secretion.
Changes in plasma cytokines following a 60-h fast are not influenced by the addition of exercise despite elevated ketones in healthy young adults.
The Warburg effect: the hacked mitochondrial-nuclear communication in cancer.
Impact of SGLT2 inhibitors on survival in gastrointestinal cancer patients undergoing chemotherapy and/or radiotherapy: a real-world data retrospective cohort study.
Time-restricted eating in people at high diabetes risk does not affect mitochondrial bioenergetics in peripheral blood mononuclear cells and platelets.
Associations between serum insulin-like growth factor-related molecules and colorectal cancer risk by tumor location: a nested case-control study.
The impact of the tumor microenvironment in the dual burden of obesity-cancer link.
Nutritional ketosis modulates the methylation of cancer-related genes in patients with obesity and in breast cancer cells.

J Nutr Metab. 2025 ;2025 7935879

Safety, Feasibility, and Effectiveness of Ketogenic Diet in Pediatric Patients With Brain Tumors: A Systematic Review.

Hanan AlMutairi, Fiona Mccullough, Khawar Siddiqui, Ibrahim Ghemlas, Manal AlHarbi, Richard Grundy, Madhumita Dandapani.

  Background: Evidence suggests the positive effects of ketogenic diet (KD) on cancers by limiting glucose availability to cancer cells. This systematic review aimed to explore the safety, feasibility, and effectiveness of KD in children with brain tumors including diet side effects, patient tolerance and compliance, tumor response, quality of life, and nutritional status. Methods: Six databases were searched for relevant publications between 1995 and 2022; non-English language publications were excluded to avoid misinterpretation. The Joanna Briggs Institute assessment scale for observational studies was used to measure study methodology quality and evaluate the extent to which the bias possibility in study design, conduct, and analysis has been stated. The study was registered in PROSPERO under registration number (CRD42021281620). Results: Ultimately, eight eligible publications involving a total of 11 children with brain tumors following KD were included. Nine patients followed classic KD with medium-chain triglyceride oil, whereas others followed a modified Atkin or low-carbohydrate diet. KD was well-tolerated, having nonsevere side effects. Six patients showed positive tumor response, five improved neurological skills, and four reported growth improvement. Six patients reported a median overall survival of 17.6 months. Lastly, statistical analyses could not be performed; hence, a meta-analysis was not possible. Conclusion: KD may be a safe and feasible dietary intervention for children with brain tumors. However, the effects on tumors remain unclear and require further study. The study limitation included the lack of high-quality and appropriately controlled trials with large samples. Moreover, heterogeneity was observed, and quality-of-life assessments were self-reported, which might have resulted in bias or inaccuracy.

Keywords:  astrocytoma; brain; classic ketogenic diet; ependymoma; glioma; low-carbohydrate; medulloblastoma; modified Atkins; pediatric; tumor

DOI:  https://doi.org/10.1155/jnme/7935879
Geroscience. 2025 Mar 28.

Time restricted feeding with or without ketosis influences metabolism-related gene expression in a tissue-specific manner in aged rats.

Sarah Ding, Anisha Banerjee, Sara N Burke, Abbi R Hernandez.

  Many of the "hallmarks of aging" involve alterations in cellular and organismal metabolism. One pathway with the potential to impact several traditional markers of impaired function with aging is the PI3K/AKT metabolic pathway. Regulation of this pathway includes many aspects of cellular function, including protein synthesis, proliferation, and survival, as well as many downstream targets, including mTOR and FOXOs. Importantly, this pathway is pivotal to the function of every organ system in the human body. Thus, we investigated the expression of several genes along this pathway in multiple organs, including the brain, liver, and skeletal muscle, in aged subjects that had been on different experimental diets to regulate metabolic function since mid-life. Specifically, rats were fed a control ad lib diet (AL), a time restricted feeding diet (cTRF), or a time restricted feeding diet with ketogenic macronutrients (kTRF) for the majority of their adult lives (from 8 to 25 months). We previously reported that regardless of macronutrient ratio, TRF-fed rats in both macronutrient groups required significantly less training to acquire a biconditional association task than their ad lib fed counterparts. The current experiments expand on this work by quantifying metabolism-related gene expression across tissues and interrogating for potential relationships with cognitive performance. Within the brain, SIRT1 and MAPK8 were reduced in CA3 of kTRF-fed rats. Additionally, IGF1 expression was significantly upregulated in the CA1 of cTRF-fed rats, but this effect was ameliorated in the kTRF fed group. AKT and FOXO1 expression were significantly reduced in kTRF-fed rats within liver. Interestingly, AKT expression within the perirhinal cortex (PER) was higher in kTRF rats with the best cognitive performance, and FOXO1 expression was higher in the CA3 of AL-fed rats correlated with the poorest cognitive performance. Together, these data demonstrate diet- and tissue-specific alterations in metabolism-related gene expression and their correlation with cognitive status.

Keywords:  Aging; Brain; Diet; Liver; Metabolism; Muscle

DOI:  https://doi.org/10.1007/s11357-025-01632-7
Nature. 2025 Mar 26.

A human brain map of mitochondrial respiratory capacity and diversity.

Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Alex Junker, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark D Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.

Mitochondrial oxidative phosphorylation (OXPHOS) powers brain activity1,2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders3,4. To understand the basis of brain activity and behaviour, there is a need to define the molecular energetic landscape of the brain5-10. Here, to bridge the scale gap between cognitive neuroscience and cell biology, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3 × 3 × 3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes, including OXPHOS enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains diverse mitochondrial phenotypes driven by both topology and cell types. Compared with white matter, grey matter contains >50% more mitochondria. Moreover, the mitochondria in grey matter are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backwards linear regression model that integrates several neuroimaging modalities11 to generate a brain-wide map of mitochondrial distribution and specialization. This model predicted mitochondrial characteristics in an independent brain region of the same donor brain. This approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain function. This resource also relates to neuroimaging data and defines the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders. All data are available at http://humanmitobrainmap.bcblab.com .

DOI: https://doi.org/10.1038/s41586-025-08740-6
J Biol Chem. 2025 Mar 25. pii: S0021-9258(25)00299-6. [Epub ahead of print] 108450

Low dose Taxol causes mitochondrial dysfunction in actively respiring cancer cells.

Rozhin Penjweini, Katie A Link, Shureed Qazi, Nikhil Mattu, Adam Zuchowski, Alexandra Vasta, Dan L Sackett, Jay R Knutson.

  Mitochondrial oxygen consumption, dynamics and morphology play roles in the occurrence, development and drug resistance of cancer; thus they are main targets for many anticancer drugs. Increased mitochondrial oxygen consumption and impaired oxygen delivery creates hypoxia, which influences the balance of metabolic co-factors for biogenesis, disease progression and response to therapeutics. We therefore investigated the effects of Taxol, a well-known anticancer drug, on mitochondrial respiration (principally via a measure of oxidative phosphorylation (OXPHOS) versus glycolysis), morphology and dynamics. The concomitant effects of Taxol on mitochondrial adenosine triphosphate (ATP) and reactive oxygen species (ROS) production, mitochondrial membrane potential, radical-induced formation of carbonyl groups, mitochondrial release of cytochrome c, as well as cell cycle were investigated. Cells used in this study include: A549 (non-small cell lung epithelial cancer cell line), A549-ρ0 (mitochondrial DNA-depleted derivative of A549), and BEAS-2B (a non-cancer cell line derived from normal bronchial epithelium), as well as PC3 (prostate cancer) and HepG2 (hepatocellular carcinoma); these cell lines are known to have disparate metabolic profiles. Using a multitude of fluorescence-based measurements, we show that Taxol, even at a low dose, still adversely effects mitochondria of actively respiring (aerobic) cancer cells. We find an increase in mitochondrial ROS and cytochrome c release, suppression of ATP production and OXPHOS, fragmentation of the mitochondrial network and disruption of mitochondria-microtubule linkage. We find these changes in oxidative, but not glycolytic, cancer cells. Non-cancer cells, which are oxidative, do not show these changes.

Keywords:  Low-dose Taxol; Mitochondrial metabolism; OXPHOS; morphology and dynamics

DOI:  https://doi.org/10.1016/j.jbc.2025.108450
Exp Cell Res. 2025 Mar 22. pii: S0014-4827(25)00104-1. [Epub ahead of print]447(2): 114508

The mutual effects of stearoyl-CoA desaturase and cancer-associated fibroblasts: A focus on cancer biology.

Suleiman Ibrahim Mohammad, Asokan Vasudevan, Ahmad Hussein Alzewmel, Safia Obaidur Rab, Suhas Ballal, Rishiv Kalia, J Bethanney Janney, Subhashree Ray, Kamal Kant Joshi, Hatif Abdulrazaq Yasin.

  The tumor microenvironment (TME) 's primary constituents that promote cancer development are cancer-associated fibroblasts (CAFs). Metabolic remodeling has been shown to control CAF activity, particularly aberrant lipid metabolism. SCD1 can be thought of as the primary enzyme controlling the fluidity of lipid bilayers by gradually converting saturated fatty acids into monounsaturated fatty acids. Furthermore, its crucial function in the onset and spread of cancer is well acknowledged. Even with the increasing amount of research on changes in lipid metabolism, this problem remains a relatively understudied aspect of cancer research. Blocking several fatty acid synthesis-related enzymes highly expressed in cancerous cells inhibits cell division and encourages apoptosis. This is the situation with SCD1, whose overexpression has been linked to several changed tumors and cells. Both genetic and pharmacological silencing of SCD1 in cancer cells prevents glucose-mediated lipogenesis and tumor cell growth. However, its role in CAFs, hence, cancer biology, has been less studied. This study aimed to review the role of SCD1 in CAF biology, shedding light on their function in cancer cell biology.

Keywords:  CAFs; Lipid metabolism; Malignancy; SCD1

DOI:  https://doi.org/10.1016/j.yexcr.2025.114508
Pharmacol Res. 2025 Mar 22. pii: S1043-6618(25)00131-8. [Epub ahead of print]215 107706

Dual inhibition of hepatic ACLY and ACSS2: A synergistic approach to combat NAFLD through lipogenesis reduction and mitochondrial enhancement.

Mengdi Zhang, Jinliang Ji, Yuanyuan Lei, Fujian Qin, Yitong Tao, Ning Li, Jinlei Bian, Zhiyu Li, Maode Lai, Zhixia Qiu.

  Inhibiting de novo lipogenesis (DNL) in hepatocytes is a promising strategy for treating metabolic fatty liver diseases. ACLY, a key enzyme in the DNL pathway, has become a therapeutic target for non-alcoholic fatty liver disease (NAFLD). However, its inhibition shows mixed outcomes, depending on interventions and diets. Evidence suggests ACLY inhibition activates the ACSS2-mediated acetate metabolism and the subsequent DNL, though potential mechanisms and possible consequences remain unclear. This study found that targeting hepatic ACLY with AAV8-shRNA failed to improve NAFLD in mice fed a high-fat, high-fructose diet. Instead, it worsened inflammation and liver injury. ACLY inhibition conditionally upregulated DNL enzymes, but consistently activated the ACSS2-acetyl-CoA pathway and suppressed fatty acid oxidation. Further, ACLY inhibition led to polyunsaturated fatty acid accumulation, triggering mitochondrial dysfunction. The resulting ROS redirected carbon flux into acetate, activating the ACSS2-acetyl-CoA pathway, which promoted lipid biosynthesis and exacerbated mitochondrial dysfunction-a vicious cycle that fueled inflammation and liver damage. Dual inhibition of ACLY and ACSS2 broke this cycle by reducing hepatic acetyl-CoA flux, suppressing DNL, enhancing fatty acid oxidation via PPAR-α activation, and improving mitochondrial function. This combined targeting strategy reduced lipid accumulation, alleviated inflammation, and normalized aminotransferase levels, effectively reversing NAFLD progression.

Keywords:  ATP citrate lyase (ACLY); Acetyl-CoA; Acyl-coenzyme A synthetase short-chain family member 2 (ACSS2); De novo lipogenesis (DNL); Fatty acid oxidation; Non-alcoholic fatty liver disease (NAFLD)

DOI:  https://doi.org/10.1016/j.phrs.2025.107706
STAR Protoc. 2025 Mar 27. pii: S2666-1667(25)00122-4. [Epub ahead of print]6(2): 103716

Protocol for spatial metabolomics and isotope tracing in the mouse brain.

Watit Sontising, Francine Yanchik-Slade, Carlos Rodriguez-Navas, Md Amir Hossen, Manuel Gonzalez-Rodriguez, Jake Vaynshteyn, Shinichi Yamaguchi, Mohamed Nazim Boutaghou, Isaac Marin-Valencia.

  Mass spectrometry imaging enables high-resolution spatial chemical mapping, yet its application for dynamic analysis with tracers poses challenges. Here, we present a protocol for spatial metabolomics and isotope tracing in the mouse brain. We describe steps for tracer administration, tissue collection, and cryosectioning. We then detail procedures for matrix application, ion identification, and data analysis. This protocol delivers high-quality spatial metabolomics data and is well suited for region-specific tracing analysis in the brain.

Keywords:  mass spectrometry; metabolism; neuroscience

DOI:  https://doi.org/10.1016/j.xpro.2025.103716
Chem Sci. 2025 Mar 21.

A leigh syndrome mutation perturbs long-range energy coupling in respiratory complex I.

Franziska Hoeser, Patricia Saura, Caroline Harter, Ville R I Kaila, Thorsten Friedrich.

Respiratory complex I is a central enzyme of cellular energy metabolism that couples electron transfer with proton translocation across a biological membrane. In doing so, it powers oxidative phosphorylation that drives energy consuming processes. Mutations in complex I lead to severe neurodegenerative diseases in humans. However, the biochemical consequences of these mutations remain largely unknown. Here, we use the Escherichia coli complex I as a model to biochemically characterize the F124LMT-ND5 mutation found in patients suffering from Leigh syndrome. We show that the mutation drastically perturbs proton translocation and electron transfer activities to the same extent, despite the remarkable 140 Å distance between the mutated position and the electron transfer domain. Our molecular dynamics simulations suggest that the disease-causing mutation induces conformational changes that hamper the propagation of an electric wave through an ion-paired network essential for proton translocation. Our findings imply that malfunction of the proton translocation domain is entirely transmitted to the electron transfer domain underlining the action-at-a-distance coupling in the proton-coupled electron transfer of respiratory complex I.

DOI: https://doi.org/10.1039/d4sc04036h
Biomedicines. 2025 Mar 13. pii: 707. [Epub ahead of print]13(3):

Fatty Acid Metabolism Provides an Essential Survival Signal in OxPhos and BCR DLBCL Cells.

Aurélie Montagne, Konstantina Kotta, Karoline Kielbassa-Elkadi, Isabelle Martins, José Ángel Martinez-Climent, Guido Kroemer, Catherine Thieblemont, Véronique Baud.

  Backgroung/objectives: Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of malignant lymphoma and is a heterogeneous disease with various gene and chromosomal abnormalities. The development of novel therapeutic treatments has improved DLBCL prognosis, but patients with early relapse or refractory disease have a poor outcome (with a mortality of around 40%). Metabolic reprogramming is a hallmark of cancer cells. Fatty acid (FA) metabolism is frequently altered in cancer cells and recently emerged as a critical survival path for cancer cell survival. Methods: We first performed the metabolic characterization of an extended panel of DLBCL cell lines, including lipid droplet content. Then, we investigated the effect of drugs targeting FA metabolism on DLBCL cell survival. Further, we studied how the combination of drugs targeting FA and either mitochondrial metabolism or mTOR pathway impacts on DLBCL cell death. Results: Here, we reveal, using a large panel of DLBCL cell lines characterized by their metabolic status, that targeting of FA metabolism induces massive DLBCL cell death regardless of their OxPhos or BCR/glycolytic subtype. Further, FA drives resistance of DLBCL cell death induced by mitochondrial stress upon treatment with either metformin or L-asparaginase, two FDA-approved antimetabolic drugs. Interestingly, combining inhibition of FA metabolism with that of the mTOR oncogenic pathway strongly potentiates DLBCL cell death. Conclusion: Altogether, our data highlight the central role played by FA metabolism in DLBCL cell survival, independently of their metabolic subtype, and provide the framework for the use of drugs targeting this metabolic vulnerability to overcome resistance in DLBCL patients.

Keywords:  B-cell lymphoma; DLBCL; fatty acid; metabolism; mitochondrial stress; survival

DOI:  https://doi.org/10.3390/biomedicines13030707
Epilepsia. 2025 Mar 22.

Mitochondrial respiration defects in lymphoblast cell lines from patients with Dravet syndrome.

Anna G Figueroa, Ruth E Fulton, Rajeswari Banerji, Kelly G Knupp, Manisha N Patel.

   OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy with early life intractable seizures and lifelong comorbidities. There is growing evidence linking energy metabolism to DS, from mitochondrial respiration deficits in skeletal muscle and fibroblasts from children with DS to responsiveness to ketogenic diets. Lymphoblast cell lines (LCLs) have revealed metabolic alterations in neurological disorders, suggesting their utility for studying systemic bioenergetics. In this pilot study, we used LCLs from patients with DS to evaluate energy metabolism.
METHODS: LCLs were established from eight children with DS (DS-LCLs) and sex-/age-matched controls (control-LCLs). Extracellular flux analysis measured glycolytic function, mitochondrial respiration, and fatty acid oxidation (FAO). High-resolution respirometry was used to determine sites of mitochondrial respiration defects. Mitochondrial content and membrane potential were analyzed using high-content screening methods.
RESULTS: DS-LCLs exhibit impaired bioenergetics, characterized by deficiencies in mitochondrial respiration with 25% lower baseline and adenosine triphosphate-linked respiration. Similarly, maximal mitochondrial capacity was 26% lower, leading to a 40% decrease in respiratory reserves. They exhibit a metabolic shift toward FAO, indicated by increased endogenous fatty acid utilization to counter cellular stress. Mitochondrial oxygen flux was impaired, with greatest deficiency in complex I, and reduced complex II activity. Leak respiration, mitochondrial content, membrane potential, and glycolytic function were unaffected.
SIGNIFICANCE: LCLs from patients with DS reveal reduced mitochondrial respiratory capacity. These preliminary findings may enhance our understanding of energy metabolism in DS pathogenesis. Beyond helping identify new therapies, this model may noninvasively serve as a surrogate for evaluating metabolic function throughout a patient's life.

Keywords:  developmental epileptic encephalopathy; energy metabolism; fatty acid oxidation; lymphoblast; mitochondria; patient‐derived cell line

DOI:  https://doi.org/10.1111/epi.18382
J Chemother. 2025 Mar 21. 1-17

Concurrent inhibition of FLT3 and sphingosine kinase-1 triggers synergistic cytotoxicity in midostaurin resistant FLT3-ITD positive acute myeloid leukemia cells via blocking FLT3/STAT5A signaling to induce apoptosis.

Melisa Tecik, Aysun Adan.

  The FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations observed in acute myeloid leukemia (AML) which contributes to disease progression and unfavorable prognosis. Midostaurin, a small FLT3 inhibitor (FLT3I), is clinically approved. However, patients generally possess acquired resistance when midostaurin used alone. Shifting the balance in the sphingolipid rheostat toward anti-apoptotic sphingosine kinase-1 (SK-1) or glucosylceramide synthase (GCS) is related to therapy resistance in cancer, however, their role in midostaurin resistant FLT3-ITD positive AML has not been previously investigated. We generated midostaurin resistant MV4-11 and MOLM-13 cell lines which showed increased IC50 values compared to their sensitive partner cells. SK-1 is overexpressed in resistant cells while GCS remains unchanged. Subsequent pharmacological targeting of SK-1 in resistant cells decreased SK-1 protein level, inhibited cell proliferation and showed additive or synergistic effect on cell growth, as confirmed by the Chou-Talalay combination index, and induced G0/G1 arrest (PI staining by flow cytometry). Cotreatment (SKI-II plus midostaurin) triggered apoptosis via phosphatidylserine exposure (annexin V/PI double staining). Mechanistically, induction of the intrinsic pathway of apoptosis was confirmed as increased activating cleavages of caspase-3 and PARP and increased Bax/Bcl-2 ratios. Activating phosphorylations of FLT3 (at tyrosine residue 591) and STAT5A (at tyrosine residue 694) dramatically inhibited in resistant cells treated with the combination. In conclusion, midostaurin resistance could be reversed by dual SK-1 and FLT3 inhibition in midostaurin resistant AML cell lines, providing the first evidence of a novel treatment approach to re-sensitize FLT3-ITD positive AML.

Keywords:  FLT3-ITD AML; STAT5A; drug resistance; midostaurin; sphingosine kinase-1

DOI:  https://doi.org/10.1080/1120009X.2025.2478340
FASEB J. 2025 Apr 15. 39(7): e70500

Pyruvate kinase modulates the link between β-cell fructose metabolism and insulin secretion.

Naoya Murao, Risa Morikawa, Yusuke Seino, Kenju Shimomura, Yuko Maejima, Tamio Ohno, Norihide Yokoi, Yuichiro Yamada, Atsushi Suzuki.

  The intricate link between glucose metabolism, ATP production, and glucose-stimulated insulin secretion (GIIS) in pancreatic β-cells has been well established. However, the effects of other digestible monosaccharides on this mechanism remain unclear. This study examined the interaction between intracellular fructose metabolism and GIIS using MIN6-K8 β-cell lines and mouse pancreatic islets. Fructose at millimolar concentrations potentiated insulin secretion in the presence of stimulatory levels (8.8 mM) of glucose. This potentiation was dependent on sweet taste receptor-activated phospholipase Cβ2 (PLCβ2) signaling. Concurrently, metabolic tracing using 13C-labeled fructose and glucose in conjunction with biochemical analyses demonstrated that fructose blunted the glucose-induced increase in the ATP/ADP ratio. Mechanistically, fructose is substantially converted to fructose 1-phosphate (F1P) at the expense of ATP. F1P directly inhibited PKM2 (pyruvate kinase M2), thereby reducing the later glycolytic flux used for ATP production. Remarkably, F1P-mediated PKM2 inhibition was counteracted by TEPP-46, a small-molecule PKM2 activator. TEPP-46 restored glycolytic flux and the ATP/ADP ratio, leading to the enhancement of fructose-potentiated GIIS in MIN6-K8 cells, normal mouse islets, and fructose-unresponsive diabetic mouse islets. These findings reveal an antagonistic interplay between glucose and fructose metabolism in β-cells, highlighting PKM2 as a crucial regulator and broadening our understanding of the relationship between β-cell fuel metabolism and insulin secretion.

Keywords:  diabetes mellitus; fructose; glycolysis; insulin secretion; pancreatic beta cells; pyruvate kinase

DOI:  https://doi.org/10.1096/fj.202401912RR
Physiol Rep. 2025 Mar;13(6): e70294

Changes in plasma cytokines following a 60-h fast are not influenced by the addition of exercise despite elevated ketones in healthy young adults.

Tori Bouck, Justin Monteleone, Jennifer Duffy, Philip N Ainslie, Jonathan P Little, Kate N Thomas, Travis D Gibbons, Hashim Islam.

  Immunometabolic processes maintain physiological homeostasis and are implicated in various chronic diseases. Fasting and exercise independently alter metabolic and immunological processes; their combination could provide insights into immunometabolic interactions. Using a randomized crossover design, 15 healthy adults (six females, nine males, 26.5 ± 4.3 years) fasted for 60 h with and without the addition of a 3 h cycling bout (65%-80% VO2 peak). Fasting alone (FAST) and with exercise (FEX) reduced plasma glucose, insulin, respiratory exchange ratio, and increased β-hydroxybutyrate (BHB; all p < 0.01). FEX elicited more rapid changes in glucose and BHB and higher BHB concentrations at 60 h (all p < 0.01). Both conditions decreased circulating TNF-⍺ concentrations and increased IL-10 (p < 0.01), although the increase in IL-10 appeared to be driven by the FEX condition (p = 0.03). IL-6 concentrations tended to increase in both conditions (p = 0.1). Total white blood cell count remained unchanged after 60 h in both conditions, with only modest changes in some leukocyte subpopulations. Collectively, the observed changes in circulating cytokine concentrations support an overall anti-inflammatory effect of prolonged fasting, while the maintenance of leukocyte concentrations suggests immune function is not compromised. Despite greater metabolic strain, the addition of prolonged exercise did not appear to augment changes in systemic cytokines and leukocytes.

Keywords:  immunometabolism; inflammation; interleukin‐10; interleukin‐6; leukocytes; tumor necrosis factor‐alpha

DOI:  https://doi.org/10.14814/phy2.70294
Semin Cancer Biol. 2025 Mar 25. pii: S1044-579X(25)00053-7. [Epub ahead of print]

The Warburg effect: the hacked mitochondrial-nuclear communication in cancer.

Haowen Jiang, Jiangbin Ye.

  Mitochondrial-nuclear communication is vital for maintaining cellular homeostasis. This communication begins with mitochondria sensing environmental cues and transmitting signals to the nucleus through the retrograde cascade, involving metabolic signals such as substrates for epigenetic modifications, ATP and AMP levels, calcium flux, etc. These signals inform the nucleus about the cell's metabolic state, remodel epigenome and regulate gene expression, and modulate mitochondrial function and dynamics through the anterograde feedback cascade to control cell fate and physiology. Disruption of this communication can lead to cellular dysfunction and disease progression, particularly in cancer. The Warburg effect is the metabolic hallmark of cancer, characterized by disruption of mitochondrial respiration and increased lactate generation from glycolysis. This metabolic reprogramming rewires retrograde signaling, leading to epigenetic changes and dedifferentiation, further reprogramming mitochondrial function and promoting carcinogenesis. Understanding these processes and their link to tumorigenesis is crucial for uncovering tumorigenesis mechanisms. Therapeutic strategies targeting these disrupted pathways, including metabolic and epigenetic components, provide promising avenues for cancer treatment.

Keywords:  Warburg effect; cell dedifferentiation; epigenetic remodeling; metabolic reprogramming; metabolic therapy; mitochondrial dynamics; mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.semcancer.2025.03.006
BMC Cancer. 2025 Mar 25. 25(1): 542

Impact of SGLT2 inhibitors on survival in gastrointestinal cancer patients undergoing chemotherapy and/or radiotherapy: a real-world data retrospective cohort study.

Lucas E Flausino, Alexis Germán Murillo Carrasco, Tatiane Katsue Furuya, Wen-Jan Tuan, Roger Chammas.

   BACKGROUND: The role of sodium-glucose co-transporter 2 inhibitor (SGLT2i) drugs in the management of diabetes and cardiovascular disease is well-established, but emerging evidence suggests potential effects on cancer outcomes, including gastrointestinal (GI) cancers. We conducted an extensive, sex-oriented, real-world data analysis to investigate whether SGLT2i can enhance GI cancer outcomes when used alongside standard therapies such as chemotherapy and radiotherapy.
METHODS: The study applied a retrospective cohort design with data from the TriNetX research database ( https://trinetx.com ), examining GI cancer patients treated with chemotherapy and/or radiotherapy between 2013 and 2023. The intervention cohort consisted of Gl cancer patients who received SGLT2i, while the control cohort did not. A 5-year follow-up period was used, and baseline characteristics were balanced using a 1:1 propensity score matching technique. Cox proportional-hazards and logistic regression models assessed mortality and morbidity risks between the cohorts.
RESULTS: The study included 6,389 male and 3,457 female patients with GI cancer (ICD-10: C15-C25). The use of SGLT2i was significantly associated with improved survival for both male (HR 0.568; 95% CI 0.534-0.605) and female (HR 0.561; 95% CI 0.513-0.614) patients undergoing chemotherapy and/or radiotherapy. SGLT2i use also correlated significantly with lower hospitalisation rates both in male (OR 0.684; 95% CI 0.637-0.734) and female (OR, 0.590; 95% CI 0.536-0.650) patients. The analysis of GI cancer subtypes also demonstrated similar benefits, without significant adverse effects.
CONCLUSIONS: Repurposing SGLT2 inhibitors for cancer treatment could potentially improve outcomes for GI cancer patients without causing significant side effects. Further clinical trials are needed to confirm these findings and establish the optimal condition for its application in GI cancer treatment.

Keywords:  Cancer treatment; Chemotherapy; Gastrointestinal cancer; Multicenter collaborative network study; Radiotherapy; Sodium-glucose co-transporter 2 inhibitor (SGLT2i)

DOI:  https://doi.org/10.1186/s12885-025-13966-8
Sci Rep. 2025 Mar 24. 15(1): 10175

Time-restricted eating in people at high diabetes risk does not affect mitochondrial bioenergetics in peripheral blood mononuclear cells and platelets.

Joana Mendes Lopes de Melo, Martin Bæk Blond, Verena Hirschberg Jensen, Hanne Pedersen, Kim Katrine Bjerring Clemmensen, Marie Møller Jensen, Kristine Færch, Jonas Salling Quist, Joachim Størling.

  Overweight and obesity are linked to mitochondrial alterations, impaired glucose tolerance and a high risk of type 2 diabetes. Time-restricted eating (TRE) may aid in facilitating weight loss to prevent diabetes. Here, we investigated if TRE in individuals with overweight and prediabetes or obesity affects mitochondrial bioenergetics of peripheral blood mononuclear cells (PBMCs) and platelets using the Seahorse extracellular flux technology. In a 3-month randomized controlled trial, PBMCs/platelets were analyzed from 52 participants before and after a TRE intervention with a 10-h eating window or habitual living. PBMC and platelet respiratory function was evaluated through sequential addition of substrates, uncouplers, and inhibitors in living cells. After 3 months, there were no statistically significant differences in mitochondrial respiration within or between the TRE and control groups. Association analyses between PBMC/platelet respiration and clinical parameters including body mass index and fat mass showed no significant effects. In conclusion, 3 months of 10-h TRE does not alter the mitochondrial bioenergetics of PBMCs and platelets in individuals with high risk of type 2 diabetes.

Keywords:  Bioenergetics; Mitochondria; Obesity; Overweight; Oxidative phosphorylation; Oxygen consumption rate (OCR); Peripheral blood mononuclear cells (PBMCs); Platelets; Pre-diabetes; Seahorse extracellular flux; Time-restricted eating (TRE); Type 2 diabetes (T2D)

DOI:  https://doi.org/10.1038/s41598-025-94652-4
Digestion. 2025 Mar 25. 1-19

Associations between serum insulin-like growth factor-related molecules and colorectal cancer risk by tumor location: a nested case-control study.

for Japan Collaborative Cohort (JACC) study

Introduction, The activity of the mitogen insulin-like growth factor (IGF) is controlled by IGF-binding protein (IGFBP). Colorectal cancers (CRCs) are heterogeneous, with left- and right-sided CRC showing different clinical and molecular characteristics. This case-control study, nested in the Japan Collaborative Cohort study, assessed associations between serum levels of IGF-related molecules and incidences of CRC by location. Methods, A baseline survey obtained serum samples from 39,242 participants. Subjects diagnosed with CRC during follow-up were regarded as cases. Conditional logistic regression modeling was used to calculate odds ratios (ORs) for cancer incidence associated with IGF-related molecules. Results, This analysis included 176 cases and 524 controls. No IGF-related molecules appeared associated with risks of overall or left-sided CRC. Both total IGFBP3 and free IGFBP3 (estimated as IGFBP3-(IGF1+IGF2)) were associated with incidence of right-sided CRC (P-for-trends=0.027 and 0.003, respectively), with the third tertile of total and free IGFBP3 showing the highest risk (OR=6.25 and 7.96, respectively). Free IGF, estimated as (IGF1+IGF2)/IGFBP3, was inversely associated with incidence of right-sided CRC (P-for-trends=0.014), with the third tertile showing the lowest risk (OR=0.18). Among subjects followed for over 3 years, association of IGF-related molecules with overall CRC was similar. Free IGFBP3 was associated with incidence of right-sided CRC (P-for-trends=0.004). Free IGF was inversely associated with incidence of right-sided CRC (P-for-trends=0.002). However, free IGFs were associated with risk of left-sided CRC (P-for-trends=0.041), with the third tertile showing the highest risk (OR=3.10). Conclusions, Serum IGF-related molecules are associated with risk of CRC. These associations might differ by tumor location.

DOI: https://doi.org/10.1159/000545457
Semin Cancer Biol. 2025 Mar 22. pii: S1044-579X(25)00048-3. [Epub ahead of print]112 36-42

The impact of the tumor microenvironment in the dual burden of obesity-cancer link.

Serena Sagliocchi, Lucia Acampora, Biagio Barone, Felice Crocetto, Monica Dentice.

  Obesity induces systemic perturbations of tissue homeostasis, leading to dyslipidemia, insulin resistance and chronic state of inflammation. Evidence from clinical and preclinical studies links excess of adiposity with increased cancer incidence and suggests that chronic inflammation may contribute to increased cancer risk in obese patients. Over the last decades of obesity research, multifaced and complicated effects of abnormal or excessive expansion of Adipose Tissue have been uncovered. In particular, it is widely described how obesity can exacerbate the tumorigenesis for instance by fueling soluble signals and adipokines and by enhancing tissue inflammation and altering the hormonal balance. Less is known about the paracrine effects of the cancer-associated adipocytes on the tumor cells and still poorly explored is the reciprocal communication between cancer cells and the adipose component of the tumor microenvironment (TME). In this review, we will address the mechanisms by which the peritumoral Adipose Tissue can influence the dynamics of tumoral cells. We will discuss how obesity-induced changes in the tumor microenvironment may enhance tumor growth and aggressive characteristics leading to increased invasiveness and metastatic progression of cancer that leads to a worsen cancer survival in obese subjects. We conclude that targeting the peritumoral adipose component of the TME would be a therapeutic option to prevent cancer development.

Keywords:  Cancer Associated Adipocytes; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2025.03.001
J Physiol Biochem. 2025 Mar 27.

Nutritional ketosis modulates the methylation of cancer-related genes in patients with obesity and in breast cancer cells.

Paula M Lorenzo, Andrea G Izquierdo, Gemma Rodriguez-Carnero, Nicolas Costa-Fraga, Angel Díaz-Lagares, Cristina Porca, Daniel de Luis, Cristina Tejera, Laura De Paz, Juan Cueva, Diego Bellido, Ana B Crujeiras.

  Scientific evidence demonstrates that a very low-calorie ketogenic diet (VLCKD) is effective and beneficial in the treatment of obesity, capable of reversing the methylome associated with obesity and has immunomodulatory capacity. This effect is in part promoted by nutritional ketosis and could be involved in counteracting obesity-related cancer. The aim of this study was to evaluate the effect of nutritional ketosis on the methylation of genes related to tumor processes in patients with obesity and in breast cancer cells. Based on methylome data (Infinium MethylationEPIC BeadChip, Illumina) from patients with obesity treated with a VLCKD for weight loss (n = 10; n = 5 women, age = 48.8 ± 9.20 years, BMI = 32.9 ± 1.4 kg/m2), genes belonging to cancer-related pathways were specifically evaluated and further validated in vitro in MDA-MB-231 (triple negative) and MCF7 (RE positive) breast tumor cells pretreated for 72 h with βOHB, the main ketone body, secretome from visceral (VATs) or subcutaneous (SATs) adipose tissue of patients with obesity. The cell tumoral phenotype was evaluated by proliferation assay and expression of cancer-related genes. VLCKD-induced nutritional ketosis promoted changes in the methylation of 18 genes (20 CpGs; 17 hypomethylated, 3 hypermethylated) belonged to cancer-related pathways with MAPK10, CCN1, CTNNA2, LAMC3 and GLI2 being the most representative genes. A similar pattern was observed in the MDA-MB-231 cells treated with β-OHB, without changes in MCF7. These epigenetic changes paralleled the tumoral phenotype modulated by the treatments. Taking together these results highlight the potential role of VLCKD as an adjuvant to anticancer treatment in groups more susceptible to the development of cancer such as patients with obesity, exerting epigenetic regulation through nutritional ketosis and weight loss.

Keywords:  Adipose tissue; Breast cancer; DNMTs; Epigenetics; Ketogenic diet; Ketone bodies; Oncogenes; Sirtuins; Tumor suppressors

DOI:  https://doi.org/10.1007/s13105-025-01076-9