bims-medica 2025-06-15 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–06–15
twenty-two papers selected by
Brett Chrest, Wake Forest University

Dietary lipids, not ketone body metabolites, influence intestinal tumorigenesis in a ketogenic diet.
Randomized controlled trial of time-restricted eating: secondary analyses of breath acetone.
Metabolic profile of human non-small cell lung cancer cells through combined 13C and 2H NMR.
Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming.
Low Carbohydrate Diet Containing Soy Protein and Fish Oil Reduces AOM/DSS-Induced Colon Cancer, in Part, by an Acetate-Mediated Reduction in TH17 Cell Differentiation.
Metabolic adaptations direct cell fate during tissue regeneration.
Leveraging autophagy and pyrimidine metabolism to target pancreatic cancer.
Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia via a cytotoxic integrated stress response.
Ketogenesis is dispensable for the metabolic adaptations to caloric restriction.
Metabolic Pathway Tracing for NAD+ Synthesis and Consumption.
Lifting the veil on tumor metabolism: A GDH1-focused perspective.
Protocol to extract and measure ubiquinone and rhodoquinone in murine tissues.
Impact of mtG3PDH inhibitors on proliferation and metabolism of androgen receptor-negative prostate cancer cells: Role of extracellular pyruvate.
Quantifying the impact of treatment delays on breast cancer survival outcomes: a comprehensive meta-analysis.
Outcomes of Frontline Triplet Regimens With a Hypomethylating Agent, Venetoclax, and Isocitrate Dehydrogenase Inhibitor for Intensive Chemotherapy-Ineligible Patients With Isocitrate Dehydrogenase-Mutated AML.
Mitochondrial molecule has unexpected role in tissue healing.
Outcomes of patients with Acute Myeloid Leukemia receiving venetoclax in combination with azacitidine: A single center retrospective study from Pakistan.
Unveiling the Maze: Branched-Chain Amino Acids Fueling the Dynamics of Cancer Metabolism and Progression.
Elevation of hepatic de novo lipogenesis in mice with overnutrition is dependent on multiple substrates.
Carbohydrate Deprivation Improves Glycolipid Metabolism and Activates AMPK/PGC1α Signaling Pathway in Mice.
Exercise reduces the risk of colon cancer recurrence.
ATP-Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance and Is Depressed in Human Failing Myocardium.

bioRxiv. 2025 Jun 07. pii: 2025.06.06.658169. [Epub ahead of print]

Dietary lipids, not ketone body metabolites, influence intestinal tumorigenesis in a ketogenic diet.

Jessica E S Shay, Fangtao Chi, Constantine N Tzouanas, Johanna Ten Hoeve, Kevin J Williams, Tolga Sever, Isabela Fuentes, Ömer H Yilmaz.

Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state, and cellular dynamics. In the gastrointestinal tract, obesogenic high-fat diets enhance intestinal stem cell activity and tumorigenesis. However, the impact of ketogenic diets (KD), which contain even higher lipid content but induce ketogenesis, remains poorly understood. This is particularly relevant for patients with familial adenomatous polyposis (FAP), who face a high risk of small intestinal tumours. Here, we combine dietary, genetic, and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone body production. Through genetic manipulation of the ketogenic pathway, we modulate local and systemic ketone body production; however, neither inhibition nor augmentation of the ketogenic enzyme HMGCS2 nor disruption of ketolysis altered tumour progression. In contrast, inhibition of fatty acid oxidation did limit adenomatous formation. These findings reveal that dietary lipid content, through FAO rather than ketone body metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.

DOI: https://doi.org/10.1101/2025.06.06.658169
Int J Obes (Lond). 2025 Jun 11.

Randomized controlled trial of time-restricted eating: secondary analyses of breath acetone.

Candida J Rebello, Dachuan Zhang, Joseph C Anderson, Rebecca F Bowman, Pamela M Peeke, Frank L Greenway.

Studies of prolonged fasting produced spectacular weight loss and demonstrated that ketone bodies rise for approximately three weeks before stabilizing as production and utilization rates equilibrate. Although starvation is no longer an accepted obesity treatment, an extended period of fasting is the basis of time-restricted eating which produces metabolic benefits. Nevertheless, the pattern of change in ketone bodies with time-restricted eating has never been investigated. We collected weekly fasting measures of breath acetone from subjects (N = 60) who were on an eight-week, calorie-restricted diet and were randomized to different time-restricted eating windows. Subjects participating in a 14-hour fast, 10-hour eating window (14:10) lost more weight than subjects participating in a 12-hour fast, 12-hour eating window (12:12) as previously reported (Nutr Diabetes 2021; 11(1): 6). Ketone bodies assessed via breath acetone showed an increase for the first three weeks without a significant difference between groups. From weeks four to eight, breath acetone levels were lower in the 14:10 compared to the 12:12 group (between group difference: 5.45 ± 2.1 parts per million, mean ± SE, p = 0.012). We show for the first time that ketone bodies decrease after a period of adaptation to time-restricted eating of a calorie-restricted diet likely from enhanced fat oxidation and ketone utilization.

DOI: https://doi.org/10.1038/s41366-025-01818-1
Biochim Biophys Acta Mol Basis Dis. 2025 Jun 05. pii: S0925-4439(25)00297-2. [Epub ahead of print] 167949

Metabolic profile of human non-small cell lung cancer cells through combined 13C and 2H NMR.

Ludgero C Tavares, Ricardo Amorim, José Teixeira, Paulo J Oliveira, Rui A Carvalho.

  The metabolic remodeling occurring in carcinogenesis cells is firmly established. However, to understand the connection between the cellular metabolic profile and carcinogene sis, an accurate measurement of metabolic fluxes is required. In order to quantify the fluxes in these metabolic pathways, stable isotopes tracers and nuclear magnetic resonance (NMR) techniques were employed. For that purpose, two human non-small lung cancer cell lines (A549 and H1299) were used. For the quantification of carbon intermediary metabolism cells were grown in 13C labelled glucose while for de novo lipogenesis (DNL) assessment 2H2O was supplemented to the culture media. To better understand and characterize cellular bioenergetics, mitochondrial membrane potential, oxygen consumption, and energy charge were also assessed. Finally, to establish a bridge between metabolic fluxes and cancer proliferation, substrate dependency studies were performed. Several metabolic inhibitors were also tested, targeting glycolysis, TCA cycle, pentose phosphate pathway (PPP) and transaminases. Our results showed the occurrence of metabolic heterogeneity between the two non-small lung cancer cell lines: H1299 exhibited a relatively active TCA cycle, while A549 showed a more glycolytic phenotype. The overall mitochondrial bioenergetic parameters were in agreement with the metabolic profiles. The mitochondrial network was polarized and active in all cell lines, although the H1299 cell line exhibited higher basal oxygen consumption and spare respiratory capacity. Nonetheless, DNL rate did not differ in H1299 and A549 lung cancer cell lines. Additionally, α-ketoglutarate availability was proven a key determinant for H1299 non-small cell lung cancer cells survival and proliferation. In conclusion, this work revealed that cells derived from a lymph node metastasis (H1299) have a more active TCA cycle and altered oxidative stress levels when compared to cells derived from a primary tumor (A549). In the process, we successfully implemented a new 2H enrichment method for DNL assessment for the first time in in vitro cancer research.

Keywords:  A549; Glycolysis; H1299; Krebs cycle; Lipogenesis; NADPH; Stable isotope tracers

DOI:  https://doi.org/10.1016/j.bbadis.2025.167949
Cell Metab. 2025 Jun 09. pii: S1550-4131(25)00265-7. [Epub ahead of print]

Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming.

Ting Zhao, Lingli He, Lai Ping Wong, Shenglin Mei, Jun Xia, Yanxin Xu, Jonathan G Van Vranken, Michael Mazzola, Lei Chen, Catherine Rhee, Tiancheng Fang, Tsuyoshi Fukushima, Leanne C Sayles, Matthew Diaz, J Alex B Gibbons, Raul Mostoslavsky, Steven P Gygi, Zhixun Dou, David B Sykes, Ruslan I Sadreyev, E Alejandro Sweet-Cordero, David T Scadden.

  Metabolites are essential substrates for epigenetic modifications. Although nuclear acetyl-coenzyme A (CoA) constitutes a small fraction of the whole-cell pool, it regulates cell fate by locally providing histone acetylation substrate. Here, we report a nucleus-specific acetyl-CoA regulatory mechanism that can be modulated to achieve therapeutic cancer cell reprogramming. Combining phenotypic chemical screen, genome-wide CRISPR screen, and proteomics, we identified that the nucleus-localized pyruvate dehydrogenase complex (nPDC) is constitutively inhibited by the nuclear protein ELMSAN1 through direct interaction. Pharmacologic inhibition of the ELMSAN1-nPDC interaction derepressed nPDC activity, enhancing nuclear acetyl-CoA generation and reprogramming cancer cells to a postmitotic state with diminished cell-of-origin signatures. Reprogramming was synergistically enhanced by histone deacetylase 1/2 inhibition, resulting in inhibited tumor growth, durably suppressed tumor-initiating ability, and improved survival in multiple cancer types in vivo, including therapy-resistant sarcoma patient-derived xenografts and carcinoma cell line xenografts. Our findings highlight the potential of targeting ELMSAN1-nPDC as an epigenetic cancer therapy.

Keywords:  ELMSAN1; HDAC; ISX9; acetyl-CoA metabolism; cancer therapy; compartmentalized metabolism; epigenetic reprogramming; nuclear metabolism; pyruvate dehydrogenase complex; therapeutic reprogramming

DOI:  https://doi.org/10.1016/j.cmet.2025.05.009
Mol Nutr Food Res. 2025 Jun 09. e70113

Low Carbohydrate Diet Containing Soy Protein and Fish Oil Reduces AOM/DSS-Induced Colon Cancer, in Part, by an Acetate-Mediated Reduction in TH17 Cell Differentiation.

Ingrid Elisia, Michelle Yeung, Sara Kowalski, Amy Wong, Colton Dietrich, Vianne Chang, Samantha Wu, Serena Hollman, Roger Dyer, Khoi Nguyen Nguyen, Gerald Krystal.

  Since our previous studies found a low-carbohydrate (CHO) diet containing soy protein and fish oil (i.e., 15%Amylose/Soy/FO) significantly reduced tobacco carcinogen-induced lung nodules in A/J mice, breast tumors in C3(1)/Tag mice, and myelomalignancy in miR-146a knockout mice, we asked herein if this CHO diet could also reduce colorectal cancer. We tested the efficacy of the 15%Amylose/Soy/FO diet in preventing colitis-induced colorectal cancer using an azoxymethane/dextran sodium sulfate BALB/c mouse model. The 15%Amylose/Soy/FO diet significantly reduced colon tumor numbers compared to a Western diet and this was associated with a reduction in blood glucose, and a trend towards an increase in plasma β-hydroxybutyrate and an increase in liver fatty acid synthase, suggesting a systemic metabolic shift from glucose to fatty acids as an energy source. In addition, our CHO diet reduced proinflammatory cytokines, induced a marked change in the fecal microbiome, an increase in cecal and fecal acetate, and a reduction in interleukin-17A expressing cells in the colonic tumors of mice on the 15%Amylose/Soy/FO diet. Taken together, our results suggest the 15%Amylose/Soy/FO diet ameliorates colitis and prevents the subsequent development of colorectal cancer, in part by an acetate-mediated reduction in TH17 cell development.

Keywords:  TH17 cells; acetate; colitis; colon cancer; low‐carb diet

DOI:  https://doi.org/10.1002/mnfr.70113
Nature. 2025 Jun 11.

Metabolic adaptations direct cell fate during tissue regeneration.

Almudena Chaves-Perez, Scott E Millman, Sudha Janaki-Raman, Yu-Jui Ho, Clemens Hinterleitner, Valentin J A Barthet, John P Morris, Francisco M Barriga, Jose Reyes, Aye Kyaw, H Amalia Pasolli, Dana Pe'er, Craig B Thompson, Lydia W S Finley, Justin R Cross, Scott W Lowe.

Although cell-fate specification is generally attributed to transcriptional regulation, emerging data also indicate a role for molecules linked with intermediary metabolism. For example, α-ketoglutarate (αKG), which fuels energy production and biosynthetic pathways in the tricarboxylic acid (TCA) cycle, is also a co-factor for chromatin-modifying enzymes1-3. Nevertheless, whether TCA-cycle metabolites regulate cell fate during tissue homeostasis and regeneration remains unclear. Here we show that TCA-cycle enzymes are expressed in the intestine in a heterogeneous manner, with components of the αKG dehydrogenase complex4-6 upregulated in the absorptive lineage and downregulated in the secretory lineage. Using genetically modified mouse models and organoids, we reveal that 2-oxoglutarate dehydrogenase (OGDH), the enzymatic subunit of the αKG dehydrogenase complex, has a dual, lineage-specific role. In the absorptive lineage, OGDH is upregulated by HNF4 transcription factors to maintain the bioenergetic and biosynthetic needs of enterocytes. In the secretory lineage, OGDH is downregulated through a process that, when modelled, increases the levels of αKG and stimulates the differentiation of secretory cells. Consistent with this, in mouse models of colitis with impaired differentiation and maturation of secretory cells, inhibition of OGDH or supplementation with αKG reversed these impairments and promoted tissue healing. Hence, OGDH dependency is lineage-specific, and its regulation helps to direct cell fate, offering insights for targeted therapies in regenerative medicine.

DOI: https://doi.org/10.1038/s41586-025-09097-6
bioRxiv. 2025 Jun 05. pii: 2025.05.29.656904. [Epub ahead of print]

Leveraging autophagy and pyrimidine metabolism to target pancreatic cancer.

Suzanne Dufresne, Ramya S Kuna, Kristiana Wong, Anvita Komarla, Angelica Rock, Joel Rosada-Encarnación, Celina Shen, Payel Mondal, Louis R Parham, Fabiana Izidro Layng, Kristina L Peck, Alexandra Fowler, Andrew M Lowy, Dannielle Engle, Herve Tiriac, Reuben Shaw, Nicholas Cosford, Christian Metallo, Christina Towers.

Autophagy inhibitors are promising compounds to treat pancreatic ductal adenocarcinoma (PDA) but their efficacy in patients is unclear, highlighting a need to understand mechanisms of resistance. We used a novel approach to uncover metabolic adaptations that bypass autophagy inhibition. Utilizing PDA cells with acquired resistance to different autophagy inhibitors, we found that severe autophagy depletion induces metabolic rewiring to sustain TCA intermediates and nucleotides for biosynthesis. Long-term autophagy inhibition results in altered pyruvate metabolism likely regulated by lower pyrimidine pools. Cells adapting to loss of autophagy preferentially salvage pyrimidines to replenish these pools instead of synthesizing them de novo. Exploiting this metabolic vulnerability, we found that acquired resistance to autophagy inhibition promotes increased salvage and therefore sensitivity to pyrimidine analogues, including gemcitabine and trifluridine/tipiracil leading to combinatory effects with autophagy inhibitors and pyrimidine analogs. These studies provide mechanistic insight defining how autophagy inhibition can be leveraged to treat pancreatic cancer.

DOI: https://doi.org/10.1101/2025.05.29.656904
bioRxiv. 2025 Jun 07. pii: 2025.06.06.657881. [Epub ahead of print]

Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia via a cytotoxic integrated stress response.

Johnson Ung, Su-Fern Tan, Jeremy J P Shaw, Maansi Taori, Tess M Deddens, Giovana da Costa Venancio, McLane M Montgomery, James T Hagen, Raphael T Aruleba, Upendar R Golla, Arati Sharma, B Bishal Paudel, Irene Sung-Ah Lee, Bhavishya Ramamoorthy, Kevin A Janes, Francine Garrett-Bakelman, Myles C Cabot, Kelsey H Fisher-Wellman, Todd E Fox, David F Claxton, Charles E Chalfant, David J Feith, Thomas P Loughran.

Resistance to combination regimens containing the BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) is a growing clinical challenge for this extensively utilized agent. We previously established the anti-leukemic properties of ceramide, a tumor-suppressive sphingolipid, in AML and demonstrated that upregulated expression of acid ceramidase (AC), a ceramide-neutralizing enzyme, supported leukemic survival and resistance to BH3 mimetics. Here, we report the anti-leukemic efficacy and mechanisms of co-targeting AC and BCL-2 in venetoclax-resistant AML. Analysis of the BeatAML dataset revealed a positive relationship between increased AC gene expression and venetoclax resistance. Targeting AC enhanced single-agent venetoclax cytotoxicity and the venetoclax + cytarabine combination in AML cell lines with primary or acquired venetoclax resistance. SACLAC + venetoclax was equipotent to the combination of venetoclax + cytarabine at reducing cell viability when evaluated ex vivo across a cohort of 71 primary AML patient samples. Mechanistically, SACLAC + venetoclax increased ceramide to levels that trigger a cytotoxic integrated stress response (ISR), ISR-mediated NOXA protein upregulation, mitochondrial dysregulation, and caspase-dependent cell death. Collectively, these data demonstrate the efficacy of co-targeting AC and BCL-2 in AML and rationalize targeting AC as a therapeutic approach to overcome venetoclax resistance.

DOI: https://doi.org/10.1101/2025.06.06.657881
bioRxiv. 2025 Jun 01. pii: 2025.05.29.656153. [Epub ahead of print]

Ketogenesis is dispensable for the metabolic adaptations to caloric restriction.

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

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

DOI: https://doi.org/10.1101/2025.05.29.656153
Methods Mol Biol. 2025 ;2925 203-222

Metabolic Pathway Tracing for NAD+ Synthesis and Consumption.

Tumpa Dutta, Stephen J Gardell.

  NAD+ is an abundant cellular metabolite which plays vital roles in central metabolism while serving as a cofactor for oxidoreductases and cosubstrate for sirtuins and poly(ADP-ribose)polymerases (PARPs). Decreased tissue NAD+ levels have been linked to aging-associated metabolic decline and a host of chronic diseases. Cellular steady-state NAD+ levels are governed by contemporaneous synthetic and consumptive processes. Hence, lower NAD+ levels in aged tissues can arise from decreased synthesis or increased consumption. A static snapshot of the tissue levels of NAD+ is inadequate for assessing the highly dynamic pathway network which mediates NAD+ synthesis and consumption. Metabolic pathway tracing with stable isotope-labeled NAD+ precursors (e.g., nicotinamide (NAM), nicotinic acid (NA), tryptophan) and high-resolution mass spectrometry (HRMS) can unveil the individual contributions of synthesis and consumption to the steady-state NAD+ concentration. The metabolic fate of the NAD+ precursor can also be traced to metabolic products of NAD+ including NADH, NADP, and NADPH as well as intermediates in the various NAD+ biosynthetic pathways. Metabolic tracing of NAD+ synthesis and degradation as well as conversion of NAD+ to its downstream products is a highly versatile technique. It can be used to interrogate isolated cells, tissues slices, or specimens collected from preclinical or clinical in vivo studies (e.g., blood, urine, tissues). Bold claims about the pivotal role of NAD+ in human health and disease are typically fraught with uncertainty due to an incomplete understanding of NAD+ metabolism. Insight gleaned from metabolic pathway tracing can shed important new light on NAD+ metabolism and help to critically evaluate the intriguing link between cellular NAD+ levels and healthy aging.

Keywords:  Mass isotopomer distribution profiling; Mass spectrometry; NAD+ consumption; NAD+ flux; NAD+ metabolism; NAD+ synthesis; Stable isotope tracing

DOI:  https://doi.org/10.1007/978-1-0716-4534-5_14
iScience. 2025 Jun 20. 28(6): 112551

Lifting the veil on tumor metabolism: A GDH1-focused perspective.

Sisi Zhou, Huaer Wu, Yun Chen, Jiawei Lv, Shufang Chen, Hua Yu, Tiezhu Shi, Xiongjun Wang, Lingyun Xiao.

  Tumors depend on glutamine for energy production, biosynthesis, and redox homeostasis. Glutamate dehydrogenase 1 (GDH1) primarily catalyzes the oxidative deamination of glutamate to α-ketoglutarate (α-KG) and ammonia, utilizing NAD+ or NADP+ as cofactors. α-KG is a tricarboxylic acid (TCA) cycle intermediate at the nexus of multiple metabolic pathways, fueling the TCA cycle for energy production or providing intermediates essential for lipid, amino acid, and nucleotide synthesis. Its derivatives, succinate and fumarate, function as oncometabolites that promote tumor progression through diverse mechanisms. Additionally, α-KG is an essential cofactor for α-KG-dependent dioxygenases (2-OGDDs), regulating epigenetic modifications that drive tumorigenesis. GDH1 may also catalyze the reductive amination of α-KG to glutamate under glutamine deprivation or hypoxic conditions. The roles of GDH1 in tumors are context-dependent, influencing progression through metabolic and epigenetic mechanisms. This review discusses GDH1's multifaceted functions and advances in targeting it for cancer therapy.

Keywords:  Cancer

DOI:  https://doi.org/10.1016/j.isci.2025.112551
STAR Protoc. 2025 Jun 12. pii: S2666-1667(25)00286-2. [Epub ahead of print]6(2): 103880

Protocol to extract and measure ubiquinone and rhodoquinone in murine tissues.

Madison Jerome, Jessica B Spinelli.

  Ubiquinone (UQ) and rhodoquinone (RQ) are electron carriers for the electron transport chain (ETC). Here, we present a protocol for measuring UQ and RQ in mitochondria purified from murine tissues. We describe steps for isolating mitochondria by centrifugation, isolating UQ and RQ by biphasic extraction, and normalizing samples to the protein content of the mitochondrial pellet. We then detail procedures for analyzing UQ and RQ by integrating peak areas for UQ-9 and RQ-9 (abundant in mice) or UQ-10 and RQ-10 (abundant in human). Thus, through enrichment of mitochondria, we establish a method to measure UQ and RQ in tissues. For complete details on the use and execution of this protocol, please refer to Valeros et al.1.

Keywords:  cell biology; metabolism; metabolomics

DOI:  https://doi.org/10.1016/j.xpro.2025.103880
PLoS One. 2025 ;20(6): e0325509

Impact of mtG3PDH inhibitors on proliferation and metabolism of androgen receptor-negative prostate cancer cells: Role of extracellular pyruvate.

Floriana Jessica Di Paola, Luiza Hd Cardoso, Efterpi Nikitopoulou, Bianca Kulik, Sandra Rühl, Alexander Eva, Natascha Sommer, Thomas Linn, Erich Gnaiger, Klaus Failing, Kathrin Büttner, Christian Frezza, Sybille Mazurek.

Mitochondrial glycerol 3-P dehydrogenase (mtG3PDH) plays a significant role in cellular bioenergetics by serving as a rate-limiting element in the glycerophosphate shuttle, which connects cytosolic glycolysis to mitochondrial oxidative metabolism. mtG3PDH was identified as an important site of electron leakage leading to ROS production to the mitochondrial matrix and intermembrane space. Our research focused on the role of two published mtG3PDH inhibitors (RH02211 and iGP-1) on the proliferation and metabolism of PC-3 and DU145 prostate cancer cells characterized by different mtG3PDH activities. Since pyruvate as a substrate of lactate dehydrogenase (LDH) may represent an escape mechanism for the recycling of cytosolic NAD+ via the glycerophosphate shuttle, we investigated the effect of pyruvate on the mode of action of the mtG3PDH inhibitors. Extracellular pyruvate weakened the growth-inhibitory effects of RH02211 and iGP-1 in PC-3 cells but not in DU145 cells, which correlated with higher H-type LDH and lower mitochondrial glutamate-oxaloacetate transaminase in DU145 cells. In the pyruvate-low medium, the strength of inhibition was more pronounced in PC-3 cells, characterized by higher mtG3PDH activities compared to DU145 cells. Pyruvate conversion rates (production in pyruvate-low and consumption in pyruvate-high PC-3 cells) were not impaired by RH02211 and iGP-1, suggesting that the conversion of extracellular pyruvate to lactate was not the primary factor responsible for the weakening effect of extracellular pyruvate on the RH02211-induced inhibition of PC-3 proliferation. In pyruvate-high PC-3 cells, the intracellular glycerol-3-P and dihydroxyacetone-P concentrations were consistent with an inhibition of mtG3PDH. In contrast, in pyruvate-low cells, the concentrations of these metabolites suggested an activation of mtG3PDH in parallel with an impairment of cytosolic G3PDH by RH02211. Of all metabolic characterizations recorded in this study (fluxes, intracellular intermediates, O2 consumption and H2O2 production), the decrease in glutaminolysis correlated best with the RH02211-induced inhibition of proliferation in pyruvate-low and pyruvate-high PC-3 cells.

DOI: https://doi.org/10.1371/journal.pone.0325509
Geroscience. 2025 Jun 10.

Quantifying the impact of treatment delays on breast cancer survival outcomes: a comprehensive meta-analysis.

Zoltan Ungvari, Mónika Fekete, Annamaria Buda, Andrea Lehoczki, Gyöngyi Munkácsy, Paola Scaffidi, Tiziana Bonaldi, János Tibor Fekete, Giampaolo Bianchini, Péter Varga, Anna Ungvari, Balázs Győrffy.

  Treatment delay in breast cancer care represents a significant concern in oncology, potentially impacting patient survival outcomes. While various factors can contribute to delayed treatment initiation, the quantitative relationship between specific delay intervals and survival remains incompletely understood in breast cancer management. Our study aims to explore the impact of treatment delays on survival outcomes in breast cancer. A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science databases, covering publications from 2000 to 2025. From an initial 6222 records, 18 eligible studies comprising 25 cohorts were included. Hazard ratios (HRs) for all-cause and breast cancer-specific mortality were extracted or calculated for treatment delays of 4, 8, and 12 weeks. Random-effects meta-analyses were performed, and heterogeneity and publication bias were assessed using I2 statistics, funnel plots, and Egger's test. This meta-analysis revealed progressively increasing mortality risks with longer treatment delays. For all-cause mortality, HRs increased from 1.12 (95% CI 1.08-1.15) at 4 weeks to 1.25 (95% CI 1.17-1.33) at 8 weeks, and 1.39 (95% CI 1.26-1.53) at 12 weeks. Breast cancer-specific mortality showed more pronounced effects, with HRs of 1.20 (95% CI 1.06-1.36), 1.43 (95% CI 1.11-1.84), and 1.71 (95% CI 1.18-2.49) for 4-, 8-, and 12-week delays, respectively. Analyses combining both survival outcomes demonstrated consistent risk elevation across all time intervals (4 weeks: HR = 1.12, 95% CI 1.09-1.16; 8 weeks: HR = 1.26, 95% CI 1.18-1.34; 12 weeks: HR = 1.41, 95% CI 1.29-1.55). While heterogeneity was significant (I2 = 54-92%), no substantial publication bias was detected. Delays in initiating breast cancer treatment are associated with significantly worse survival, particularly for cancer-specific mortality. Each additional 4-week delay increases the hazard of death by over 10%, underscoring the urgency of minimizing delays in diagnosis-to-treatment pathways. These findings have critical implications for healthcare systems, clinical decision-making, and public health policy.

Keywords:  All-cause mortality; Breast cancer–specific mortality; Cancer prognosis; Hazard ratio; Mortality risk; Survival outcomes; Treatment delay

DOI:  https://doi.org/10.1007/s11357-025-01719-1
J Clin Oncol. 2025 Jun 13. JCO2500640

Outcomes of Frontline Triplet Regimens With a Hypomethylating Agent, Venetoclax, and Isocitrate Dehydrogenase Inhibitor for Intensive Chemotherapy-Ineligible Patients With Isocitrate Dehydrogenase-Mutated AML.

Courtney D DiNardo, Jennifer Marvin-Peek, Sanam Loghavi, Koichi Takahashi, Ghayas C Issa, Wei-Ying Jen, Naval G Daver, Patrick K Reville, Nicholas J Short, Koji Sasaki, Jillian K Mullin, Corey A Bradley, Gautam Borthakur, Abhishek Maiti, Yesid Alvarado, Naveen Pemmaraju, Hussein A Abbas, Danielle E Hammond, Fadi Haddad, Guillermo Montalban Bravo, Kelly S Chien, Musa Yilmaz, Steven M Kornblau, Elias Jabbour, Farhad Ravandi, Tapan Kadia, Guillermo Garcia-Manero, Marina Y Konopleva, Hagop M Kantarjian.

PURPOSE: The development of targeted therapeutics has revolutionized treatment for elderly patients with AML. Two doublet regimens are approved in the frontline setting for intensive chemotherapy (IC)-ineligible AML: venetoclax (VEN) in combination with hypomethylating agent (HMA) therapy and azacitidine (AZA) plus ivosidenib (IVO) specifically for IDH1-mutated AML. Although both regimens have improved AML outcomes, most patients will either not respond to frontline therapy or relapse, with dismal salvage outcomes.
METHODS: We herein report on 60 newly diagnosed IC-ineligible patients treated at our institution with triplet regimens for isocitrate dehydrogenase (IDH)-mutant AML. Patients received either AZA + VEN + IVO on NCT03471260 (IDH1-mutated patients only) or oral decitabine + VEN + IVO/enasidenib on NCT04774393 (arms for IDH1- and IDH2-mutant disease, respectively).
RESULTS: The triplet regimens were well tolerated with low early mortality (n = 1 [2%] in 60 days) and a similar safety profile to HMA + VEN and isocitrate dehydrogenase inhibitor doublet regimens. The composite complete remission rate (CRc) was 92% (55/60), with an overall response rate of 95% (57/60). With a median follow-up of 27.4 months, the median overall survival (OS) has not yet been reached. The 2-year OS was 69% with a 2-year cumulative incidence of relapse of 24%. Patients with treated-secondary AML (tsAML) experienced inferior outcomes with a CRc of 71% (12/17) and a 2-year OS of 34%; the 2-year OS was 84% in patients without tsAML. Nineteen patients (32%) transitioned to stem cell transplant, and 51% remain on study.
CONCLUSION: Given the excellent outcomes of IDH-triplet therapy for newly diagnosed, IC-ineligible IDH-mutant AML, further prospective studies comparing IDH-triplet versus IDH-doublet regimens are warranted.

DOI: https://doi.org/10.1200/JCO-25-00640
Nature. 2025 Jun 11.

Mitochondrial molecule has unexpected role in tissue healing.

Ram P Chakrabarty, Navdeep S Chandel.



Keywords:  Biochemistry; Cell biology; Metabolism; Stem cells

DOI:  https://doi.org/10.1038/d41586-025-01583-1
J Cancer Allied Spec. 2025 Jan;11(1): 1-7

Outcomes of patients with Acute Myeloid Leukemia receiving venetoclax in combination with azacitidine: A single center retrospective study from Pakistan.

Junaid Alam, Lavita Kumari, Usman Shaikh, Akbar Khan Muhammad Ali.

   Introduction: Acute Myeloid Leukemia (AML) has a peak incidence in elderly patients with the median age of onset being 68 years. Owing to the advanced age and multiple comorbidities, such patients are not candidates for the standard chemotherapeutic protocols. Here we discuss the treatment strategies employed for newly diagnosed elderly patients with AML at our institution and their associated outcomes.
Materials and Methods: We conducted a single institutional retrospective review of cases which included elderly patients aged ≥ 50 years diagnosed with AML and treated with venetolcax in combination with azacitidine. Data relating to patients' characteristics, cytogenetics, molecular aberrations and vital status were extracted. We evaluated the overall survival (OS) as our primary outcome of interest.
Results: This study involved 58 patients with confirmed AML, with a median age of 61.5 years. The majority of patients were male (77.6%). Most patients (75.9%) died, while 15.5% were still under treatment at the end of the study period. The median OS was 7.0 months. There was no significant difference in survival based on comorbid conditions (p = 0.586). However, survival differed by gender, with a median OS of 6 months for males and 16 months for females (p = 0.021). The number of chemotherapy cycles significantly impacted survival, with increased cycles associated with a reduced hazard of death (HR = 0.74, p < 0.01).
Conclusion: Our findings contribute to the growing evidence that venetoclax combined with azacitidine is an effective treatment option for elderly patients with AML who are not eligible for intensive treatment.

Keywords:  Acute myeloid Leukaemia; Azacitidine; Haematological Malignancies; Outcome in elderly; Venetoclax

DOI:  https://doi.org/10.2478/jcas-2025-0001
Cancers (Basel). 2025 May 23. pii: 1751. [Epub ahead of print]17(11):

Unveiling the Maze: Branched-Chain Amino Acids Fueling the Dynamics of Cancer Metabolism and Progression.

Kai Xu, Pratham Shah, Dhruvi Makhanasa, Md Wasim Khan.

  Branched-chain amino acids (BCAAs) are essential for protein synthesis and play a crucial role in activating signaling pathways that regulate cell growth and division. Growing evidence reveals their complex role in cancer, particularly in how they support the metabolic reprogramming of tumor cells. BCAAs contribute to an environment that promotes tumor growth and survival by affecting energy balance and key cellular signaling networks. This review highlights recent advances in understanding how BCAAs influence cancer metabolism, emphasizing their dual function as both essential nutrients and sources of metabolic fuel. It also explores how BCAAs interact with other metabolic pathways, revealing potential targets for therapy. By uncovering these cancer-specific dependencies on BCAAs, this work points to promising strategies for disrupting tumor progression and developing new treatment approaches.

Keywords:  BCAAs; cancer metabolism; metabolic reprogramming

DOI:  https://doi.org/10.3390/cancers17111751
J Lipid Res. 2025 Jun 09. pii: S0022-2275(25)00098-7. [Epub ahead of print] 100838

Elevation of hepatic de novo lipogenesis in mice with overnutrition is dependent on multiple substrates.

Jordan W Strober, Stephan Siebel, Susan F Murray, Manuel González Rodríguez, Carlos Rodriguez-Navas Gonzalez, Daniel F Vatner.

  Increased de novo lipogenesis (DNL) contributes to hyperlipidemia, MASLD, and ASCVD in insulin resistant subjects. However, multiple pathways support lipogenesis and few have sought to quantify the contributions of the discrete metabolic pathways that contribute to lipogenesis. In this study, antisense oligonucleotides (ASOs) targeting glucokinase (Gck), lactate dehydrogenase A (Ldha), and glutamic-pyruvic transaminase 2 (Gpt2) were utilized to restrict substrate flux from lipogenic precursors in C57BL6/J mice, comparing controls (CO) and chronic overnutrition (ON). In CO mice, ASO treatments did not significantly alter lipogenesis; however, there was a trend toward decreased hepatic triglyceride content and DNL, especially with the GPT2 ASO (TG=-46.8%; DNL=-53.7%). Expectedly, increased hepatic TG content and DNL (ON vs CO: TG=+187.9%; DNL=+41.8%) was observed in mice with chronic overnutrition. Gas chromatography-mass spectrometry analyses demonstrated increased hepatic TCA cycle metabolites (ON vs CO: fumarate +74.2%; malate +54.0%; and citrate +43.2) and decreased hepatic concentrations of multiple amino acids (ON vs CO: Leu -41.7%; Ile -45.0%; Val -56.3%; Ser -22.6%). With ON, TG content and DNL were reduced by restricting lipogenic carbon entry from alanine (GPT2: TG=-45.5%; DNL=-48.1%), lactate (LDHA: TG=-25.8%; DNL=-33.1%), or glucose (GCK: TG=-59.2%; DNL=-69.2%). Amino acids appear to be a consistent carbon source for DNL in mice; however, carbon entry from all sources is required to maintain the significantly elevated rates of hepatic DNL in chronically overfed mice. These findings may inform the development of novel therapies and underscore the importance of peripheral substrate storage and oxidation in the prevention of dyslipidemia in the metabolic syndrome.

Keywords:  Antisense oligonucleotide; De Novo Lipogenesis; Insulin Resistance; Lipolysis and fatty acid metabolism; Liver; Mitochondria; TCA cycle; Triglyceride

DOI:  https://doi.org/10.1016/j.jlr.2025.100838
Mol Nutr Food Res. 2025 Jun 08. e70123

Carbohydrate Deprivation Improves Glycolipid Metabolism and Activates AMPK/PGC1α Signaling Pathway in Mice.

Qiang Gao, Kuiliang Zhang, Mingcong Fan, Haifeng Qian, Yan Li, Li Wang.

   SCOPE: Carbohydrate intake profoundly shapes hepatic metabolism, impacting crucial pathways like glycolysis, lipogenesis, and ketogenesis. This study aimed to investigate the effects of carbohydrate deprivation on hepatic glycolipid metabolism in mice.
METHODS & RESULTS: Male C57BL/6J mice were subjected to a 4-week dietary intervention where they were assigned to one of four groups: standard diet (CON), low-carbohydrate high-fat diet (LCD), no-carbohydrate high-fat diet (NCD), and high-carbohydrate no-fat diet (HCD). Post-intervention analysis revealed that the NCD group exhibited reduced blood glucose, HbA1c, and LDL-C levels compared to the CON group. Additionally, the NCD group showed decreased liver glycogen content and liver index. Histopathological examination of liver sections indicated less lipid accumulation and a significant down-regulation of hepatic de novo lipogenesis (DNL)-related proteins in the NCD group. Metabolomics analysis demonstrated higher hepatic acylcarnitine levels and lower lysophosphatidylcholine and fatty acyl metabolites levels in the NCD group. Furthermore, protein expression levels of pAMPK, pHSL, PGC1α, CPT1A, and OXPHOS were elevated in the NCD group, suggesting enhanced hepatic energy metabolism and lipolysis ability.
CONCLUSION: These findings suggested that carbohydrate deprivation enhances fatty acid metabolism capacity and inhibits lipogenesis via the AMPK/PGC1α pathway to improve glucose and lipid metabolism in mice.

Keywords:  AMPK; dietary carbohydrate; glycolipid metabolism; lipolysis; metabolomics

DOI:  https://doi.org/10.1002/mnfr.70123
Nat Med. 2025 Jun 09.

Exercise reduces the risk of colon cancer recurrence.

Karen O'Leary.



Keywords:  Cancer; Clinical trials; Lifestyle modification

DOI:  https://doi.org/10.1038/d41591-025-00038-4
JACC Basic Transl Sci. 2025 Jun 10. pii: S2452-302X(25)00221-9. [Epub ahead of print]10(7): 101301

ATP-Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance and Is Depressed in Human Failing Myocardium.

Mariam Meddeb, Navid Koleini, Mohammad Keykhaei, Ting Liu, Marcus Rhodehamel, Lorena Mandarano, Farnaz Farshidfar, Liang Zhao, Seoyoung Kwon, Gizem Keceli, Ismayil Ahmet, Nazareno Paolocci, Virginia Hahn, Kavita Sharma, Erika L Pearce, David A Kass.

  ATP-citrate lyase (ACLY) regulates lipogenesis and cell proliferation, and forms a cytosolic TCA-bypass circuit impacting NADH. We show that acute and chronic ACLY inhibition in cardiomyocytes depresses the NAD+/NADH ratio by increasing mitochondrial NADH. Acute suppression causes dose-dependent cytotoxicity, but at low doses augments aerobic respiration without impeding myocyte function. ACLY is reduced in human failing myocardium, and mice with myocardial or myocyte ACLY knockdown display mildly depressed function, particularly after pressure-overload, and exertional limitations. NAD+ enhancement ameliorates dysfunction/toxicity from ACLY inhibition. These results reveal that ACLY intrinsically regulates cardiac NAD+/NADH balance and respiration, which can affect rest and reserve heart function.

Keywords:  TCA cycle; heart disease; metabolism; myocardium; redox; reductive stress

DOI:  https://doi.org/10.1016/j.jacbts.2025.04.015