bims-medica 2025-09-07 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–09–07
thirty-six papers selected by
Brett Chrest, Wake Forest University

Hyperlipidemia drives tumor growth in a mouse model of obesity-accelerated breast cancer growth.
Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.
β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.
Metabolomic signatures of hypocaloric dietary interventions associate with breast cancer risk in the Nurses' Health Study II.
Lactate Metabolism in Health and Disease.
Brain tumours in mice grow more slowly when starved of key amino acid.
Impaired xCT-mediated cystine uptake drives serine and proline metabolic reprogramming and mitochondrial fission in skeletal muscle cells.
CDCP1/mitochondrial Src axis increases electron transport chain function to promote metastasis in triple-negative breast cancer.
Rewiring of cortical glucose metabolism fuels human brain cancer growth.
Effects of aging and anti-aging dietary restriction on regulators of the [NADPH]/[NADP+] in different neural cell types and brain regions.
Beat-locked ATP microdomains in the sinoatrial node map a Ca2+-timed energetic hierarchy and regional pacemaker roles.
The synergistic effect of 2-deoxy-D-glucose and cytarabine on mitochondria of stem-like cells derived from KG1-a.
Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.
Underestimation of mitochondrial respiratory capacity in gray matter voxels of the human brain map due to limited OXPHOS and TCA cycle in astrocytes.
Classic or classical ketogenic diet? Definitions and nomenclature.
The lactylation of glucose-6-phosphate dehydrogenase promotes malignant phenotypes in cancer cell lines.
High Glucose and Glucose-derived Intermediates are Linked To Lung Cancer Aggressiveness.
NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism.
A Citrate Synthase Splice Variant Rewires the TCA Cycle to Promote Colorectal Cancer Progression.
An Optimized Enzyme-Coupled Spectrophotometric Method for Measuring Pyruvate Kinase Kinetics.
Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML.
Depriving brain tumours of an amino acid could enhance chemotherapy.
In vivo measurement of NADH fluorescence lifetime in skeletal muscle via fiber-coupled time-correlated single photon counting.
The Role of Ceramide and Sphingolipid Metabolism in Cancer Therapeutics.
Unsupervised machine learning for mass spectrometry imaging data analysis with in vivo isotope labeling.
Comparative efficacy of venetoclax and hypomethylating agents in acute myeloid leukemia treatment: a meta-analysis of clinical trials and Real-World outcomes.
Light-Activated CD36-Targeted Cuproptosis Triggers Metabolic-Immune Synergy for Precision Breast Cancer Therapy.
Activity-based probes and chemical proteomics uncover the biological impact of targeting HMGCS1 in the mevalonate pathway.
SLC25A1 reprograms mitochondrial and fatty acid metabolism to promote the progression of acute myeloid leukemia.
Plasma metabolic landscape unveils key regulators of leukemia subtype progression.
Tumors hijack macrophages for iron supply to promote bone metastasis and anemia.
Targeting dormant tumor cells to prevent recurrent breast cancer: a randomized phase 2 trial.
An Olive Oil-Based High-Fat Diet Promotes Obesity-Driven Metastasis of Triple-Negative Breast Cancer.
Method to Study Metabolism in Lymphoid Cells using Chemistry to Measure Puromycin Incorporation by Flow Cytometry.
Lipid Composition Alters Ferroptosis Sensitivity.
Monitoring nucleoside metabolism in living cells with a nucleobase analogue via fluorescence lifetime imaging.

Cancer Metab. 2025 Aug 28. 13(1): 39

Hyperlipidemia drives tumor growth in a mouse model of obesity-accelerated breast cancer growth.

Renan Fl Vieira, Sawyer R Sanchez, Menusha Arumugam, Peyton D Mower, Meghan C Curtin, Abigail E Jackson, Molly R Gallop, Jillian Wright, Alexis Bowles, Gregory S Ducker, Keren I Hilgendorf, Amandine Chaix.

Obesity is an established risk factor for breast cancer (BC), yet the specific mechanisms driving this association remain unclear. Dysregulated lipid metabolism has emerged as a key factor in cancer cell biology, and, while obesity is often accompanied by hyperlipidemia, the isolated impact of elevated lipid levels on BC growth has not been experimentally tested. Using the E0771 and Py230 orthotopic models of obesity-accelerated BC growth in immune-competent mice, we investigated the role of systemic lipids on tumor growth. Combining dietary and genetic mouse models, we show that elevated circulating lipids are sufficient to accelerate BC tumor growth even in the absence of obesity or alterations in blood glucose and/or insulin levels. Pharmacological lowering of systemic lipid levels attenuates BC growth in obese mice, suggesting a direct role for lipids in fueling tumor expansion. Notably, we also show that weight loss alone, without a corresponding reduction in lipid levels such as that induced by a ketogenic diet, fails to protect against BC, highlighting the necessity of targeting lipid metabolism in obesity-associated BC. Our findings establish hyperlipidemia as a critical driver of BC progression and suggest that lipid-lowering interventions may be a promising strategy to mitigate BC risk in individuals with obesity.

DOI: https://doi.org/10.1186/s40170-025-00407-0
Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2502483122

Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.

Haowen Jiang, Sarah Jane Tiche, Clifford Jiajun He, Junyan Liu, Fuyun Bian, Mohamed Jedoui, Balint Forgo, Md Tauhidul Islam, Meng Zhao, Pamela Emengo, Bo He, Yang Li, Albert M Li, Anh T Truong, Jestine Ho, Cathyrin Simmermaker, Yanan Yang, Meng-Ning Zhou, Zhen Hu, Katrin J Svensson, Daniel J Cuthbertson, Florette K Hazard, Lei Xing, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye.

  Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the tricarboxylic acid cycle and switching substrate preference from glutamine to glucose. These effects were abolished by electron transport chain (ETC) inhibitors or in ρ0 cells lacking mitochondrial DNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing of xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, potentially improving patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.

Keywords:  differentiation; mitochondria; neuroblastoma; retinoic acid; uncoupler

DOI:  https://doi.org/10.1073/pnas.2502483122
J Biol Chem. 2025 Aug 28. pii: S0021-9258(25)02488-3. [Epub ahead of print] 110636

β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.

Xiujuan Wei, Chengkai Zhang, Xiaoguang Zheng, Kexin Pan, Xiaojun Ren, Xiaoting Lou, Zhengquan Yang, Ting Fu, Hezhi Fang, Jianxin Lu.

  Ketone bodies are a key alternative energy source during carbohydrate deficiency. In addition to their metabolic function, they regulate essential cellular processes, including metabolism, signal transduction, and protein post-translational modifications (PTMs). However, the role of ketone body metabolism in tumorigenesis remains poorly understood. Here, we demonstrate that ketone body synthesis metabolism is activated in pancreatic cancer, while exogenous ketone supplementation does not affect PDAC cell proliferation. Moreover, we observe a significant upregulation of β-Hydroxybutyrate dehydrogenase (BDH1), a key enzyme in ketone body metabolism, in human pancreatic ductal adenocarcinoma (PDAC) tissues compared to adjacent normal pancreatic tissues. BDH1 promotes PDAC cell proliferation by maintaining mitochondrial acetylation levels through regulation of the intracellular NAD+/NADH ratio. These findings underscore the importance of ketone body metabolism in pancreatic cancer progression and highlight the regulatory role of BDH1 in maintaining cellular NAD+/NADH balance and mitochondrial acetylation.

Keywords:  BDH1; Ketone body; NAD(+)/NADH; Pancreatic Cancer; mitochondrial acetylation

DOI:  https://doi.org/10.1016/j.jbc.2025.110636
medRxiv. 2025 Aug 24. pii: 2025.08.18.25333805. [Epub ahead of print]

Metabolomic signatures of hypocaloric dietary interventions associate with breast cancer risk in the Nurses' Health Study II.

Annalise Schweickart, Cheng Peng, Oana Zeleznik, William Dartora, Maurice A Hurd, Alex Buga, Madison L Kackley, Clary Clish, Laura Beth McIntire, Jeff S Volek, Vicky Makker, A Heather Eliassen, Marcus D Goncalves, Rulla M Tamimi, Jan Krumsiek.

Background: An individual's metabolic state plays a critical role in breast cancer (BC) risk, influenced by factors such as obesity and insulin signaling. Hypocaloric diets induce metabolic changes that influence these metabolic factors, thereby potentially influencing BC risk. However, it remains unclear whether metabolic profiles like those induced by such beneficial diets are associated with BC risk.
Methods: We compared the impact of a hypocaloric low-carbohydrate ketogenic diet (KD) and a low-fat diet (LFD) on BC risk in two stages. First, we developed metabolomics-based scores representing the metabolic states resulting from these two hypocaloric diets. Plasma metabolomics data of 43 individuals from two controlled dietary interventions were analyzed (N = 31 KD, N = 12 LFD) and a metabolite-based score was generated for both KD and LFD using diet-induced fold-changes. Second, these scores were applied to metabolomics data from a nested case-control study of participants from the Nurses' Health Study II (NHSII, 1,058 BC cases, 1,054 controls, predominantly premenopausal women). Using multivariable-adjusted models, we assessed the association between the metabolomic scores and BC risk.
Results: KD and LFD had similar but distinct metabolic signatures. Both metabolomics scores were positively associated with breast cancer risk in NHSII. Women in the highest quartile of the KD metabolomic score had a 37% increased risk of BC compared to women in the lowest quartile (p=0.021). Similarly, women in the highest quartile of the LFD metabolomic score had a 32% increased BC risk compared to women in the lowest quartile (p=0.008). Similar increases in risk were seen when further adjusting for BMI at age 18 and weight change since age 18. Increased levels of cholesterol esters (CE), particularly CE 22:6, and long-chain polyunsaturated triglycerides were associated with higher risk in both diet scores, while increases in short-chain, more saturated triglycerides were associated with lower risk.
Conclusion: Metabolomic profiles resembling those induced by hypocaloric ketogenic and low-fat diets were unexpectedly associated with an increased risk of breast cancer in a predominantly premenopausal cohort. These associations were independent of BMI, highlighting the complex relationship between metabolic states and cancer risk, independent of actual dietary interventions.

DOI: https://doi.org/10.1101/2025.08.18.25333805
Adv Exp Med Biol. 2025 ;1478 573-613

Lactate Metabolism in Health and Disease.

Daniel A Kane, Matthew L Goodwin, L Bruce Gladden.

  Lactate (La-) is a ubiquitous carbohydrate-derived metabolite and a major player in the coordination of whole-body metabolism. As the redox-balanced end-product of glycolysis, La- forms the conceptual node linking glycolysis, a process that does not require oxygen, and which occurs in the cytosol, to the TCA cycle and aerobic bioenergetics in the mitochondria. Through rapid multisystem exchange involving membrane monocarboxylate transporters, lactate concentration ([La-]) in the blood offers a "snapshot" of relative rates of glycolytic La- production and its mitochondrial consumption. Thus, while strenuous physical activity elicits a transient La- accumulation, adaptations to exercise training often include attenuated [La-]s for a given submaximal work rate, as well as lower [La-]s at rest. Conversely, elevated resting [La-] in the fasted state can reflect an often-ortentous metabolic scenario involving multisystem metabolic (dys)function characteristic of acute and chronic health issues. At the cellular level, tumors often exhibit augmented glucose uptake and preferential production of La-, even in the presence of oxygen (i.e., the Warburg effect). From coordination of whole-body metabolism during exercise to signaling in cancer cells, the role of La- in metabolism continues to expand and holds potential for multiple clinical and sub-clinical applications.

Keywords:  Cancer; Cardiometabolic disease; Diabetes; Oxygen; Pyruvate; Sepsis

DOI:  https://doi.org/10.1007/978-3-031-88361-3_24
Nature. 2025 Sep 03.

Brain tumours in mice grow more slowly when starved of key amino acid.

Traci Watson.



Keywords:  Brain; Cancer; Metabolism

DOI:  https://doi.org/10.1038/d41586-025-02801-6
Redox Biol. 2025 Aug 21. pii: S2213-2317(25)00352-0. [Epub ahead of print]86 103839

Impaired xCT-mediated cystine uptake drives serine and proline metabolic reprogramming and mitochondrial fission in skeletal muscle cells.

Michel N Kanaan, Charbel Y Karam, Luke S Kennedy, Chantal A Pileggi, Lauren Hamilton, Miroslava Cuperlovic-Culf, Mary-Ellen Harper.

  Muscle satellite cell (MuSC) proliferation is tightly regulated by redox homeostasis and nutrient availability, which are often disrupted in muscular pathologies. Beyond its role in maintaining cellular redox homeostasis, this study identified a key metabolic role for cystine/glutamate antiporter xCT in proliferating MuSCs. We investigated the impact of impaired xCT-mediated cystine import in Slc7a11sut/sut MuSCs isolated from mice that harbor a mutation in the SLC7A11 gene, which encodes xCT. We used complementary approaches to study how disrupted cystine import affects glutathione (GSH) redox, cellular bioenergetics, mitochondrial dynamics, and metabolism. Oxygen consumption rates of Slc7a11sut/sut MuSCs were lower, indicative of compromised mitochondrial oxidative capacity. This was accompanied by a fragmented mitochondrial network associated with OPA1 cleavage and redox-sensitive DRP1 oligomerization. Metabolomic profiling revealed a distinct metabolic signature in Slc7a11sut/sut MuSCs, manifested by major differences in BCAAs, pyrimidines, cysteine, methionine, and GSH. Despite lower overall bioenergetic flux, stable-isotope tracing analyses (SITA) showed that xCT deficiency increased glucose uptake, channeling glucose-derived carbons into de novo serine biosynthesis to fuel cysteine production via the transsulfuration pathway, partially compensating for disrupted GSH redox. Furthermore, xCT deficiency triggered upregulated pyrroline-5-carboxylate synthase (P5CS)-mediated proline reductive biosynthesis. By directing glutamate into proline synthesis, MuSCs apparently downregulate oxidative phosphorylation (OXPHOS) and regulate intracellular glutamate levels in response to impaired cystine/glutamate antiporter function. Our findings highlight the roles of xCT in regulating redox balance and metabolic reprogramming in proliferating MuSCs, providing insights that may inform therapeutic strategies for muscular and redox-related pathologies.

Keywords:  Cysteine; Cystine/glutamate antiporter; Glycolysis; Metabolic reprogramming; Mitochondria; Myopathy; Oxidative phosphorylation; Proline; Skeletal muscle; Slc7a11; System Xc−; Transsulfuration pathway

DOI:  https://doi.org/10.1016/j.redox.2025.103839
Br J Cancer. 2025 Sep 04.

CDCP1/mitochondrial Src axis increases electron transport chain function to promote metastasis in triple-negative breast cancer.

Jordan A Woytash, Austin E Y T Lefebvre, Ziang Zhang, Binzhi Xu, Stephanie A Harchenko, Hoa T Le, Andrew R McColloch, Xiaoyu Shi, Michelle A Digman, Olga V Razorenova.

BACKGROUND: Triple-negative type of breast cancer (TNBC) has limited therapeutic options and frequently metastasizes, leading to low survival rates. Oxidative phosphorylation (OXPHOS) is a driver of TNBC metastasis, but the signaling underlying this metabolic change is poorly understood.
METHODS: We performed metabolic assays and assessed migratory and metastatic potential in cells with manipulated CDCP1/mitochondrial Src signaling.
RESULTS: We show that the pro-metastatic cell surface protein CUB-domain containing protein 1 (CDCP1) activates Src kinase localized in mitochondria, which potently induces OXPHOS and TNBC migration. Genetic targeting of either CDCP1 or mitochondrial Src, as well as pharmacological inhibition of Src reduce OXPHOS in vitro. We further show that mitochondrial Src increases OXPHOS by stimulating Complex I activity in the electron transport chain. Importantly, rescuing Complex I activity in cells devoid of CDCP1/mitochondrial Src signaling restores both OXPHOS and migration. We also provide evidence that NAD+ pool generated by Complex I is contributing to the observed migratory phenotype. Lastly, we determined that inhibiting mitochondrial Src reduces metastasis in TNBC cells.
CONCLUSIONS: Both CDCP1 and mitochondrial Src represent potential therapeutic targets to inhibit OXPHOS-mediated TNBC metastasis.

DOI: https://doi.org/10.1038/s41416-025-03163-6
Nature. 2025 Sep 03.

Rewiring of cortical glucose metabolism fuels human brain cancer growth.

Andrew J Scott, Anjali Mittal, Baharan Meghdadi, Alexandra O'Brien, Justine Bailleul, Palavalasa Sravya, Abhinav Achreja, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Ningning Liang, Ayesha U Kothari, Navyateja Korimerla, Donna M Edwards, Zhe Wu, Jiane Feng, Sophia Su, Li Zhang, Peter Sajjakulnukit, Anthony C Andren, Junyoung O Park, Johanna Ten Hoeve, Vijay Tarnal, Kimberly A Redic, Nathan R Qi, Joshua L Fischer, Ethan Yang, Michael S Regan, Sylwia A Stopka, Gerard Baquer, Krithika Suresh, Jann N Sarkaria, Theodore S Lawrence, Sriram Venneti, Nathalie Y R Agar, Erina Vlashi, Costas A Lyssiotis, Wajd N Al-Holou, Deepak Nagrath, Daniel R Wahl.

The brain avidly consumes glucose to fuel neurophysiology1. Cancers of the brain, such as glioblastoma, relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue2. How brain cancers rewire glucose use to drive aggressive growth remains unclear. Here we infused 13C-labelled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumour versus cortex. Through direct and comprehensive measurements of carbon and nitrogen labelling in both cortex and glioma tissues, we identify profound metabolic transformations. In the human cortex, glucose carbons fuel essential physiological processes, including tricarboxylic acid cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters glioblastoma metabolism, slows tumour growth and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumours exploit glucose to suppress normal physiological activity in favour of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.

DOI: https://doi.org/10.1038/s41586-025-09460-7
Free Radic Biol Med. 2025 Sep 02. pii: S0891-5849(25)00949-9. [Epub ahead of print]

Effects of aging and anti-aging dietary restriction on regulators of the [NADPH]/[NADP+] in different neural cell types and brain regions.

Leah E Jamerson, Patrick C Bradshaw.

  Dietary restriction (DR), which slows aging, increases the ratio of reduced glutathione (GSH) to oxidized glutathione disulfide (GSSG) in the brain. DR increases liver cytoplasmic [NADPH]/[NADP+] where much of the NADPH is generated by the folate cycle. This could also occur in astrocytes, the neural cell type with the highest folate cycle flux. Mice on a DR diet showed increased expression of folate cycle enzyme MTHFD1L in several brain regions and likely show increased astrocyte sarcosine catabolism increasing folate cycle cytoplasmic NADPH generation by ALDH1L1. Fasting also increases blood malate/pyruvate that increases tissue [NADPH]/[NADP+]. These events together with decreased NADPH-utilizing lipid synthesis during DR could lead to an increased brain cytoplasmic [NADPH]/[NADP+]. The more reduced NADP(H) pool, combined with the increased expression of brain glutathione disulfide reductase (GSR) and the decreased brain mitochondrial H2O2 generation, decreasing H2O2-induced oxidation of GSH, could lead to the increased brain GSH/GSSG. Aging also decreased the expression of mouse hippocampal NAD+ kinase (NADK) that was restored by DR. Studies that measure the [NADPH]/[NADP+], cysteine/cystine, and GSH/GSSG in different brain regions, subcellular compartments, and neural cell types, especially in astrocytes, during aging and DR are needed to establish effective targets and therapies for aging-related disorders.

Keywords:  NADPH; aging; astrocyte; dietary restriction; folate cycle; pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.001
bioRxiv. 2025 Aug 22. pii: 2025.08.18.670947. [Epub ahead of print]

Beat-locked ATP microdomains in the sinoatrial node map a Ca2+-timed energetic hierarchy and regional pacemaker roles.

Manuel F Muñoz, Collin Matsumoto, Paula Rhana, Daniel M Collier, L Fernando Santana.

  Pacemaker myocytes of the sinoatrial (SA) node initiate each heartbeat through coupled voltage and Ca2+ oscillators, but whether ATP supply is regulated on a beat-by-beat schedule in these cells has been unclear. Using genetically encoded sensors targeted to the cytosol and mitochondria, we tracked beat-resolved ATP dynamics in intact mouse SA node and isolated myocytes. Cytosolic ATP rose transiently with each Ca2+ transient and segregated into high- and low-gain phenotypes defined by the Ca2+-ATP coupling slope. Mitochondrial ATP flux adopted two stereotyped waveforms-Mode-1 "gains" and Mode-2 "dips." Within Mode-1 cells, ATP gains mirrored the cytosolic high/low-gain dichotomy; Mode-2 dips scaled linearly with Ca2+ load and predominated in slower-firing cells. In the intact node, high-gain/Mode-1 phenotypes localized to superior regions and low-gain/Mode-2 to inferior regions, paralleling gradients in rate, mitochondrial volume, and capillary density. Pharmacology placed the Ca2+ clock upstream of ATP production: the HCN channel blocker ivabradine slowed the ATP cycle without changing amplitude, whereas the SERCA pump inhibitor thapsigargin or the mitochondrial uncoupler FCCP abolished transients. Mode-2 recovery kinetics indicate slower ATP replenishment that would favor low-frequency, fluctuation-rich firing in a subset of cells. Together, these findings reveal beat-locked metabolic microdomains in which the Ca2+ clock times oxidative phosphorylation under a local O2 ceiling, unifying vascular architecture, mitochondrial organization, and Ca2+ signaling to coordinate energy supply with excitability. This energetic hierarchy helps explain why some SA node myocytes are more likely to set rate whereas others may widen bandwidth.

Keywords:  Bioenergetics; entrainment; excitation-contraction coupling; mitochondria; oxidative phosphorylation; pacemaking; stochastic resonance

DOI:  https://doi.org/10.1101/2025.08.18.670947
Leuk Res Rep. 2025 ;24 100537

The synergistic effect of 2-deoxy-D-glucose and cytarabine on mitochondria of stem-like cells derived from KG1-a.

Sona Rezaei, Mohammad Mohammadzadeh-Vardin, Keyvan Amirshahrokhi, Mojtaba Amani.

  Acute myeloid leukemia (AML) often relapses post-chemotherapy due to leukemia stem cells (LSCs), which rely on mitochondria for energy, ROS regulation, and apoptosis. Targeting mitochondrial pathways may overcome LSC resistance. This study evaluated Cytarabine (Ara-C), 2-Deoxy-d-Glucose (2-DG), and their combination on AML-derived KG1-a cells using MTT assays, showing reduced viability with combined treatment. The Magnetic sorting isolated CD34+ (stem-like) and CD34- cells. Flow cytometry revealed increased ROS and decreased mitochondrial membrane potential (MMP) in KG1-a and CD34+ cells with 2-DG and Ara-C, suggesting a promising strategy to target resistant LSCs in AML therapy.

Keywords:  CD34+ stem-like cells; Cytarabine, 2-deoxy-D-glucose; Mitochondrial membrane potential; Reactive oxygen specious

DOI:  https://doi.org/10.1016/j.lrr.2025.100537
bioRxiv. 2025 Aug 30. pii: 2025.05.19.654973. [Epub ahead of print]

Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.

Luisa F Castillo, Katarina E Heyden, Abigail R Williamson, Wenxia Ma, Olga V Malysheva, Nathaniel M Vacanti, Anna E Thalacker-Mercer, Martha S Field.

OBJECTIVES: Vitamin B12 plays a vital role in folate-mediated one-carbon metabolism (FOCM), a series of one-carbon transfer reactions that generate nucleotides (thymidylate (dTMP) and purines) and methionine. Inadequate levels of B12 impair FOCM, depressing de novo thymidylate (dTMP) synthesis, which in turn leads to uracil accumulation in DNA. This phenomenon has been well documented in nuclear DNA. Our previous work in liver tissue has shown that mitochondrial DNA (mtDNA) is more sensitive to FOCM impairments in that mtDNA exhibits elevated uracil levels before uracil concentrations in nuclear DNA change. However, the functional consequences of uracil accumulation in mtDNA are largely unknown. The purpose of this study was to determine how a functional B12 deficiency (induced by reduced levels of the B12-dependent enzyme methionine synthase (MTR)) and dietary B12 deficiency affects mtDNA integrity and mitochondrial function in energetic and mitochondria-rich tissues such as skeletal muscle.
METHODS: Male Mtr+/+ and Mtr+/- mice were weaned to either an AIN93G-based control (C) diet containing 25 μ/kg vitamin B12 or a B12-deficient (-B12) diet containing 0 μ/kg vitamin B12 to explore the effects of functional (Mtr+/-) and dietary B12 deficiency on muscle weight, uracil content in mtDNA, mtDNA content, and oxidative phosphorylation complex capacity in skeletal muscle. Aged (20-22mo) male C57BL6/N mice were acclimated to an AIN93G control diet four weeks, then received either weekly injections of saline (vehicle control [30 uL 0.9% NaCl]) or B12 (0.65mg per 30uL 0.9% NaCl) in each of two hindleg muscles [1.25 mg B12 total]) for 8 weeks.
RESULTS: The tibialis anterior (TA) muscle from Mtr+/- mice exhibited lowered maximal respiratory capacity of complex I, II, and IV of the electron transport chain than did TA from Mtr+/+ mice. Exposure to the -B12 diet lowered maximal capacity of complex I in red, mitochondrially rich muscle (soleus and mitochondria-rich portions of quadriceps and gastrocnemius) (p=0.02). Levels of uracil accumulation in mtDNA in red muscle and gastrocnemius were elevated ~10 fold with exposure to -B12 diet (p=0.04 and p<0.001, respectively). In aged mice gastrocnemius complex IV activity increased with intramuscular B12 supplementation (p=0.04).
CONCLUSIONS: Exposure to a B12-deficient diet led to uracil accumulation in mtDNA and impaired maximal oxidative capacity in two different types of skeletal muscle. B12 supplementation improved complex IV maximal capacity in gastrocnemius from aged mice.

DOI: https://doi.org/10.1101/2025.05.19.654973
Front Cell Neurosci. 2025 ;19 1661231

Underestimation of mitochondrial respiratory capacity in gray matter voxels of the human brain map due to limited OXPHOS and TCA cycle in astrocytes.

Christos Chinopoulos.

  Considering that the aerobic energetic landscape of the brain is shaped by its mitochondria, Mosharov et al. generated an atlas of mitochondrial content and enzymatic OXPHOS activities at a resolution comparable to MRI by physically voxelizing frozen human brain tissue. However, astrocytes in the adult human brain lack expression of several TCA cycle and OXPHOS enzymes. Therefore, their formula expressing mitochondrial respiratory capacity (MRC) -defined as tissue respiratory capacity normalized to mitochondrial density- underestimates actual values by a factor proportional to the square root of the fraction of respiration-capable cells (primarily neurons) in gray matter voxels.

Keywords:  MRI; OXPHOS; astrocytes; mitochondria; neurons; respiratory capacity

DOI:  https://doi.org/10.3389/fncel.2025.1661231
Epileptic Disord. 2025 Aug 29.

Classic or classical ketogenic diet? Definitions and nomenclature.

Rajesh RamachandranNair, Carl E Stafstrom, Eric H Kossoff.

  Dr. Ruby M. Schwartz coined the term "classical" ketogenic diet (KD) in 1989, followed by Dr. Stephen L. Kinsman in the USA, who introduced the term "classic" KD in 1992. Over the next decade, the term "classic KD" became increasingly common. So, which term is preferable-classic or classical? Given the widespread usage, we advocate for consistently using "classic KD." As there is also significant ambiguity about what exactly defines the classic KD compared to other diets, we believe two key aspects are required for the definition of classic KD: the principle of administration and the minimum ketogenic ratio (grams of fat to carbohydrates and protein). Classic KD studies emphasize a tailored, individualized approach to caloric intake and macronutrient distribution, with food items precisely measured. This personalized prescription is the defining feature of classic KD. Recent studies have proposed lower ratios, such as 2:1 or 2.5:1, yet the modified Atkins diet, introduced 80 years later, shows that a 1:1 ratio or lower can also induce ketosis. Therefore, labeling a classic KD with a minimum ratio of 3:1 or 4:1 is misleading. We contend that the classic KD should primarily be defined by its precise, individualized ratios, rather than by an arbitrary minimum value.

Keywords:  classic ketogenic diet; ketogenic ratio; terminology

DOI:  https://doi.org/10.1002/epd2.70093
Mol Biol Rep. 2025 Sep 03. 52(1): 861

The lactylation of glucose-6-phosphate dehydrogenase promotes malignant phenotypes in cancer cell lines.

Yan Zhang, Ying Wu, Aoxing Cheng, Fengjuan Cui, Zhenye Yang, Jing Guo.

   BACKGROUND: Malignant tumors are characterized by their reliance on hyperactive glycolysis (Warburg effect), marked by increased glucose uptake, lactate secretion, and preferential glucose flux into glycolysis and the pentose phosphate pathway (PPP). These metabolic shifts provide energy, biosynthetic precursors, and maintain redox balance, supporting tumor proliferation. However, the regulatory crosstalk between glycolysis and PPP remains poorly understood. This study investigates how tumors coordinate these pathways to drive progression via metabolic reprogramming.
METHODS AND RESULTS: Exogenous lactate supplementation in A549 cells increased the NADPH/NADP+ ratio, enhanced fatty acid synthesis, and upregulated the PPP. Western blotting revealed lactylation of glucose-6-phosphate dehydrogenase (G6PD), which correlated with intracellular lactate levels, modulated by rotenone treatment or lactate dehydrogenase A (LDHA) overexpression. LDHA knockdown significantly reduced G6PD lactylation. Enzyme assays confirmed that lactylation enhanced G6PD activity. Through truncation and mutagenesis analyses, we identified lysines 45-47 as the key lactylation site, which enhances NADP⁺ binding and promotes G6PD dimerization. Mutation of this site impaired cancer cell proliferation and migration in vitro and suppressed tumor growth in vivo. Mechanistically, G6PD lactylation serves as a metabolic switch, linking PPP activation to oncogenic progression.
CONCLUSIONS: Lactate drives tumor progression through G6PD lactylation, activating the PPP and facilitating glycolysis-PPP crosstalk. This study uncovers a novel metabolic rewiring mechanism that promotes oncogenic synergy.

Keywords:  Cancer; Glucose-6-phosphate dehydrogenase; Lactylation; Pentose phosphate pathway

DOI:  https://doi.org/10.1007/s11033-025-10960-y
Curr Cancer Drug Targets. 2025 Aug 29.

High Glucose and Glucose-derived Intermediates are Linked To Lung Cancer Aggressiveness.

Himani Joshi, Raiyan Satti, M Saeed Sheikh.



Keywords:  Metabolic reprogramming; electron transport chain; lung cancer; metastasis< complex-i inhibitor.; tricarboxylic acid cycle

DOI:  https://doi.org/10.2174/0115680096415724250822061328
Cell Metab. 2025 Aug 27. pii: S1550-4131(25)00363-8. [Epub ahead of print]

NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism.

Chia-Lin Chen, Dinesh Babu Uthaya Kumar, Vasu Punj, Jun Xu, Linda Sher, Stanley M Tahara, Sonja Hess, Keigo Machida.

DOI: https://doi.org/10.1016/j.cmet.2025.08.007
Cancer Res. 2025 Sep 03.

A Citrate Synthase Splice Variant Rewires the TCA Cycle to Promote Colorectal Cancer Progression.

Justin Chak Ting Cheung, Lok Wan Ng, Zhongxu Zhu, Bonan Chen, Stephen Li, Mingjing Xu, Xiaofan Ding, Dandan Pu, Yi Hu, Yuqing Ren, Wei Kang, Ming Li, Jason Wing Hon Wong, Xin Wang, Yuen Kit Cheng, Wei Shen Aik, Ka Leung Wong, Simon Siu Man Ng, Nathalie Wong, Yujuan Dong.

Metabolic reprogramming, notably alterations in the tricarboxylic acid (TCA) cycle, has emerged as a hallmark of cancer that supports tumor growth and metastasis. Despite the TCA cycle being a classical central metabolic pathway, further exploration is needed to fully elucidate the intricate manifestations and contributory mechanisms of TCA cycle rewiring in colorectal carcinogenesis. Herein, we identified a splicing isoform of citrate synthase (CS), CS-ΔEx4, and unveiled its role in TCA cycle dysregulation in colorectal cancer (CRC). CS-ΔEx4 was distinctly upregulated in CRC tumors compared with the canonical full-length (CS-FL) isoform. Clinical analyses established a strong correlation between elevated CS-ΔEx4 expression and cancer recurrence as well as inferior survival outcomes in patients with CRC. Functional experiments revealed the active contribution of CS-ΔEx4 to the aggressive phenotype of CRC cells both in vitro and in vivo. Mechanistically, CS-ΔEx4 formed a heterocomplex with CS-FL within the mitochondria that influenced the enzymatic function of canonical CS and accelerated TCA cycle flux, thereby promoting accumulation of the oncometabolite 2-hydroxyglutarate. The CS-ΔEx4-mediated metabolic alterations engendered epigenomic modulations that drove the upregulation of oncogenic gene signatures. In silico screening identified a small molecule with potent anti-proliferative effects in CRC cell line and organoid models that selectively antagonized the CS-ΔEx4 and CS-FL heterocomplex activity while sparing the CS-FL homodimers. Together, this study discovered the presence of a spliced CS isoform that promotes CRC progression and identified a molecule that holds potential for targeting the CS-ΔEx4 and CS-FL heterocomplex.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2355
Bio Protoc. 2025 Aug 20. 15(16): e5415

An Optimized Enzyme-Coupled Spectrophotometric Method for Measuring Pyruvate Kinase Kinetics.

Saurabh Upadhyay.

  Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme that catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate, producing ATP in the final step of glycolysis. Unlike other isoforms, PKM2 is uniquely regulated, shifting between active tetramers and less active dimers to balance energy production with biosynthetic demands. This flexibility is exploited in cancer cells to support the Warburg effect and anabolic growth. Additionally, PKM2 can translocate to the nucleus and act as a transcriptional co-activator, influencing gene expression and tumor progression. To facilitate functional studies of PKM2, we present a robust and reproducible protocol for its expression, purification, and enzymatic characterization. PKM2 is expressed in E. coli and purified via Ni-NTA affinity and size-exclusion chromatography to ensure high purity and proper folding. Enzymatic activity is measured using a lactate dehydrogenase (LDH)-coupled assay that tracks NADH oxidation at 340 nm, allowing sensitive kinetic analysis under various conditions, including different PEP concentrations, pH levels, and presence of the allosteric activator fructose-1,6-bisphosphate (FBP). This non-radioactive, high-resolution method is suitable for analyzing PKM2 regulation, post-translational modifications, and mutant variants, as well as for screening potential therapeutic modulators, providing a valuable tool for cancer metabolism research. Key features • Enables robust and scalable expression of recombinant wild-type PKM2 in E. coli, yielding protein suitable for biochemical and structural studies. • Utilizes a non-radioactive, LDH-coupled spectrophotometric assay to accurately measure PKM2 enzymatic activity in real time by monitoring NADH consumption at 340 nm. • Supports kinetic analysis under physiologically relevant conditions, including variable pH and in the presence or absence of the allosteric activator fructose-1,6-bisphosphate (FBP). • Suitable for comparative activity profiling of PKM2 variants, mutants, or post-translationally modified forms.

Keywords:  Enzyme kinetics; Glycolysis; LDH-coupled assay; Michaelis–Menten kinetics; PKM2; Pyruvate kinase M2; Recombinant protein expression; Spectrophotometric assay

DOI:  https://doi.org/10.21769/BioProtoc.5415
EMBO Mol Med. 2025 Aug 29.

Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML.

Lise Brault, Edwige Voisset, Mathieu Desaunay, Antonia Boudet, Paraskevi Kousteridou, Sébastien Letard, Nadine Carbuccia, Armelle Goubard, Rémy Castellano, Yves Collette, Julien Vernerey, Isabelle Vigon, Jean-Max Pasquet, Patrice Dubreuil, Sophie Lopez, Paulo De Sepulveda.

  The heterogeneity of leukemic cells is the main cause of resistance to therapy in acute myeloid leukemia (AML). Consequently, innovative therapeutic approaches are critical to target a wide spectrum of leukemic clones, regardless of their genetic and non-genetic complexity. In this report, we leverage the vulnerability of AML cells to CDK6 to identify a combination therapy capable of targeting common biological processes shared by all leukemic cells, while sparing non-transformed cells. We demonstrate that the combined inhibition of CDK6 and LSD1 restores myeloid differentiation and depletes the leukemic progenitor compartment in AML samples. Mechanistically, this combination induces major changes in chromatin accessibility, leading to the transcription of differentiation genes and diminished LSC signatures. Remarkably, the combination is synergistic, induces durable changes in the cells, and is effective in PDX mouse models. While many AML samples exhibit only modest responses to LSD1 inhibition, co-targeting CDK6 restores the expected transcription response associated with LSD1 inhibition. Given the availability of clinical-grade CDK6 and LSD1 inhibitors, this combination holds significant potential for implementation in clinical settings through drug repositioning.

Keywords:  Iadademstat; Inhibitor; Kinase; Leukemia; Palbociclib

DOI:  https://doi.org/10.1038/s44321-025-00296-2
Nature. 2025 Sep 03.

Depriving brain tumours of an amino acid could enhance chemotherapy.

Daniel Mobilio, Sheila Singh.



Keywords:  Brain; Cancer; Medical research; Metabolism

DOI:  https://doi.org/10.1038/d41586-025-02531-9
J Innov Opt Health Sci. 2024 Jan;pii: 2350030. [Epub ahead of print]17(1):

In vivo measurement of NADH fluorescence lifetime in skeletal muscle via fiber-coupled time-correlated single photon counting.

Kathryn M Priest, Jacob V Schluns, Nathania Nischal, Colton L Gattis, Jeffrey C Wolchok, Timothy J Muldoon.

  Nicotinamide adenine dinucleotide (NADH) is a cofactor that serves to shuttle electrons during metabolic processes such as glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation (OXPHOS). NADH is autofluorescent, and its fluorescence lifetime can be used to infer metabolic dynamics in living cells. Fiber-coupled time-correlated single photon counting (TCSPC) equipped with an implantable needle probe can be used to measure NADH lifetime in vivo, enabling investigation of changing metabolic demand during muscle contraction or tissue regeneration. This study illustrates a proof of concept for point-based, minimally-invasive NADH fluorescence lifetime measurement in vivo. Volumetric muscle loss (VML) injuries were created in the left tibialis anterior (TA) muscle of male Sprague Dawley rats. NADH lifetime measurements were collected before, during, and after a 30 s tetanic contraction in the injured and uninjured TA muscles, which was subsequently fit to a biexponential decay model to yield a metric of NADH utilization (cytoplasmic vs protein-bound NADH, the A1τ1/A2τ2 ratio). On average, this ratio was higher during and after contraction in uninjured muscle compared to muscle at rest, suggesting higher levels of free NADH in contracting and recovering muscle, indicating increased rates of glycolysis. In injured muscle, this ratio was higher than uninjured muscle overall but decreased over time, which is consistent with current knowledge of inflammatory response to injury, suggesting tissue regeneration has occurred. These data suggest that fiber-coupled TCSPC has the potential to measure changes in NADH binding in vivo in a minimally invasive manner that requires further investigation.

Keywords:  Glycolysis; energy metabolism; oxidative phosphorylation; volumetric muscle loss

DOI:  https://doi.org/10.1142/s179354582350030x
J Oncol Res Ther. 2024 ;pii: 10257. [Epub ahead of print]9(4):

The Role of Ceramide and Sphingolipid Metabolism in Cancer Therapeutics.

Andrea L Cote, Kyla S Jarvis, Brian M Barth.

Sphingolipids are a class of bioactive lipids which are highly involved in cellular functions such as signaling, membrane composition, and determining cell fate. The metabolism of these lipids plays important roles in the development and progression of many diseases such as cancer. The role of sphingolipid metabolism in cancer overall is not yet fully understood. However, key sphingolipids such as sphingosine-1-phosphate (S1P) and ceramide have been shown to be influential on the death or survival of cancer cells. S1P is known to exert pro-survival signaling effects when expressed at higher levels in cells. Ceramide, on the other hand, has been established as a pro-death lipid, regulating apoptosis, cell cycle arrest, autophagy, and mitophagy. Cancer cells are typically characterized by an increased ratio in S1P to ceramide, thus granting the survival of the cancer. This ceramide/S1P biostat is the target of many new therapeutics which aim to increase ceramide levels in cancer cells. Additionally, many previously established drugs have been rediscovered for their unexpected ability to perturb sphingolipid metabolism. This review serves to summarize the current use of ceramide and sphingolipid metabolism-related therapies for the treatment of many cancers.

DOI: https://doi.org/10.29011/2574-710x.10257
Analyst. 2025 Sep 03.

Unsupervised machine learning for mass spectrometry imaging data analysis with in vivo isotope labeling.

Raven L Buckman Johnson, Vy T Tat, Young Jin Lee.

Mass spectrometry imaging (MSI) has emerged as a powerful tool for spatial metabolomics, but untargeted data analysis has proven to be challenging. When combined with in vivo isotope labeling (MSIi), MSI provides insights into metabolic dynamics with high spatial resolution; however, the data analysis becomes even more complex. Although various tools exist for advanced MSI analyses, machine learning (ML) applications to MSIi have not been explored. In this study, we leverage Cardinal to process MSIi datasets of duckweeds labeled with either 13CO2 or D2O. We apply spatial shrunken centroid (SSC) segmentation, an unsupervised ML algorithm, to differentiate metabolite localizations and investigate isotope labeling of untargeted metabolites. In the SSC segmentation of three-day 13C-labeled duckweed dataset, five spatial segments were identified based on distinct lipid isotopologue distributions, in contrast to classification of only three tissue regions in previous manual analysis based on galactolipid isotopologues. Similarly, SSC segmentation of five-day D-labeled dataset revealed five spatial segments based on distinct metabolite and isotopologue profiles. Further, this untargeted segmentation analysis of MSIi dataset provided insights on tissue-specific relative flux of each metabolite by calculating the fraction of de novo biosynthesis in each segment. Overall, the application of unsupervised machine learning to MSIi datasets has proven to significantly reduce analysis time, increase throughput, and improve the clarity of spatial isotopologue distributions.

DOI: https://doi.org/10.1039/d5an00649j
Ann Hematol. 2025 Aug 30.

Comparative efficacy of venetoclax and hypomethylating agents in acute myeloid leukemia treatment: a meta-analysis of clinical trials and Real-World outcomes.

Antonio Sanz-Solas, Miriam Saiz-Rodríguez, Sara Calvo Simal, Rebeca Rodríguez-Veiga, Antonio Solana-Altabella, Pau Montesinos, Jorge Labrador.

This meta-analysis, comprising 24 studies, evaluated the efficacy of venetoclax (VEN) in combination with hypomethylating agents (HMAs), including azacitidine (AZA) and decitabine (DEC), in untreated patients with acute myeloid leukemia (AML), comparing outcomes from clinical trials and real-world practice. No significant difference in composite complete response (CRc) rates was observed between clinical trials (52%, 95% CI: 39-65%) and real-world studies (67%, 95% CI: 47-87%). However, overall survival (OS) was significantly longer in clinical trials (13.98 months, 95% CI: 11.89-16.07) compared to real-world cohorts (9.35 months, 95% CI: 8.46-10.23; p < 0.005). In real-world studies, the VEN + HMA combination was associated with a significantly higher CRc rate (67%, 95% CI: 48-85%) compared to HMA monotherapy (17%, 95% CI: 13-21%; p < 0.005), although no significant difference in OS was observed between these groups (9.35 vs. 9.38 months; p = 0.964). These findings highlight the need to optimize the implementation of VEN + HMA regimens in clinical practice, as real-world outcomes remain inferior to those reported in clinical trials.

DOI: https://doi.org/10.1007/s00277-025-06543-3
ACS Appl Mater Interfaces. 2025 Aug 31.

Light-Activated CD36-Targeted Cuproptosis Triggers Metabolic-Immune Synergy for Precision Breast Cancer Therapy.

Shiwen Wang, Ying Shen, Binbin Hu, Qiping Wu, Nanzhou Wang, Zichao Wang, Zifeng Zhang, Yujie Li, Jianhui Jiang.

  Breast cancer therapy confronts dual challenges of metabolic plasticity-driven drug resistance and immunosuppression. To address this, we developed DCP-TPP, a therapeutic nanoplatform that integrates dysregulation of copper homeostasis and lipid metabolism for precise breast cancer therapy. Leveraging the overexpression of cluster of differentiation 36 (CD36) in breast cancer cells, DCP-TPP employs fatty acid camouflage (PCM) to deliver disulfiram (DSF) and photothermal Cu3BiS3 to cancer cells and features triphenylphosphonium (TPP) modification for targeted mitochondrial drug delivery. Near-infrared (NIR) irradiation triggers the phase transition of DCP-TPP's outer layer, inducing spatiotemporal release of DSF to liberate copper ions from inert Cu3BiS3, thereby generating diethyldithiocarbamate-copper complex (CuET). This disrupts copper homeostasis and induces cuproptosis, which subsequently triggers S-acetyltransferase (DLAT) aggregation, impairing tricarboxylic acid (TCA) cycle flux, acetyl-CoA production, ATP citrate lyase (Acly)-dependent lipogenesis, and ultimately collapses mitochondrial oxidative phosphorylation. Multiomics profiling revealed oleic acid depletion, arachidonic acid oxidation, and glutathione exhaustion, collectively amplifying metabolic collapse. DCP-TPP-induced cell death enhanced dendritic cell (DC) activation and CD8+ T cell infiltration. In breast cancer models, DCP-TPP achieved 90.9% tumor suppression, with 60% of mice resisting rechallenge. By transforming lipid metabolic dependency into a therapeutic vulnerability and coupling it with copper ion toxicity, DCP-TPP offers a promising strategy for breast cancer therapy.

Keywords:  CD36; cancer immunotherapy; cuproptosis; lipid metabolism reprogram; phase-transitional material

DOI:  https://doi.org/10.1021/acsami.5c11318
J Biol Chem. 2025 Sep 03. pii: S0021-9258(25)02512-8. [Epub ahead of print] 110660

Activity-based probes and chemical proteomics uncover the biological impact of targeting HMGCS1 in the mevalonate pathway.

Sang Ah Yi, Liang Sun, Yi Rao, Alban Ordureau, Jason S Lewis, Heeseon An.

  Mevalonate is a precursor for essential metabolites, such as isoprenoids and sterols. Its synthesis starts with HMGCS1 producing HMG-CoA, which is then converted to mevalonate by HMGCR, a target of statins. Cancer cells often upregulate enzymes in the mevalonate pathway (MVP) to meet their metabolic demands, leading to the development of inhibitors targeting several enzymes in this pathway. However, current inhibitors have not yet shown significant anti-cancer activity. While HMGCS1 has unique biochemical properties that distinguish it from other MVP enzymes, the effects of inhibiting HMGCS1 have not been thoroughly investigated. Here, we present a set of chemical probes that enable us to systematically assess the proteome-wide selectivity and potency of Hymeglusin, the primary inhibitor of HMGCS1 used in the field, confirming it as a useful tool for short-term HMGCS1 inhibition. Inhibiting HMGCS1 with Hymeglusin causes proteome changes that are nearly identical to those caused by inhibiting HMGCR or degrading HMGCS1. Accordingly, simultaneously targeting HMGCS1 and HMGCR effectively suppresses the growth of statin-resistant cells and xenograft models, without increasing the risk of side effects. Finally, we find that while Hymeglusin is a valuable tool for short-term mechanistic studies, its usefulness is limited for long-term efficacy studies due to its poor stability in serum. Together, this study highlights the biological implications of targeting HMGCS1 as monotherapy or in combination with statins, and caution is required when using Hymeglusin as a tool.

Keywords:  HMGCR; HMGCS1; Hymeglusin; Mevalonate; activity-based probe; chemical proteomics; statin

DOI:  https://doi.org/10.1016/j.jbc.2025.110660
Haematologica. 2025 Sep 04.

SLC25A1 reprograms mitochondrial and fatty acid metabolism to promote the progression of acute myeloid leukemia.

Miao Chen, Wenze Li, Yuan Tao, Chenglong Hu, Rui Ge, Sijing Kang, Pengjie Yue, Cheuk Him Man, Lan Wang, Xiaojing Yan.

Abnormal metabolic reprogramming is a hallmark of acute myeloid leukemia (AML), contributing to leukemia initiation, progression and drug resistance. The key mitochondrial citrate transporter SLC25A1 plays an essential role in regulating cellular energy metabolism and shows to play an important role in lipid metabolism regulation. However, the role of SLC25A1 in the pathogenesis and aberrant lipid metabolism in AML remain unexplored. In this study, our analysis of public datasets and patient samples revealed that SLC25A1 expression was markedly elevated in AML and was associated with poor prognosis. Knockdown or pharmacological inhibition of SLC25A1 significantly suppressed AML cell proliferation by inducing apoptosis, without affecting cell cycle progression or differentiation. Moreover, SLC25A1 proved vital for AML tumorigenesis in vivo. Mechanistically, we demonstrated that SLC25A1 inhibition disrupted citrate homeostasis, leading to mitochondrial dysfunction and reduced fatty acid metabolism. Notably, we developed a novel SLC25A1 inhibitor, CTPI3, which effectively inhibits the progression of AML in vivo, and synergizes with venetoclax to kill AML cells by mitochondrial and fatty acid metabolism regulation. In summary, our findings highlight that SLC25A1 plays a vital role of in maintaining AML cell survival and regulating its drug sensitivity, and further developed a more effective novel drug targeting SLC25A1, providing additional therapeutic options for venetoclax-resistant patients and highlighting SLC25A1 as a promising biomarker and therapeutic target for AML.

DOI: https://doi.org/10.3324/haematol.2024.287269
Future Sci OA. 2025 Dec;11(1): 2527015

Plasma metabolic landscape unveils key regulators of leukemia subtype progression.

Cong Liang, Jia-Yu Lin, Liu-Hua Liao, Shi-Yao Song, Jia-Tong Dai, Jia-Jie Chen, Zhi-Yong Ke, Hong-Man Xue.

   BACKGROUND: Leukemia is driven by metabolic reprogramming, yet the specific causal roles of plasma metabolites in distinct leukemia subtypes remain unclear.
METHODS: This study employed Mendelian randomization (MR) to explore potential causal links between 690 plasma metabolites (and 143 metabolite ratios) and four leukemia subtypes: ALL, AML, CLL, and CML. Genetic variants from genome-wide association studies served as instrumental variables. Multiple MR approaches, including IVW, MR-Egger, and Weighted Median, along with sensitivity analyses, were applied to ensure robust results.
RESULTS: Our findings revealed subtype-specific metabolite associations. In ALL, metabolites such as 3-Hydroxyisobutyrate and γ-Glutamylglutamate showed positive associations, while Phosphocholine and Ceramide showed negative associations. AML was positively linked to GlcNAc/GalNAc and negatively to 1-Methylnicotinamide. CLL showed positive associations with Butyrate/Isobutyrate and Androstenediol Monosulfate, and negative ones with Docosatrienoate and α-Tocopherol to Sulfate ratio. CML exhibited negative associations with Cysteine-Glutathione disulfide and Piperine.
CONCLUSION: Our MR study provides a comprehensive evaluation of the metabolomic landscape of leukemia, identifying subtype-specific causal associations involving pathways such as energy metabolism, amino acid metabolism, lipid signaling, and redox homeostasis. These findings offer insights into potential plasma biomarkers and therapeutic targets, revealing distinct metabolic vulnerabilities that warrant further investigation for precision treatment strategies across leukemia subtypes.

Keywords:  Leukemia; biomarkerss; mendelian Randomization; metabolic reprogramming; plasma metabolites

DOI:  https://doi.org/10.1080/20565623.2025.2527015
Cell. 2025 Aug 26. pii: S0092-8674(25)00927-4. [Epub ahead of print]

Tumors hijack macrophages for iron supply to promote bone metastasis and anemia.

Yujiao Han, Hirak Sarkar, Zhan Xu, Sereno Lopez-Darwin, Yong Wei, Xiang Hang, Fengshuo Liu, Kimberley Tran, Wei Wang, Jennifer M Miller, Christina J DeCoste, Dylan S Blohm, Robert L Satcher, Xiang H-F Zhang, Yibin Kang.

  Bone marrow is both a primary site for hematopoiesis and a fertile niche for metastasis. The mechanism of the common occurrence of anemia among patients with bone metastasis remains poorly understood. Here, we show that a specialized population of VCAM1+CD163+CCR3+ macrophages, normally essential for erythropoiesis by transporting iron to erythroblasts, are highly enriched in the bone metastatic niche in mouse models. Tumor cells hijack these macrophages for iron supply, reducing iron availability for erythroblasts, impairing erythropoiesis, and contributing to anemia. Increased iron supply enables tumor cells to produce hemoglobin in response to hypoxia, mimicking erythroblasts. We identify macrophages with similar iron-transporting features in human bone metastases and show that elevated HBB expression correlates with increased risk of bone metastasis. These findings establish iron-transporting macrophages as an essential component of the metastatic bone niche, revealing a critical interplay between immune cells, metal metabolism, and tumor cell plasticity in driving metastasis and anemia.

Keywords:  anemia; bone metastasis; breast cancer; cellular plasticity; erythropoiesis; hypoxia; iron metabolism; macrophage; metastatic niche; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cell.2025.08.013
Nat Med. 2025 Sep 02.

Targeting dormant tumor cells to prevent recurrent breast cancer: a randomized phase 2 trial.

Angela DeMichele, Amy S Clark, Emily Shea, Lauren J Bayne, Christopher J Sterner, Killian Rohn, Samantha Dwyer, Tien-Chi Pan, Isoris Nivar, Yan Chen, Paul Wileyto, Lindsay R Berry, Shannon Deluca, Jessica Savage, Igor Makhlin, Dhruv K Pant, Heather Martin, Adetutu Egunsola, Nathan Mears, Brooke L Goodspeed, Elizabeth M Chislock, Jewell Graves, Jianping Wang, Natalie Shih, George K Belka, Don Berry, Anupma Nayak, Michael Feldman, Lewis A Chodosh.

Breast cancer recurrence may arise from dormant disseminated tumor cells (DTCs) that persist in bone marrow and other sites. Clinically, DTCs are independently associated with breast cancer recurrence and death. Preclinical studies in mouse models identified autophagy and mammalian target of rapamycin (mTOR) signaling as critical mechanisms of tumor dormancy and escape. We subsequently tested the effects of transient versus chronic inhibition of autophagy with chloroquine or hydroxychloroquine (HCQ) and mTOR signaling with rapamycin (RAPA) or everolimus (EVE) on residual tumor cell (RTC) burden and recurrence-free survival (RFS). In mice harboring dormant RTCs, inhibition of mTOR alone or in combination with autophagy inhibition decreased RTC burden and improved RFS in a duration-dependent manner. RTC number was strongly and inversely correlated with RFS, suggesting that RTC reduction mediated an improvement in RFS. To translate findings clinically, we performed a randomized phase 2 trial (CLEVER) of HCQ, EVE or their combination in breast cancer survivors within 5 years of diagnosis who had detectable DTCs on bone marrow aspirate. Primary endpoints were feasibility and safety; secondary endpoints included DTC reduction/clearance and RFS. In total, 51 DTC+ patients initiated HCQ (n = 15), EVE (n = 15) or HCQ + EVE (n = 21). Treatment was feasible and tolerable; only one patient discontinued early for grade 3 toxicity. At 42 months median follow-up, landmark 3-year RFS for HCQ, EVE and HCQ + EVE was 91.7%, 92.9% and 100%, respectively, and was greater in those who cleared DTCs versus those who did not (hazard ratio (HR) = 0.21 (95% confidence interval 0.01-3.4)). Posterior probabilities were 98-99.9% that three cycles of HCQ, EVE or HCQ + EVE led to reduced or undetectable DTCs compared to observation alone, with estimated DTC reductions of 80%, 78% and 87%, respectively. These findings provide proof-of-concept that targeting dormant RTCs with HCQ, EVE or their combination in breast cancer survivors or mouse models depletes minimal residual disease, warranting a definitive human randomized controlled trial. ClinicalTrials.gov registration: NCT03032406 .

DOI: https://doi.org/10.1038/s41591-025-03877-3
Cancer Res. 2025 Sep 05.

An Olive Oil-Based High-Fat Diet Promotes Obesity-Driven Metastasis of Triple-Negative Breast Cancer.

Anthony Avellino, Xingshan Jiang, Michael Lee, Jianyu Yu, Shanshan Liu, Xiaochun Han, Jerry Li, Jonathan Shilyansky, Zhaohua Wang, Melissa Curry, Yiqin Xiong, Ingrid M Lizarraga, Yi Huang, Sonia L Sugg, Jiaqing Hao, Bing Li.

Obesity is strongly associated with triple-negative breast cancer (TNBC). A better understanding of the molecular mechanisms driving obesity-induced TNBC progression could facilitate development of precision dietary intervention strategies. Here, we used murine models of obesity induced by different high-fat diets (HFDs) to examine their impact on TNBC progression. Compared to a low-fat diet (LFD), both cocoa butter and olive oil HFD induced similar levels of obesity. However, only the olive oil HFD-induced obesity increased TNBC stemness and lung metastasis. Mechanistically, oleic acid (OA) in the olive oil HFD facilitated TNBC metastasis by activating the protein kinase C (PKC)-aldehyde dehydrogenase (ALDH) pathway. Furthermore, fatty acid-binding protein 5 (FABP5) in TNBC cells was identified as essential for OA-mediated PKC/ALDH pathway activation. FABP5 deficiency reduced TNBC metastasis in multiple mouse models, whereas higher FABP5 expression correlated with worse outcomes of TNBC in various human studies. These findings collectively suggest that consumption of olive oil HFD promotes obesity-associated TNBC metastasis through OA/FABP5-driven oncogenic signaling.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0822
J Vis Exp. 2025 Aug 15.

Method to Study Metabolism in Lymphoid Cells using Chemistry to Measure Puromycin Incorporation by Flow Cytometry.

Zenia Kaul, Hirofumi Shibata, Pamela L Schwartzberg.

Upon antigen stimulation, naïve T cells undergo rapid proliferation and expansion to effector T cells. Metabolism plays an important role in the generation of biomass needed for these rapidly proliferating cells and for the generation of molecules required for effector T cell differentiation and function, which influence the outcome of the adaptive immune response in infection or cancers. Naïve T cells reprogram their metabolism upon antigenic stimulation to increase the generation of ATP, which is required to support their growth, biosynthesis, and effector functions. ATP can be generated in a cell either by the mitochondrial-oxidative phosphorylation (OXPHOS) pathway or by the glycolytic pathway. Because most of the ATP generated in a dividing, growing cell is used up for the synthesis of proteins, protein synthesis has been used as a surrogate for ATP levels. Protein synthesis can be measured by the incorporation of puromycin, which mimics the 3' adenosine of a tRNA charged with a modified tyrosine and leads to spontaneous termination of protein translation. Metabolic inhibitors like 2-deoxyglucose (2DG), which blocks the glycolytic pathway, and Oligomycin (O), which blocks complex 5 of the electron transport chain (ETC), can be used to study the dependencies of cellular ATP generation on these two pathways in conjunction with evaluation of protein synthesis in a method called SCENITH. We describe here a variation of this method that detects puromycin incorporation by flow cytometry using chemistry. This method of studying metabolism is relatively easy and can be used for evaluating rare cell populations, as well as patient samples, by flow cytometry.

DOI: https://doi.org/10.3791/67377
Cancer Res. 2025 Sep 05.

Lipid Composition Alters Ferroptosis Sensitivity.

Vivian S Park, Lauren E Pope, Justin P Ingram, Grace A Alchemy, Julie J Purkal, Magdalena B Murray, Sha Jin, Eli Y Andino-Frydman, Sanjana Singh, Anlu Chen, Priya Narayanan, Sarah Kongpachith, Darren C Phillips, Scott J Dixon, Relja Popovic.

Ferroptosis is a regulated non-apoptotic cell death process characterized by iron-dependent lipid peroxidation. Peroxidation of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) is necessary for the execution of ferroptosis. Glutathione peroxidase 4 (GPX4) suppresses ferroptosis by reducing lipid hydroperoxides to lipid alcohols. GPX4 may be a useful target for drug development, highlighting the need to identify factors that govern GPX4 inhibitor sensitivity. Here, we found that reduced GPX4 expression was sufficient to induce ferroptosis in multiple adherent (2D) cancer cell cultures. However, lower GPX4 protein levels did not consistently affect tumor xenograft growth in mice. Culturing cells as spheroids (3D) was sufficient to reduce sensitivity to pharmacological GPX4 inhibition. Mechanistically, growth in 3D versus 2D conditions upregulated expression of the monounsaturated fatty acid (MUFA) biosynthetic gene stearoyl-CoA desaturase (SCD), altering the ratio of MUFA-PLs to PUFA-PLs in a direction favoring ferroptosis resistance. Similar shifts in MUFA-PL to PUFA-PL ratios were observed in xenograft tumors. Thus, lipidome remodeling in 3D growth conditions and in vivo may limit GPX4 inhibitor efficacy.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4207
Chem Commun (Camb). 2025 Sep 01.

Monitoring nucleoside metabolism in living cells with a nucleobase analogue via fluorescence lifetime imaging.

Pauline Pfeiffer, Niusha Bagheri, Chen Qian, Jerker Widengren, L Marcus Wilhelmsson.

To overcome challenges in fluorescence labelling of RNA inside living cells we have recently introduced a direct approach using the fluorescent nucleobase analogue 2CNqA. Here we demonstrate its potential for use in fluorescence lifetime imaging (FLIM) to investigate nucleoside metabolism and for metabolic RNA labelling.

DOI: https://doi.org/10.1039/d5cc03959b