bims-medica 2025-04-13 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–04–13
29 papers selected by
Brett Chrest, Wake Forest University

Impact of Intermittent Fasting with a Ketogenic Diet on AMPK Levels in Breast Cancer Patients Receiving Chemotherapy.
The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer.
Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.
Modeling Krebs cycle from liver, heart and hepatoma mitochondria, supported Complex I as target for specific inhibition of cancer cell proliferation.
Stable isotope tracing reveals glucose metabolism characteristics of drug-resistant B-cell acute lymphoblastic leukemia.
Patient-derived organotypic tissue cultures as a platform to evaluate metabolic reprogramming in breast cancer patients.
TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia.
Inactivation of mitochondrial pyruvate dehydrogenase by singlet oxygen involves lipoic acid oxidation, side-chain modification and structural changes.
Inhibition of FLT3-induced signalling in refractory acute myeloid leukaemia.
Amino acids in cancer: Understanding metabolic plasticity and divergence for better therapeutic approaches.
Analytical approach to distinguishing lactate dehydrogenase fractions for oncological diagnostics.
Ketomimetic nutrients remodel the glycocalyx and trigger a metabolic defense in breast cancer cells.
Hepatic toll of keto: unveiling the inflammatory and structural consequences of ketogenic diet in rats.
Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.
Targeting vulnerability in tumor therapy: Dihydroorotate dehydrogenase.
Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates.
Excessive dietary fat and fructose enhance hepatic lipogenesis and impair mitochondrial dynamics to cause MASLD in C57BL/6 mice.
The role of diet, obesity and body composition in epithelial ovarian cancer development and progression: Mechanisms and therapeutic implications.
Exploring physiological beta-hydroxybutyrate level in children treated with the classical ketogenic diet for drug-resistant epilepsy.
Causal associations between blood metabolites and breast cancer.
Identification of glucuronic acid as a biomarker of poor prognosis in acute myeloid leukemia based on plasma metabolomics.
Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors.
Treatment delay significantly increases mortality in colorectal cancer: a meta-analysis.
Heart Has Intrinsic Ketogenic Capacity that Mediates NAD+ Therapy in HFpEF.
The potential role of BCL-2 inhibition in amyloidosis and plasma cell leukemia.
Discovery of FLT3-ITD Inhibitor Clifutinib: A Novel Biphenylacetylene Urea Derivative in Clinical Trials for the Treatment of Relapsed/Refractory FLT3-ITD+ Acute Myeloid Leukemia.
Ultra-processed food consumption affects structural integrity of feeding-related brain regions independent of and via adiposity.
Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.
Early Detection of Elevated Ketone Bodies in Type 1 Diabetes Using Insulin and Glucose Dynamics Across Age Groups: Model Development Study.

Nutr Cancer. 2025 Apr 08. 1-7

Impact of Intermittent Fasting with a Ketogenic Diet on AMPK Levels in Breast Cancer Patients Receiving Chemotherapy.

Ahsan Raza Khan Lughmani, Nouman Ibrahim, Wasiq Ali, Yasmeen Bibi, Adnan Afzal, Mizna Javed, Ammara Hameed, Wania Shahzadi, Saba Saddique, Maria Ahmed.

Adenosine monophosphate-activated protein kinase (AMPK), a metabolic sensor activated by nutrient starvation, plays a multifaceted role in cancer. Whether AMPK is beneficial or malevolent is controversial. This study aimed to investigate AMPK levels in breast cancer patients receiving chemotherapy and compare the effects of intermittent fasting combined with different diets on these levels. Forty-five breast cancer patients were divided into three groups: a control, a group practicing 23:1-h intermittent fasting (IF) with a routine diet (RD), and another with a ketogenic diet (KD) over 4 weeks. Body mass index (BMI), Carbohydrate Antigen 15-3 (CA 15-3) levels, and serum AMPK levels were measured pre and post-intervention. Results showed a significant increase in AMPK levels in both the fasting groups and no significant difference in the non-fasting group, with the keto diet group showing the most significant growth. CA 15-3 levels were reduced in all the groups but significantly reduced in the KD group as compared to the RD group. This study shows that intermittent fasting with the keto diet improves AMPK levels and may serve as a valuable non-pharmacological complementary strategy for reducing or eliminating the tumor and, simultaneously, preventing the healthy cells from the toxic side effects of chemotherapy.

DOI: https://doi.org/10.1080/01635581.2025.2488065
J Bioenerg Biomembr. 2025 Apr 08.

The Warburg hypothesis and the emergence of the mitochondrial metabolic theory of cancer.

Thomas N Seyfried, Derek C Lee, Tomas Duraj, Nathan L Ta, Purna Mukherjee, Michael Kiebish, Gabriel Arismendi-Morillo, Christos Chinopoulos.

  Otto Warburg originally proposed that cancer arose from a two-step process. The first step involved a chronic insufficiency of mitochondrial oxidative phosphorylation (OxPhos), while the second step involved a protracted compensatory energy synthesis through lactic acid fermentation. His extensive findings showed that oxygen consumption was lower while lactate production was higher in cancerous tissues than in non-cancerous tissues. Warburg considered both oxygen consumption and extracellular lactate as accurate markers for ATP production through OxPhos and glycolysis, respectively. Warburg's hypothesis was challenged from findings showing that oxygen consumption remained high in some cancer cells despite the elevated production of lactate suggesting that OxPhos was largely unimpaired. New information indicates that neither oxygen consumption nor lactate production are accurate surrogates for quantification of ATP production in cancer cells. Warburg also did not know that a significant amount of ATP could come from glutamine-driven mitochondrial substrate level phosphorylation in the glutaminolysis pathway with succinate produced as end product, thus confounding the linkage of oxygen consumption to the origin of ATP production within mitochondria. Moreover, new information shows that cytoplasmic lipid droplets and elevated aerobic lactic acid fermentation are both biomarkers for OxPhos insufficiency. Warburg's original hypothesis can now be linked to a more complete understanding of how OxPhos insufficiency underlies dysregulated cancer cell growth. These findings can also address several questionable assumptions regarding the origin of cancer thus allowing the field to advance with more effective therapeutic strategies for a less toxic metabolic management and prevention of cancer.

Keywords:  Cardiolipin; Lactate; Lipid droplets; Oxidative phosphorylation; Oxygen consumption; Somatic mutations; Substrate level phosphorylation; Succinate

DOI:  https://doi.org/10.1007/s10863-025-10059-w
Sci Adv. 2025 Apr 11. 11(15): eadu5511

Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy.

James T Hagen, McLane M Montgomery, Raphael T Aruleba, Brett R Chrest, Polina Krassovskaia, Thomas D Green, Emely A Pacheco, Miki Kassai, Tonya N Zeczycki, Cameron A Schmidt, Debajit Bhowmick, Su-Fern Tan, David J Feith, Charles E Chalfant, Thomas P Loughran, Darla Liles, Mark D Minden, Aaron D Schimmer, Md Salman Shakil, Matthew J McBride, Myles C Cabot, Joseph M McClung, Kelsey H Fisher-Wellman.

OxPhos inhibitors have struggled to show a clinical benefit because of their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to acute myeloid leukemia (AML) mitochondria. Unlike healthy cells that couple respiration to ATP synthesis, AML mitochondria support inner-membrane polarization by consuming ATP. Matrix ATP consumption allows cells to survive bioenergetic stress. Thus, we hypothesized AML cells may resist chemotherapy-induced cell death by reversing the ATP synthase reaction. In support, BCL-2 inhibition with venetoclax abolished OxPhos flux without affecting mitochondrial polarization. In surviving AML cells, sustained mitochondrial polarization depended on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to down-regulations in the endogenous F1-ATPase inhibitor ATP5IF1. Knockdown of ATP5IF1 conferred venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. These data identify matrix ATP consumption as a cancer cell-intrinsic bioenergetic vulnerability actionable in the context of BCL-2 targeted chemotherapy.

DOI: https://doi.org/10.1126/sciadv.adu5511
Front Oncol. 2025 ;15 1557638

Modeling Krebs cycle from liver, heart and hepatoma mitochondria, supported Complex I as target for specific inhibition of cancer cell proliferation.

Luz Hernández-Esquivel, Isis Del Mazo-Monsalvo, Silvia Cecilia Pacheco-Velázquez, Rocío Daniela Feregrino-Mondragón, Diana Xochiquetzal Robledo-Cadena, Rosina Sánchez-Thomas, Ricardo Jasso-Chávez, Emma Saavedra, Álvaro Marín-Hernández.

   Introduction: The Krebs cycle (KC) is an important pathway for cancer cells because it produces reduced coenzymes for ATP synthesis and precursors for cellular proliferation. Described changes in cancer KC enzyme activities suggested modifications in the reactions that control the KC flux compared to normal cells.
Methods: In this work, kinetic metabolic models of KC of mitochondria from cancer (HepM), liver (RLM) and heart (RHM) to identify targets to decrease the KC flux were constructed from kinetic parameters (Vmax and Km) of enzymes here determined.
Results: The enzymes Vmax values were higher in the following order: RHM > HepM > RLM; meanwhile, Km values were similar. Kinetic modeling indicated that the NADH consumption reaction (complex I) exerted higher control on the Krebs cycle flux in HepM versus RLM and to a lesser extent in RHM. These results suggested that cancer cells may be more sensitive to complex I inhibition than heart and other non-cancer cells. Indeed, cancer cell proliferation was more sensitive to rotenone (a complex I inhibitor) than heart and non-cancer cells. In contrast, cell proliferation had similar sensitivities to malonate, an inhibitor of succinate dehydrogenase, an enzyme that does not exert control.
Discussion: Our results showed that kinetic modeling and metabolic control analysis allow the identification of high flux-controlling targets in cancer cells that help to design strategies to specifically inhibit their proliferation. This can minimize the toxic effects in normal cells, such as the cardiac ones that are highly sensitive to conventional chemotherapy.

Keywords:  Complex I; Krebs cycle; cancer; heart; kinetic modeling; liver; metabolic control analysis; mitochondria

DOI:  https://doi.org/10.3389/fonc.2025.1557638
Anal Chim Acta. 2025 May 22. pii: S0003-2670(25)00278-8. [Epub ahead of print]1352 343884

Stable isotope tracing reveals glucose metabolism characteristics of drug-resistant B-cell acute lymphoblastic leukemia.

Rong Hu, Zhengwei Duan, Mengyao Wang, Mengting Liu, Yaoxin Zhang, Yanxi Lu, Yuhan Qian, Enjie Wei, Jianghua Feng, Pengfei Guo, Yang Chen.

   BACKGROUND: Adult B-cell acute lymphocytic leukemia (B-ALL) is a malignant hematologic tumor characterized by the uncontrolled proliferation of B-cell lymphoblasts in the bone marrow. Despite advances in treatment, including chemotherapy and consolidation therapy, many B-ALL patients experience unfavorable prognoses due to the development of drug resistance. The precise mechanisms governing chemotherapy resistance, particularly those related to metabolic reprogramming within tumors, remain inadequately elucidated.
RESULTS: Nalm6/DOX cells exhibited significantly elevated levels of glucose, pyruvate, alanine, glutamine, and glycine compared to Nalm6 cells. Conversely, reduced levels of citrate, acetate, and leucine were observed in Nalm6/DOX cells. Upon exposure to the culture medium supplemented with tracer 13C6-glucose, the Nalm6/DOX cells showed an increase in the abundance of 13C-alanine and a decrease in the levels of 13C-lactate, indicating impaired utilization of 13C-pyruvate. Combining β-chloro-alanine (ALTi) with DOX could decrease the drug resistance phenotype of Nalm6/DOX cells. The results demonstrated that glycolysis and tricarboxylic acid cycle were suppressed in Nalm6/DOX cells, while metabolic flux through the alanine and glutamine pathways was increased. Therefore, inhibition of alanine biosynthesis in Nalm6/DOX exhibits the potential to reverse drug resistance.
SIGNIFICANCE: A new insight into the impact of metabolism on chemotherapy resistance in B-ALL has been gained through the use of stable isotope resolved metabolomics based on nuclear magnetic resonance and ultra-performance liquid chromatography/tandem mass spectrometry. This provides promising ways for the development of innovative therapeutic strategies to alleviate drug resistance and relapse in affected patients.

Keywords:  Alanine; Doxorubicin; NMR; Stable isotope resolved metabolomics; TCA cycle; UPLC-MS/MS

DOI:  https://doi.org/10.1016/j.aca.2025.343884
J Biol Chem. 2025 Apr 08. pii: S0021-9258(25)00344-8. [Epub ahead of print] 108495

Patient-derived organotypic tissue cultures as a platform to evaluate metabolic reprogramming in breast cancer patients.

Teresa W -M Fan, Jing Yan, Carlos Frederico L Goncalves, Jahid M M Islam, Penghui Lin, Mohamed M Y Kaddah, Richard M Higashi, Andrew N Lane, Xiaoqin Wang, Caigang Zhu.

  Patient-derived organotypic tissue cultures (PD-OTC) are unique models for probing cancer metabolism and therapeutic responses. They retain patient tissue architectures/ microenvironments that are difficult to recapitulate while affording comparison of cancer (CA) versus matched non-cancer (NC) tissue responses to treatments. We have developed a long-term culturing method for fresh and cryopreserved PD-OTC of breast cancer patients bearing invasive ductal carcinoma. Five PD-OTC came from patients with treatment-naïve primary ER+/PR+/HER2- tumors while one came from a patient with neoadjuvant therapy for locally metastatic ERlow/PR-/HER2- tumor. They all exhibited tissue outgrowth in one month with some CA OTC harboring isolatable organoids and fibroblasts. We interrogated reprogrammed metabolism in CA versus paired NC OTC with dual 2H7-glucose/13C5,15N2-Gln tracers coupled with Stable Isotope-Resolved Metabolomic analysis. We noted variable activation of glycolysis, cataplerotic/anaplerotic Krebs cycle including reductive carboxylation, the pentose phosphate pathway, riboneogenesis, gluconeogenesis (GNG), de novo and salvage synthesis of purine/pyrimidine nucleotides, and ADP-ribosylation in CA PD-OTC. Altered metabolic activities were in part accountable by expression changes in key enzymes measured by Reverse Phase Protein Array profiling. Notably, Gln-fueled GNG products were preferentially diverted to support purine nucleotide synthesis. When blocking this novel process with an inhibitor of phosphoenolpyruvate carboxykinase (3-mercaptopicolinic acid or 3-MPA), metastatic, ERlow/PR-/HER2- CA OTC displayed compromised cellularity, reduced outgrowth, and disrupted growth/survival-supporting metabolism but the matched NC OTC did not. Thus, our PD-OTC culturing method not only promoted understanding of actual patient's tumor metabolism to uncover viable metabolic targets but also enabled target testing and elucidation of therapeutic efficacy.

Keywords:  Patient-derived organotypic tissue cultures; Reverse Phase Protein Array; Stable Isotope-Resolved Metabolomics; breast cancer; gluconeogenesis; nucleotide synthesis; tumor metabolic reprogramming

DOI:  https://doi.org/10.1016/j.jbc.2025.108495
bioRxiv. 2025 Mar 27. pii: 2025.03.24.644993. [Epub ahead of print]

TP53 Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia.

Jeevitha D'Souza, Camille J Leung, Aishwarya C Ballapuram, Abigail S Lin, Alexa Rane Batingana, Adam J Lamble, Rhonda E Ries, Carolina E Morales, Charisa Cottonham, Pranav Gona, Li Fan, Xiaotu Ma, Kevin Shannon, Soheil Meshinchi, Benjamin S Braun, Benjamin J Huang.

Acute myeloid leukemia (AML) is a heterogeneous cancer that is associated with poor outcomes. Revumenib and other menin inhibitors have shown promising activity against AMLs with KMT2A -rearrangements or NPM1 mutations. However, mechanisms of de novo resistance have not yet been elucidated. We analyzed a panel of cell lines and generated an isogenic model to assess the impact of TP53 mutations on the response of AML cells to revumenib. TP53 mutations are associated with de novo resistance to revumenib, impaired induction of TP53 transcriptional targets, and deregulated expression of the BH3 proteins BCL-2 and MCL-1. The MCL-1 inhibitor MIK665, but not venetoclax, preferentially sensitized TP53 -mutant AML cells to revumenib. These data identify mutant TP53 as a potential biomarker for de novo resistance to revumenib, and provide a rationale to evaluate MCL-1 and menin inhibitor combinations in patients KMT2A -rearranged leukemias with TP53 mutations.

DOI: https://doi.org/10.1101/2025.03.24.644993
Free Radic Biol Med. 2025 Apr 07. pii: S0891-5849(25)00221-7. [Epub ahead of print]

Inactivation of mitochondrial pyruvate dehydrogenase by singlet oxygen involves lipoic acid oxidation, side-chain modification and structural changes.

Qing Gao, Per Hägglund, Luke F Gamon, Michael J Davies.

  The multi-subunit pyruvate dehydrogenase complex (PDC) plays a crucial role in glucose oxidation as it determines whether pyruvate is used for mitochondrial oxidative phosphorylation or is converted to lactate for aerobic glycolysis. PDC contains three lipoic acid groups, covalently attached at lysine residues to give lipoyllysine, which are responsible for acyl group transfer and critical to complex activity. We have recently reported that both free lipoic acid, and lipoyllysine in alpha-keto glutarate dehydrogenase, are highly susceptible to singlet oxygen (1O2)-induced oxidation. We therefore hypothesized that PDC activity and structure would be influenced by 1O2 (generated using Rose Bengal and light) via modification of the lipoyllysines and other residues. PDC activity was decreased by photooxidation, with this being dependent on light exposure, O2, the presence of Rose Bengal, and D2O consistent with 1O2-mediated reactions. These changes were modulated by pre-illumination addition of free lipoic acid and lipoamide. Activity loss occurred concurrently with lipoyllysine and sidechain modification (determined by mass spectrometry) and protein aggregation (detected by SDS-PAGE). Peptide mass mapping provided evidence for modification at 42 residues (Met, Trp, His and Tyr; with modification extents of 20-50%) and each of the lipoyllysine sites (6-20% modification). Structure modelling indicated the modifications occur across all 4 subunit types, and occur in functional domains or at multimer interfaces, consistent with damage at multiple sites contributing to the overall loss of activity. These data indicate that PDC activity and structure are susceptible to 1O2-induced damage with potential effects on cellular pathways of glucose metabolism.

Keywords:  Pyruvate dehydrogenase complex; crosslinking; glucose metabolism; lipoic acid; lipoyllysine; mitochondria; photooxidation; protein oxidation; singlet oxygen; tricarboxylic acid cycle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.011
Bioorg Chem. 2025 Apr 05. pii: S0045-2068(25)00304-9. [Epub ahead of print]160 108424

Inhibition of FLT3-induced signalling in refractory acute myeloid leukaemia.

Jingmei Yang, Ran Friedman.

  Mutations in FLT3 make this receptor tyrosine kinase overactive. Such mutations found in ∼30 % of the patients who suffer from acute myeloid leukaemia (AML). FLT3 mediates signalling networks that lead to cell proliferation and survival. FLT3 inhibitors are used to treat AML but patients who are treated with them typically become resistant. Such resistance often emerges through secondary mutations which either restore the activity of FLT3 in the presence of drugs or activate a key player in a signalling network such as NRAS. We had developed AML-specific cell lines resistant to two advanced FLT3 inhibitors: gilteritinib and FF-10101. Resistance in these cell lines proceeds though different mechanisms. In this study, we followed on the efficacy of five FLT3 inhibitors (gilteritinib, FF-10101 and three promising inhibitors that are being developed), two pan-PI3K inhibitors (one of which also inhibits mTOR) and two c-KIT inhibitors in order to examine the significance of different signalling cascades in FLT3+-AML. In addition, we used molecular modelling and quantum chemistry calculations to explain why specific FLT3 mutations affect some inhibitors more than others. Two novel FLT3 inhibitors were found to be only weakly affected by resistance mutations against gilteritinib and FF-10101. The efficacy of most FLT3 inhibitors was only weakly (or not at all) affected by the NRAS/G12C activating mutation. Finally, no non-FLT3 inhibitor has shown sufficient efficacy in the cells, suggesting the central role of FLT3 in FLT3-mutated AML.

Keywords:  Drug resistance; Energy decomposition analysis; FLT3-ITD; Kinase inhibitors; Resistance mutations

DOI:  https://doi.org/10.1016/j.bioorg.2025.108424
Cell Rep. 2025 Apr 05. pii: S2211-1247(25)00300-6. [Epub ahead of print]44(4): 115529

Amino acids in cancer: Understanding metabolic plasticity and divergence for better therapeutic approaches.

Linda K Do, Hyun Min Lee, Yun-Sok Ha, Chan-Hyeong Lee, Jiyeon Kim.

  Metabolic reprogramming is a hallmark of malignant transformation. While initial studies in the field of cancer metabolism focused on central carbon metabolism, the field has expanded to metabolism beyond glucose and glutamine and uncovered the important role of amino acids in tumorigenesis and tumor immunity as energy sources, signaling molecules, and precursors for (epi)genetic modification. As a result of the development and application of new technologies, a multifaceted picture has emerged, showing that context-dependent heterogeneity in amino acid metabolism exists between tumors and even within distinct regions of solid tumors. Understanding the complexity and flexibility of amino acid metabolism in cancer is critical because it can influence therapeutic responses and predict clinical outcomes. This overview discusses the current findings on the heterogeneity in amino acid metabolism in cancer and how understanding the metabolic diversity of amino acids can be translated into more clinically relevant therapeutic interventions.

Keywords:  CP: Cancer; CP: Metabolism; amino acids; cancer metabolism; metabolic heterogeneity

DOI:  https://doi.org/10.1016/j.celrep.2025.115529
Anal Chim Acta. 2025 May 22. pii: S0003-2670(25)00315-0. [Epub ahead of print]1352 343921

Analytical approach to distinguishing lactate dehydrogenase fractions for oncological diagnostics.

Justyna Głowacka-Gudanek, Kamil Gryckiewicz, Kamil Strzelak.

   BACKGROUND: One of the crucial enzymes for cancer cell growth is lactate dehydrogenase (LDH, E.C. 1.1.1.27), an oxidoreductase that catalyzes the conversion between pyruvate and lactate. It has been found that in cancer cells metabolism, the LDH isoenzyme profile changes, with forms rich in the muscle-type subunit beginning to dominate over those in which the heart-type predominates. This suggests that by examining changes in the enzymatic activity of isoforms with a specific subunit content, it may be possible to quickly distinguish a physiological sample from a pathological one.
RESULTS: This article focuses on the development of an analytical strategy that enables the estimation of the ratio of LDH fraction activities as a basis for a simple and quick screening test. Spectrophotometric detection of LDH activity is based on the ferrozine photometric reaction with ferrous ions generated during the biocatalytic reduction of ferric ions by NADH. The developed Multicommutated Flow Analysis (MCFA) system, coupled with an optoelectronic flow-through detector, enables the use of a kinetic method based on the inhibition of LDH subunits to monitor the enzyme reaction kinetics. The distinctly different responses of the muscle-type and heart-type subunits to the selected inhibitors revealed a linear relationship between the obtained analytical signal and the percentage content of each subunit. The calibration curves for selected inhibitors are linear within the tested range of standards with coefficients of determination equal to 0.99 each.
SIGNIFICANCE: The developed MCFA system was utilized in the analysis of human serum samples obtained from both healthy patients and patients with cancer. The analysis demonstrates that the proposed approach can differentiate oncological serum samples from reference ones based on the LDH fractions activity ratio, even when their total LDH activity level is low.

Keywords:  Flow analysis; Inhibition; Isoenzymes; Lactate dehydrogenase

DOI:  https://doi.org/10.1016/j.aca.2025.343921
Cancer Metab. 2025 Apr 09. 13(1): 18

Ketomimetic nutrients remodel the glycocalyx and trigger a metabolic defense in breast cancer cells.

Mohini Kamra, Yuan-I Chen, Paula C Delgado, Erin H Seeley, Stephanie K Seidlits, Hsin-Chih Yeh, Amy Brock, Sapun H Parekh.

   BACKGROUND: While the triggers for the metastatic transformation of breast cancer (BC) cells remain unknown, recent evidence suggests that intrinsic cellular metabolism could be a crucial driver of migratory disposition and chemoresistance. Aiming to decipher the molecular mechanisms involved in BC cell metabolic maneuvering, we study how a ketomimetic (ketone body-rich, low glucose) nutrient medium can engineer the glycocalyx and metabolic signature of BC cells, to further maneuver their response to therapy.
METHODS: Doxorubicin (DOX) has been used as a model chemotherapeutic in this study. Bioorthogonal imaging was used to assess the degree of sialylation of the glycocalyx along with measurements of drug-induced cytotoxicity and drug internalization. Single cell label-free metabolic imaging has been performed, coupled with measurement of cellular proliferative and migratory abilities, and MS-based metabolomic screens. Transcriptomic analysis of crucial enzymes was performed using total RNA extraction and rt-qPCR.
RESULTS: We found an inverse correlation of glycocalyx sialylation with drug-induced cytotoxicity and drug internalization, where ketomimetic media enhanced sialylation and protected BC cells from DOX. These hypersialylated cells proliferated slower and migrated faster as compared to their counterparts receiving a high glucose media, while exhibiting a preference for glycolysis. These cells also showed pronounced lipid droplet accumulation coupled with an inversion in their metabolomic profile. Enzymatic removal of sialic acid moieties at the glycocalyx revealed for the first time, a direct role of sialic acids as defense guards, blocking DOX entry at the cellular membrane to curtail internalization. Interestingly, the non-cancerous mammary epithelial cells exhibited opposite trends and this differential pattern in cancer vs. normal cells was traced to its biochemical roots, i.e. the expression levels of key enzymes involved in sialylation and fatty acid synthesis.
CONCLUSIONS: Our findings revealed that a ketomimetic medium enhances chemoresistance and invasive disposition of BC cells via two main oncogenic pathways: hypersialylation and lipid synthesis. We propose that the crosstalk between these pathways, juxtaposed at the synthesis of the glycan precursor UDP-GlcNAc, furthers advancement of a metastatic phenotype in BC cells under ketomimetic conditions. Non-cancerous cells lack this dual defense machinery and end up being sensitized to DOX under ketomimetic conditions.

Keywords:  Breast cancer metabolism; Glycocalyx engineering; Hypersialylation; Ketogenic diet; Ketomimetic; Lipid metabolism

DOI:  https://doi.org/10.1186/s40170-025-00385-3
BMC Nutr. 2025 Apr 09. 11(1): 72

Hepatic toll of keto: unveiling the inflammatory and structural consequences of ketogenic diet in rats.

Khatereh Rezazadeh, Mohammad Barzegar, Erfan Nezamdoost, Maryam Shoaran, Mehran Mesgari Abbasi, Babollah Ghasemi, Solmaz Madadi, Sina Raeisi.

   BACKGROUND: The ketogenic diet (KD) has been used as a therapeutic diet for a range of diseases such as epilepsy, obesity, and cancer. However, it may cause some adverse effects that are not well known. This study aimed to assess the possible impact of the KD on liver structure and function, as well as hepatic inflammatory markers.
METHODS: Ninety male rats were randomly divided into two groups: the normal diet group consumed a standard rat chow, and the KD group consumed a diet composed of 90% fat, 8% protein, and 2% carbohydrates for 30 days. The serum levels of lipid profile (cholesterol and triglyceride), liver enzymes, hepatic levels of inflammatory markers, and steatosis grading were evaluated and compared between the two groups.
RESULTS: The serum cholesterol and alanine transaminase (ALT) levels in the KD group were significantly higher than in the normal diet group. However, there were no significant differences between groups in serum triglyceride and aspartate transaminase (AST) levels. Hepatic inflammatory markers, interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), both were higher in the KD group compared to the normal diet group. In the liver biopsy, the degree of steatosis was significantly higher in the KD group compared to the normal diet group.
CONCLUSION: The KD may cause hepatic adverse effects by inducing steatosis and inflammation.

Keywords:  Alanin transaminase (ALT); Hepatic inflammation; Ketogenic diet; Liver function; Steatosis

DOI:  https://doi.org/10.1186/s40795-025-01057-7
J Cell Sci. 2025 Apr 07. pii: jcs.263688. [Epub ahead of print]

Tumor acidosis supports cancer cell lipid uptake via a rapid, transporter-independent mechanism.

Marc Severin, Rikke K Hansen, Michala G Rolver, Tove Hels, Kenji Maeda, Luis A Pardo, Stine F Pedersen.

  Tumor acidosis alters cancer cell metabolism and favors aggressive disease progression. Cancer cells in acidic environments increase lipid droplet (LD) accumulation and oxidative phosphorylation, characteristics of aggressive cancers. Here, we use live imaging, shotgun lipidomics, and immunofluorescence analyses of mammary and pancreatic cancer cells to demonstrate that both acute acidosis and adaptation to acidic growth drive rapid uptake of fatty acids (FA), which are converted to triacylglycerols (TAG) and stored in LDs. Consistent with its independence of de novo synthesis, TAG- and LD accumulation in acid-adapted cells is unaffected by FA-synthetase inhibitors. Macropinocytosis, which is upregulated in acid-adapted cells, partially contributes to FA uptake, which is independent of other protein-facilitated lipid uptake mechanisms, including CD36, FATP2, and caveolin- and clathrin-dependent endocytosis. We propose that a major mechanism by which tumor acidosis drives FA uptake is through neutralizing protonation of negatively charged FAs allowing their diffusive, transporter-independent uptake. We suggest that this could be a major factor triggering acidosis-driven metabolic rewiring.

Keywords:  CD36; FASN; Lipid diffusion; Macropinocytosis; Membrane contact sites; Protonation

DOI:  https://doi.org/10.1242/jcs.263688
Life Sci. 2025 Apr 03. pii: S0024-3205(25)00246-2. [Epub ahead of print]371 123612

Targeting vulnerability in tumor therapy: Dihydroorotate dehydrogenase.

Fu Lin, Jiaxin Li, Lei Zhou, Rigui Yi, Yingge Chen, Shuai He.

  Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo pyrimidine biosynthetic pathway and a recognized therapeutic target in various diseases. In oncology research, DHODH has gained increasing importance and become a hot target for various tumor therapy studies. This review highlights three key points: (1) DHODH enables its diverse biological functions through its unique structural features and dominates the regulation of tumor metabolism and cell fate; (2) DHODH activates oncogenic signals, drives metastatic adaptation, and remodels drug resistance networks in tumors, making it a metabolic-signaling dual hub; and (3) DHODH inhibitors have shown significant efficacy in preclinical models of various tumors but face multiple challenges in clinical trials, including drug-related limitations and external constraints. Given these challenges, future research should explore DHODH inhibitors as a foundation for overcoming technological and translational barriers while establishing a systematic framework for the clinical application of DHODH-targeted tumor therapies.

Keywords:  DHODH; DHODH inhibitor; Ferroptosis; Mitochondria; Pyrimidine; Tumor

DOI:  https://doi.org/10.1016/j.lfs.2025.123612
Biophys J. 2025 Apr 03. pii: S0006-3495(25)00211-5. [Epub ahead of print]

Glycolysis model shows that allostery maintains high ATP and limits accumulation of intermediates.

Mangyu Choe, Tal Einav, Rob Phillips, Denis V Titov.

  Glycolysis is a conserved metabolic pathway that produces ATP and biosynthetic precursors. It is not well understood how the control of mammalian glycolytic enzymes through allosteric feedback and mass action accomplishes various tasks of ATP homeostasis, such as controlling the rate of ATP production, maintaining high and stable ATP levels, ensuring that ATP hydrolysis generates a net excess of energy, and maintaining glycolytic intermediate concentrations within physiological levels. To investigate these questions, we developed a biophysical model of glycolysis based on enzyme rate equations derived from in vitro kinetic data. This is the first biophysical model of human glycolysis that successfully recapitulates the above tasks of ATP homeostasis and predicts absolute concentrations of glycolytic intermediates and isotope tracing kinetics that align with experimental measurements in human cells. We use the model to show that mass action alone is sufficient to control the ATP production rate and maintain the high energy of ATP hydrolysis. Meanwhile, allosteric regulation of hexokinase (HK) and phosphofructokinase (PFK) by ATP, ADP, inorganic phosphate, and glucose-6-phosphate is required to maintain high ATP levels and to prevent uncontrolled accumulation of phosphorylated intermediates of glycolysis. Allosteric feedback achieves the latter by maintaining HK and PFK enzyme activity at one-half of ATP demand and, thus, inhibiting the reaction of Harden and Young, which otherwise converts glucose to supraphysiological levels of phosphorylated glycolytic intermediates at the expense of ATP. Our methodology provides a roadmap for a quantitative understanding of how metabolic homeostasis emerges from the activities of individual enzymes.

Keywords:  allosteric feedback; glycolysis; metabolism; modeling

DOI:  https://doi.org/10.1016/j.bpj.2025.03.037
Obes Res Clin Pract. 2025 Apr 04. pii: S1871-403X(25)00044-4. [Epub ahead of print]

Excessive dietary fat and fructose enhance hepatic lipogenesis and impair mitochondrial dynamics to cause MASLD in C57BL/6 mice.

Flávia Maria Silva-Veiga, Carolline Santos Miranda, Daiana A Santana-Oliveira, Aline Fernandes-da-Silva, Carlos A Mandarim-de-Lacerda, Vanessa Souza-Mello.

   OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects around 1/3 of the worldwide population, with rising prevalence. Surplus fat and carbohydrate intake are crucial for MASLD onset. This study aimed to elucidate the interference of excess lipids and fructose (32 % as energy each), alone or in combination, on the hepatic energy metabolism of male mice.
METHODS: Forty male C57BL/6 mice (3 months old) were randomly assigned to receive a control diet (C, 10 % of energy as soybean oil, n = 10), high-fat diet (HF, 32 % of energy as lard and 10 % as soybean oil, n = 10), high-fructose diet (HFRU, 32 % of energy as fructose, and 10 % as soybean oil, n = 10) or a diet rich in lipids and associated fructose (HF-HFRU, 32 % of energy as lard, 10 % as soybean oil, and 32 % of energy as fructose, n = 10) for 12 weeks.
RESULTS: The increased consumption of saturated fat or fructose, isolated or in association, caused oral glucose intolerance, increased hepatic triacylglycerol and cholesterol, and enhanced the expression of proteins related to hepatic inflammation, lipogenesis, mitochondrial dysfunction, and ER stress, resulting in a marked increase in hepatic steatosis.
CONCLUSION: Our results showed that high consumption of diets rich in lipids and fructose contributed to the development of MASLD and revealed an intimate relationship between altered mitochondrial dynamics and ER stress. Understanding the molecular pathways that regulate the accumulation of hepatic lipids can lead to promising therapies for MASLD.

Keywords:  Fructose; Hepatic steatosis; Lipogenesis; MASLD; Mitochondria; Saturated fat

DOI:  https://doi.org/10.1016/j.orcp.2025.03.007
Gynecol Oncol Rep. 2025 Apr;58 101718

The role of diet, obesity and body composition in epithelial ovarian cancer development and progression: Mechanisms and therapeutic implications.

Jessica Suratkal, Theresa D'Silva, Mariam AlHilli.

  Epithelial ovarian cancer (EOC) ranks among the deadliest cancers, with over half of newly diagnosed patients presenting with metastatic disease, highlighting the need for early detection strategies and a deeper understanding of biologic factors that impact EOC progression and treatment response. This paper aims to synthesize the current literature on the association between diet, obesity, and body composition and EOC prognosis, drawing on translational, molecular, and clinical studies to identify gaps in research and inform preventative strategies to improve outcomes in EOC patients. The current literature on the association between diet and EOC prognosis suggests a role for several dietary interventions in the prevention of EOC development and progression, including increased intake of animal-based proteins (specifically dairy products), fiber-rich foods, cruciferous vegetables, and polyunsaturated fats, and ongoing clinical trials examine variations of intermittent fasting and fasting-mimicking diets in EOC patients. However, the impact of diet and nutritional interventions on survival and therapeutic response in EOC remains largely understudied, and low quality of evidence in this area limits the ability to form comprehensive dietary recommendations. Therefore, this study calls for future research in this area to inform dietary recommendations with the ultimate goals of improving patient outcomes and quality of life. Additionally, obesity and high-fat diets may contribute to EOC progression through chronic low-grade inflammation, and consideration of body composition and adiposity may impact intervention parameters and should be investigated in future research.

Keywords:  Body composition; Diet; Nutrition; Ovarian cancer

DOI:  https://doi.org/10.1016/j.gore.2025.101718
Acta Epileptol. 2025 Feb 07. 7(1): 10

Exploring physiological beta-hydroxybutyrate level in children treated with the classical ketogenic diet for drug-resistant epilepsy.

Xiaoying Qiao, Zimeng Ye, Jialun Wen, Sufang Lin, Dezhi Cao, Li Chen, Dongfang Zou, Huafang Zou, Man Zhang, Zhibin Chen, Patrick Kwan, Ingrid E Scheffer, Jiong Qin, Jianxiang Liao.

   BACKGROUND: The ketogenic diet (KD) therapy is a primary treatment for drug-resistant epilepsy, and beta-hydroxybutyrate (BHB) is the main ketone produced during KD. However, the pattern of increase in BHB levels is not well understood, and the reference range for BHB need to be defined. The aim of this study was to evaluate the BHB levels in the first three months, especially one week, after KD initiation, and to explore the physiological reference range for BHB.
METHODS: In our study, a fasting initiation strategy was used for the majority of patients (252/300, 84%) who underwent fasting for 24-48 h, the rest fasted for at least 12 h. The concentration of blood BHB was measured four times a day during the first week, at one month and three months. Seizure frequency was recorded at one week, one month and three months. Responders were defined as those with a seizure reduction 50% or more compared to baseline. BHB levels were compared between responders and non-responders. The BHB levels of responders were used to calculate the reference range.
RESULTS: A total of 300 patients were recruited, of whom 172 (57%) had accessible BHB data. BHB levels rapidly rose to 2.0 mmol/L at 19 h, peaked at 4.2 mmol/L at 43 h of therapy, and stabilized by three months. The reference range for BHB was 1.1 to 4.9 mmol/L.
CONCLUSIONS: BHB levels increased rapidly following fasting, reaching the peak at day 2, stabilizing from the end of the first week through three months. The lower reference limit for BHB to ensure KD efficacy should be set at 1.1 mmol/L.

Keywords:  Beta-hydroxybutyrate; Children; Epilepsy; Ketogenic diet; Reference range

DOI:  https://doi.org/10.1186/s42494-024-00199-8
Arch Med Sci. 2025 ;21(1): 206-214

Causal associations between blood metabolites and breast cancer.

Guanying Liang, Dazhuang Miao, Chun Du.

   Introduction: The associations between blood metabolites and breast cancer remain unclear. We conducted a systematic two-sample Mendelian randomization (MR) analysis to identify key human blood metabolites and potential biomarkers for breast cancer development.
Material and methods: The data were extracted from large-scale genome-wide association study (GWAS) public databases. Instrumental variables were selected from a cohort study of 453 metabolic profiles from 7,824 participants. Breast cancer incidence data were obtained from a large cohort study involving 138,389 cases and 240,341 controls. Causal associations between human blood metabolites and breast cancer incidence were assessed using inverse-variance weighting, and MR-Egger regression.
Results: Five human blood metabolites were identified as biomarkers for breast cancer: serine (OR = 2.25; 95% CI: 1.18-4.27), 10-undecenoate (11:1n1) (OR = 1.38; 95% CI: 1.00-1.90), X-12696 (OR = 2.15; 95% CI: 1.14-4.08), X-14626 (OR = 1.68; 95% CI: 1.15-2.46), and succinyl carnitine (OR = 1.58; 95% CI: 1.06-2.34). The sensitivity analysis results indicate no pleiotropy between the metabolites and breast cancer risk, confirming the robustness of the findings.
Conclusions: This study in metabolomics research identified five human blood metabolites - serine, 10-undecenoate (11:1n1), X-12696, X-14626, and succinylcarnitine - as potential biomarkers for assessing breast cancer risk. Among these metabolites, serine and X-12696 showed the strongest associations with the likelihood of developing breast cancer.

Keywords:  Mendelian randomization; breast cancer; metabolites

DOI:  https://doi.org/10.5114/aoms/188275
Clin Exp Med. 2025 Apr 10. 25(1): 111

Identification of glucuronic acid as a biomarker of poor prognosis in acute myeloid leukemia based on plasma metabolomics.

Jinrong Yang, Zixu Wang, Kun Wu, Jingyan Ruan, Bo Nie, Qiang Zhou, Liyin Li, Li Luo, Fujia Zhang, Mingxia Shi, Yun Zeng.

  Metabolic abnormalities have been identified in various solid tumors and hematologic diseases, with reprogramming of central carbon metabolism occurring to promote disease progression. However, the metabolic profile of central carbon in acute myeloid leukemia (AML) remains unknown. We employed targeted metabolomics to analyze the alterations in central carbon metabolites present in the blood of acute myeloid leukemia (AML) patients. Models constructed using orthogonal partial least squares discriminant analysis (OPLS-DA) were utilized to evaluate intergroup differences in metabolite levels. Furthermore, a public database facilitated the kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. Additionally, metabolites exhibiting significant differences were selected, and their effects on the proliferation and drug resistance of human myeloid leukemia cell lines were validated in vitro using CCK-8 analysis, MTT assays, and flow cytometry. Our results indicated that 27 targeted metabolites were up-regulated and eight targeted metabolites were down-regulated in the AML group. These metabolites were primarily enriched in pathways related to the biosynthesis of cofactors, glyoxylate and dicarboxylate metabolism, glucagon signaling, 2-oxocarboxylic acid metabolism, biosynthesis of amino acids, the citrate cycle (TCA cycle), and central carbon metabolism in cancer. Notably, significant changes were observed in malic acid, alpha-ketoisovaleric acid, and glucuronic acid. In vitro experiments demonstrated that exogenous glucuronic acid can promote the growth and drug resistance of human AML cells. In conclusion, this study reveals alterations in central carbon metabolites in the blood of AML patients and identifies metabolites that may play a role in AML development and drug resistance.

Keywords:  Acute myeloid leukemia; Biomarker; Central carbon metabolism; Glucuronic acid; Metabolomics

DOI:  https://doi.org/10.1007/s10238-025-01605-2
Cell Death Discov. 2025 Apr 06. 11(1): 147

Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors.

Jorge Antonio Elias Godoy Carlos, Mauricio Temotheo Tavares, Keli Lima, Larissa Costa de Almeida, Karoline de Barros Waitman, Leticia Veras Costa-Lotufo, Roberto Parise-Filho, João Agostinho Machado-Neto.

Epigenetic modifications significantly influence gene expression and play crucial roles in various biological processes, including carcinogenesis. This study investigates the effects of novel purine-benzohydroxamate compounds, particularly 4 f, as hybrid kinase/histone deacetylase (HDAC) inhibitors in hematological malignancies, focusing on acute myeloid leukemia (AML). Our results demonstrate that these compounds selectively reduce cell viability in blood cancer cells, with inhibitory concentration values indicating higher potency against neoplastic cells compared to normal leukocytes. Mechanistically, 4 f induces apoptosis and cell cycle arrest, promoting differentiation in leukemia cells, while effectively inhibiting HDAC activity. Furthermore, 4 f enhances the therapeutic efficacy of venetoclax, a BCL2 inhibitor, in AML models sensitive and resistant to this drug. The combination treatment significantly increases apoptosis and reduces cell viability, suggesting a synergistic effect that may overcome drug resistance. This study provides valuable insights into the potential of HDAC inhibitors, particularly 4 f, as a promising therapeutic strategy for treating resistant hematological malignancies. Our findings underscore the importance of further exploring hybrid kinase/HDAC inhibitors in combination therapies to improve outcomes in patients with acute leukemias and other hematological malignancies.

DOI: https://doi.org/10.1038/s41420-025-02446-4
Geroscience. 2025 Apr 08.

Treatment delay significantly increases mortality in colorectal cancer: a meta-analysis.

Zoltan Ungvari, Mónika Fekete, János Tibor Fekete, Andrea Lehoczki, Annamaria Buda, Gyöngyi Munkácsy, Péter Varga, Anna Ungvari, Balázs Győrffy.

  Delaying the initiation of cancer treatment increases the risk of mortality, particularly in colorectal cancer (CRC), which is among the most common and deadliest malignancies. This study aims to explore the impact of treatment delays on mortality in CRC. A systematic literature search was conducted in PubMed, Web of Science, and Scopus for studies published between 2000 and 2025. Meta-analyses were performed using random-effects models with inverse variance method to calculate hazard ratios (HRs) for both overall and cancer-specific survival at 4-, 8-, and 12-week treatment delay intervals, with heterogeneity assessed through I2-statistics and publication bias evaluated using funnel plots and Egger's test. A total of 20 relevant studies were included in the meta-analysis. The analyses of all patients demonstrated a progressively increasing risk of 12-39% with longer treatment delays (4 weeks, HR = 1.12; 95% CI, 1.08-1.16; 8 weeks, HR = 1.24; 95% CI, 1.16-1.34; 12 weeks, HR = 1.39; 95% CI, 1.25-1.55). In particular, incrementally higher hazard ratios were observed for all-cause mortality at 4 weeks (HR = 1.14; 95% CI, 1.09-1.18), 8 weeks (HR = 1.29; 95% CI, 1.20-1.39), and 12 weeks (HR = 1.47; 95% CI, 1.31-1.64). In contrast, cancer-specific survival analysis showed a similar trend but did not reach statistical significance (4 weeks, HR = 1.07; 95% CI, 0.98-1.18; 8 weeks, HR = 1.15; 95% CI, 0.95-1.39; 12 weeks, HR = 1.23; 95% CI, 0.93-1.63). Treatment delays in colorectal cancer patients were associated with progressively worsening overall survival, with each 4-week delay increment leading to a substantially higher mortality risk. This study suggests that timely treatment initiation should be prioritized in clinical practice, as these efforts can lead to substantial improvements in survival rates.

Keywords:  Cancer survival; Cancer treatment access; Colorectal cancer; Diagnostic delays; Frailty; Geriatric oncology; Healthcare disparities; Healthcare inefficiencies; Multimorbidity; Oncology care pathways; Patient navigation; Referral pathways; Telemedicine; Time-to-treatment benchmarks; Treatment delay

DOI:  https://doi.org/10.1007/s11357-025-01648-z
Circ Res. 2025 Apr 11.

Heart Has Intrinsic Ketogenic Capacity that Mediates NAD+ Therapy in HFpEF.

Yen Chin Koay, Bailey McIntosh, Yann Huey Ng, Yang Cao, XiaoSuo Wang, Yanchuang Han, Saki Tomita, Angela Yu Bai, Benjamin Hunter, Ashish Misra, Christopher M Loughrey, Paul G Bannon, Sean Lal, Aldons J Lusis, David M Kaye, Mark Larance, John F O'Sullivan.

   BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) has overtaken heart failure with reduced ejection fraction as the leading type of heart failure globally and is marked by high morbidity and mortality rates, yet with only a single approved pharmacotherapy: SGLT2i (sodium-glucose co-transporter 2 inhibitor). A prevailing theory for the mechanism underlying SGLT2i is nutrient deprivation signaling, of which ketogenesis is a hallmark. However, it is unclear whether the canonical ketogenic enzyme, HMGCS2 (3-hydroxy-3-methylglutaryl-coenzyme A synthase 2), plays any cardiac role in HFpEF pathogenesis or therapeutic response.
METHODS: We used human myocardium, human HFpEF and heart failure with reduced ejection fraction transcardiac blood sampling, an established murine model of HFpEF, ex vivo Langendorff perfusion, stable isotope tracing in isolated cardiomyocytes, targeted metabolomics, proteomics, lipidomics, and a novel cardiomyocyte-specific conditional HMGCS2-deficient model that we generated.
RESULTS: We demonstrate, for the first time, the intrinsic capacity of the human heart to produce ketones via HMGCS2. We found that increased acetylation of HMGCS2 led to a decrease in the enzyme's specific activity. However, this was overcome by an increase in the steady-state levels of protein. Oxidized form of nicotinamide adenine dinucleotide repletion restored HMGCS2 function via deacetylation, increased fatty acid oxidation, and rescued cardiac function in HFpEF. Critically, using a conditional, cardiomyocyte-specific HMGCS2 knockdown murine model, we revealed that the oxidized form of nicotinamide adenine dinucleotide is unable to rescue HFpEF in the absence of cardiomyocyte HMGCS2.
CONCLUSIONS: The canonical ketogenic enzyme, HMGCS2, mediates the therapeutic effects of the oxidized form of nicotinamide adenine dinucleotide repletion in HFpEF by restoring normal lipid metabolism and mitochondrial function.

Keywords:  heart failure; ketone bodies; myocardium; oxygen consumption; stroke volume

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325550
Front Oncol. 2025 ;15 1549891

The potential role of BCL-2 inhibition in amyloidosis and plasma cell leukemia.

Grigorios Alvanidis, Dimitrios Kotsos, Christina Frouzaki, Amalia Fola, Evdoxia Hatjiharissi.

  Plasma cell neoplasms include a spectrum of disorders, such as plasma cell leukemia (PCL) and light chain (AL) amyloidosis, all associated with poor prognosis and limited therapeutic options. Venetoclax is the first-in-class B-cell lymphoma 2 (BCL-2) inhibitor and triggers apoptosis selectively in cells reliant on the BCL-2 pathway for survival. Randomized clinical trials have established the anti-tumor activity and efficacy of venetoclax in selected patients with hematologic malignancies such as acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM). At the same time, recent studies suggest its potential application in rare plasma cell dyscrasias. Preliminary results from case reports and a small cohort of patients indicate that venetoclax may benefit patients with PCL. Regimens incorporating venetoclax have also demonstrated promising outcomes in patients with AL amyloidosis, particularly those with translocation (11;14). This review analyzes new data on venetoclax in AL amyloidosis and PCL and highlights the increasing significance of BCL-2 inhibition in plasma cell neoplasms beyond MM.

Keywords:  AL amyloidosis; BCL-2 inhibition; hematologic malignancies; plasma cell leukemia; plasma cell neoplasms; venetoclax

DOI:  https://doi.org/10.3389/fonc.2025.1549891
J Med Chem. 2025 Apr 11.

Discovery of FLT3-ITD Inhibitor Clifutinib: A Novel Biphenylacetylene Urea Derivative in Clinical Trials for the Treatment of Relapsed/Refractory FLT3-ITD+ Acute Myeloid Leukemia.

Bing Liu, Ning Kang, Fang Yang, WeiHong Zhang, XingGuo Yan, Heng Wang, Shun Bai, Cliff C Cheng, Juan Xu, WenHao Hu, YingJun Zhang.

Internal tandem duplication (ITD) mutations of FLT3 (FLT3-ITD) are a promising target for patients with acute myeloid leukemia (AML), given that they have been identified in the majority of AML patients and are associated with poor prognosis. Here, a series of biphenylacetylene derivatives was developed as selective FLT3-ITD inhibitors. Representative compound 9e exhibited excellent potency against FLT3-ITD kinase, with an IC50 value of 15.1 nM, and potently suppressed the proliferation of MV-4-11 and MOLM-13 AML cells harboring FLT3-ITD, with IC50 values of 1.5 and 1.4 nM, respectively. Moreover, compound 9e displayed favorable drug-like properties and significantly suppressed tumor growth in MV-4-11 (1.5 mg/kg, qd, tumor growth inhibition (TGI) = 193.5%) and MOLM-13 (4.5 mg/kg, qd, TGI = 94%) xenograft tumor models in mice without significant weight loss. Compound 9e (named Clifutinib) is currently being evaluated in a phase III clinical trial (NCT05586074) for the treatment of relapsed/refractory FLT3-ITD-positive AML.

DOI: https://doi.org/10.1021/acs.jmedchem.4c03023
NPJ Metab Health Dis. 2025 ;3(1): 13

Ultra-processed food consumption affects structural integrity of feeding-related brain regions independent of and via adiposity.

Filip Morys, Arsene Kanyamibwa, Daniel Fängström, Max Tweedale, Alexandre Pastor-Bernier, Houman Azizi, Lang Liu, Annette Horstmann, Alain Dagher.

  Consumption of ultra-processed foods (UPFs) increases overall caloric intake and is associated with obesity, cardiovascular disease, and brain pathology. There is scant evidence as to why UPF consumption leads to increased caloric intake and whether the negative health consequences are due to adiposity or characteristics of UPFs. Using the UK Biobank sample, we probed the associations between UPF consumption, adiposity, metabolism, and brain structure. Our analysis reveals that high UPF intake is linked to adverse adiposity and metabolic profiles, alongside cellularity changes in feeding-related subcortical brain areas. These are partially mediated by dyslipidemia, systemic inflammation and body mass index, suggesting that UPFs exert effects on the brain beyond just contributing to obesity. This dysregulation of the network of subcortical feeding-related brain structures may create a self-reinforcing cycle of increased UPF consumption.

Keywords:  Diseases; Systems biology

DOI:  https://doi.org/10.1038/s44324-025-00056-3
Cell Death Dis. 2025 Apr 05. 16(1): 254

Inhibition of mitochondrial complex I induces mitochondrial ferroptosis by regulating CoQH2 levels in cancer.

Ru Deng, Lingyi Fu, Haoyu Liang, Xixiong Ai, Fangyi Liu, Nai Li, Liyan Wu, Shuo Li, Xia Yang, Yansong Lin, Yuhua Huang, Jingping Yun.

Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment.

DOI: https://doi.org/10.1038/s41419-025-07510-6
JMIR Diabetes. 2025 Apr 10. 10 e67867

Early Detection of Elevated Ketone Bodies in Type 1 Diabetes Using Insulin and Glucose Dynamics Across Age Groups: Model Development Study.

Simon Cichosz, Clara Bender.

   Background: Diabetic ketoacidosis represents a significant and potentially life-threatening complication of diabetes, predominantly observed in individuals with type 1 diabetes (T1D). Studies have documented suboptimal adherence to diabetes management among children and adolescents, as evidenced by deficient ketone monitoring practices.
Objective: The aim of the study was to explore the potential for prediction of elevated ketone bodies from continuous glucose monitoring (CGM) and insulin data in pediatric and adult patients with T1D using a closed-loop system.
Methods: Participants used the Dexcom G6 CGM system and the iLet Bionic Pancreas system for insulin administration for up to 13 weeks. We used supervised binary classification machine learning, incorporating feature engineering to identify elevated ketone bodies (>0.6 mmol/L). Features were derived from CGM, insulin delivery data, and self-monitoring of blood glucose to develop an extreme gradient boosting-based prediction model. A total of 259 participants aged 6-79 years with over 49,000 days of full-time monitoring were included in the study.
Results: Among the participants, 1768 ketone samples were eligible for modeling, including 383 event samples with elevated ketone bodies (≥0.6 mmol/L). Insulin, self-monitoring of blood glucose, and current glucose measurements provided discriminative information on elevated ketone bodies (receiver operating characteristic area under the curve [ROC-AUC] 0.64-0.69). The CGM-derived features exhibited stronger discrimination (ROC-AUC 0.75-0.76). Integration of all feature types resulted in an ROC-AUC estimate of 0.82 (SD 0.01) and a precision recall-AUC of 0.53 (SD 0.03).
Conclusions: CGM and insulin data present a valuable avenue for early prediction of patients at risk of elevated ketone bodies. Furthermore, our findings indicate the potential application of such predictive models in both pediatric and adult populations with T1D.

Keywords:  diabetic complication; diabetic ketoacidosis; ketone level; machine learning; prediction model; type 1 diabetes

DOI:  https://doi.org/10.2196/67867