bims-medica 2025-03-23 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–03–23
twelve papers selected by
Brett Chrest, Wake Forest University

Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.
Metabolic profiling of adult and pediatric gliomas reveals enriched glucose availability in pediatric gliomas and increased fatty acid oxidation in adult gliomas.
Acetoacetate, a ketone body, attenuates neuronal bursts in acutely-induced epileptiform slices of the mouse hippocampus.
Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer.
A genetically encoded fluorescent sensor enables sensitive and specific detection of IDH mutant associated oncometabolite D-2-hydroxyglutarate.
Lipid metabolism: the potential therapeutic targets in glioblastoma.
Quantitative mapping of key glucose metabolic rates in the human brain using dynamic deuterium magnetic resonance spectroscopic imaging.
Glut-1 inhibition in breast cancer cells.
Chemotherapy Trends in Acute Myeloid Leukemia: 2004 to 2020.
Increase in plasma succinate is associated with aerobic lactate production in a model of endotoxic shock.
Plasma extracellular vesicles from recurrent GBMs carrying LDHA to activate glioblastoma stemness by enhancing glycolysis.
Pyruvate metabolism enzyme DLAT promotes tumorigenesis by suppressing leucine catabolism.

bioRxiv. 2025 Mar 07. pii: 2025.03.03.641255. [Epub ahead of print]

Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival.

Ayşegül Erdem, Séléna Kaye, Francesco Caligiore, Manuel Johanns, Fleur Leguay, Jan Jacob Schuringa, Keisuke Ito, Guido Bommer, Nick van Gastel.

Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD+. We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry. Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD+ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD+/NADH ratio in AML cells. Continuous intracellular NAD+ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition. Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD+/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD+ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells.

DOI: https://doi.org/10.1101/2025.03.03.641255
Acta Neuropathol Commun. 2025 Mar 15. 13(1): 61

Metabolic profiling of adult and pediatric gliomas reveals enriched glucose availability in pediatric gliomas and increased fatty acid oxidation in adult gliomas.

Vladislav O Sviderskiy, Varshini Vasudevaraja, Luiz Gustavo Dubois, James Stafford, Elisa K Liu, Jonathan Serrano, Richard Possemato, Matija Snuderl.

  Gliomas are the most common primary brain tumors and a major source of mortality and morbidity in adults and children. Recent genomic studies have identified multiple molecular subtypes; however metabolic characterization of these tumors has thus far been limited. We performed metabolic profiling of 114 adult and pediatric primary gliomas and integrated metabolomic data with transcriptomics and DNA methylation classes. We identified that pediatric tumors have higher levels of glucose and reduced lactate compared to adult tumors regardless of underlying genetics or grade, suggesting differences in availability of glucose and/or utilization of glucose for downstream pathways. Differences in glucose utilization in pediatric gliomas may be facilitated through overexpression of SLC2A4, which encodes the insulin-stimulated glucose transporter GLUT4. Transcriptomic comparison of adult and pediatric tumors suggests that adult tumors may have limited access to glucose and experience more hypoxia, which is supported by enrichment of lactate, 2-hydroxyglutarate (2-HG), even in isocitrate dehydrogenase (IDH) wild-type tumors, and 3-hydroxybutyrate, a ketone body that is produced by oxidation of fatty acids and ketogenic amino acids during periods of glucose scarcity. Our data support adult tumors relying more on fatty acid oxidation, as they have an abundance of acyl carnitines compared to pediatric tumors and have significant enrichment of transcripts needed for oxidative phosphorylation. Our findings suggest striking differences exist in the metabolism of pediatric and adult gliomas, which can provide new insight into metabolic vulnerabilities for therapy.

Keywords:  Adult glioma; Fatty acid oxidation; Glucose; H3 mutant; Metabolic profiling; Pediatric glioma

DOI:  https://doi.org/10.1186/s40478-025-01961-w
Front Cell Neurosci. 2025 ;19 1551700

Acetoacetate, a ketone body, attenuates neuronal bursts in acutely-induced epileptiform slices of the mouse hippocampus.

Hao Wen, Nagisa Sada, Tsuyoshi Inoue.

  The ketogenic diet increases ketone bodies (β-hydroxybutyrate and acetoacetate) in the brain, and ameliorates epileptic seizures in vivo. However, ketone bodies exert weak or no effects on electrical activity in rodent hippocampal slices. Especially, it remains unclear what kinds of conditions are required to strengthen the actions of ketone bodies in hippocampal slices. In the present study, we examined the effects of acetoacetate on hippocampal pyramidal cells in normal slices and epileptiform slices of mice. By using patch-clamp recordings from CA1 pyramidal cells, we first confirmed that acetoacetate did not change the membrane potentials and intrinsic properties of pyramidal cells in normal slices. However, we found that acetoacetate weakened spontaneous epileptiform bursts in pyramidal cells of epileptiform slices, which were acutely induced by applying convulsants to normal slices. Interestingly, acetoacetate did not change the frequency of the epileptiform bursts, but attenuated individual epileptiform bursts. We finally examined the effects of acetoacetate on excitatory synaptic barrages during epileptiform activity, and found that acetoacetate weakened epileptiform bursts by reducing synchronous synaptic inputs. These results show that acetoacetate attenuated neuronal bursts in epileptiform slices, but did not affect neuronal activity in normal slices, which leads to seizure-selective actions of ketone bodies.

Keywords:  epilepsy; hippocampus; ketogenic diet; ketone body; patch-clamp recording; slice physiology

DOI:  https://doi.org/10.3389/fncel.2025.1551700
Nat Commun. 2025 Mar 16. 16(1): 2597

Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer.

Haibin Deng, Liang Zhao, Huixiang Ge, Yanyun Gao, Yan Fu, Yantang Lin, Mojgan Masoodi, Tereza Losmanova, Michaela Medová, Julien Ott, Min Su, Wenxiang Wang, Ren-Wang Peng, Patrick Dorn, Thomas Michael Marti.

Lactate dehydrogenase B (LDHB) fuels oxidative cancer cell metabolism by converting lactate to pyruvate. This study uncovers LDHB's role in countering mitochondria-associated ferroptosis independently of lactate's function as a carbon source. LDHB silencing alters mitochondrial morphology, causes lipid peroxidation, and reduces cancer cell viability, which is potentiated by the ferroptosis inducer RSL3. Unlike LDHA, LDHB acts in parallel with glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH) to suppress mitochondria-associated ferroptosis by decreasing the ubiquinone (coenzyme Q, CoQ) to ubiquinol (CoQH2) ratio. Indeed, supplementation with mitoCoQH2 (mitochondria-targeted analogue of CoQH2) suppresses mitochondrial lipid peroxidation and cell death after combined LDHB silencing and RSL3 treatment, consistent with the presence of LDHB in the cell fraction containing the mitochondrial inner membrane. Addressing the underlying molecular mechanism, an in vitro NADH consumption assay with purified human LDHB reveals that LDHB catalyzes the transfer of reducing equivalents from NADH to CoQ and that the efficiency of this reaction increases by the addition of lactate. Finally, radiation therapy induces mitochondrial lipid peroxidation and reduces tumor growth, which is further enhanced when combined with LDHB silencing. Thus, LDHB-mediated lactate oxidation drives the CoQ-dependent suppression of mitochondria-associated ferroptosis, a promising target for combination therapies.

DOI: https://doi.org/10.1038/s41467-025-57906-3
BMC Cancer. 2025 Mar 14. 25(1): 473

A genetically encoded fluorescent sensor enables sensitive and specific detection of IDH mutant associated oncometabolite D-2-hydroxyglutarate.

Kristian A Choate, Wren W L Konickson, Zoe L Moreno, Olivia S Brill, Brett C Cromell, Bella M Detienne, Matthew J Jennings, Paul B Mann, Robert J Winn, David O Kamson, Evan P S Pratt.

  D-2-hydroxyglutarate (D-2-HG) is an oncometabolite that accumulates due to mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2). D-2-HG may be used as a surrogate marker for IDH1/2 mutant cancers, yet simple and specific methods for D-2-HG detection are limited. Here, we present the development and characterization of a genetically encoded fluorescent sensor of D-2-HG (D2HGlo). D2HGlo responds to clinically relevant concentrations of D-2-HG, demonstrates exceptional selectivity and can quantify D-2-HG in various body fluids and glioma tumor supernatants. Additionally, analysis of tumor lysates using D2HGlo accurately predicted the IDH mutational status of gliomas. The successful quantification of D-2-HG within contrived samples suggests that D2HGlo may facilitate the detection and monitoring of IDH mutant cancers through liquid biopsies following further validation. In addition to D2HGlo's potential clinical utility, we also present findings for its adaptation to the cellular environment. To assess D-2-HG production in living immortalized glioma cells, we engineered D2HGlo sensors that localize to subcellular compartments, which yielded findings of elevated D-2-HG in the cytosol, mitochondria, and nucleus of IDH1 mutant cells. D2HGlo was used to perform a side-by-side comparison of cytosolic and secreted D-2-HG to reveal that glycolysis, but not glutamine catabolism, drives D-2-HG production in IDH1 mutant cells.

Keywords:  D-2-hydroxyglutarate; Diagnostic; Fluorescent biosensor; Glioma; Isocitrate dehydrogenase

DOI:  https://doi.org/10.1186/s12885-025-13877-8
Cell Death Discov. 2025 Mar 17. 11(1): 107

Lipid metabolism: the potential therapeutic targets in glioblastoma.

Lu Lu, Yan Zhang, Yuzhong Yang, Meihua Jin, Aiyu Ma, Xu Wang, Qiuyu Zhao, Xuemei Zhang, Jinhua Zheng, Xiang Zheng.

Glioblastoma is a highly malignant tumor of the central nervous system with a high mortality rate. The mechanisms driving glioblastoma onset and progression are complex, posing substantial challenges for developing precise therapeutic interventions to improve patient survival. Over a century ago, the discovery of the Warburg effect underscored the importance of abnormal glycolysis in tumors, marking a pivotal moment in cancer research. Subsequent studies have identified mitochondrial energy conversion as a fundamental driver of tumor growth. Recently, lipid metabolism has emerged as a critical factor in cancer cell survival, providing an alternative energy source. Research has shown that lipid metabolism is reprogrammed in glioblastoma, playing a vital role in shaping the biological behavior of tumor cells. In this review, we aim to elucidate the impact of lipid metabolism on glioblastoma tumorigenesis and explore potential therapeutic targets. Additionally, we provide insights into the regulatory mechanisms that govern lipid metabolism, emphasizing the critical roles of key genes and regulators involved in this essential metabolic process.

DOI: https://doi.org/10.1038/s41420-025-02390-3
PNAS Nexus. 2025 Mar;4(3): pgaf072

Quantitative mapping of key glucose metabolic rates in the human brain using dynamic deuterium magnetic resonance spectroscopic imaging.

Xin Li, Xiao-Hong Zhu, Yudu Li, Tao Wang, Guangle Zhang, Hannes M Wiesner, Zhi-Pei Liang, Wei Chen.

  Deuterium (2H) magnetic resonance spectroscopic imaging (DMRSI) is a newly developed technology for assessing glucose metabolism by simultaneously measuring deuterium-labeled glucose and its downstream metabolites (1) and has a potential to provide a powerful neurometabolic imaging tool for quantitative studies of cerebral glucose metabolism involving multiple metabolic pathways in the human brain. In this work, we developed a dynamic DMRSI method that combines advanced radiofrequency coil and postprocessing techniques to substantially improve the imaging signal-to-noise ratio for detecting deuterated metabolites and enable robust dynamic DMRSI of the human brain at 7 T with very high resolution (HR; 0.7 cc nominal voxel and 2.5 min/image) and whole-brain coverage. Utilizing this capability, we were able to map and differentiate metabolite contents and dynamics throughout the human brain following oral administration of deuterated glucose. Furthermore, by introducing a sophisticated kinetic model, we demonstrated that three key cerebral metabolic rates of glucose consumption (CMRGlc), lactate production (CMRLac), and tricarboxylic acid (TCA) cycle (V TCA), as well as the maximum apparent rate of forward glucose transport (T max) can be simultaneously imaged in the human brain through a single dynamic DMRSI measurement. The results clearly show that the glucose transport, neurotransmitter turnover, CMRGlc, and V TCA are significantly higher in gray matter than in white matter in the human brain; and the mean metabolic rates and their ratios measured in this study are consistent with the values reported in the literature. The HR dynamic DMRSI methodology presented herein is of great significance and value for the quantitative assessment of human brain glucose metabolism, aerobic glycolysis, and metabolic reprogramming under physiopathological conditions.

Keywords:  Biological; Health; aerobic glycolysis; and Medical Sciences/neuroscience; cerebral glucose metabolism; dynamic DMRSI; imaging human brain glucose metabolic rates

DOI:  https://doi.org/10.1093/pnasnexus/pgaf072
Vitam Horm. 2025 ;pii: S0083-6729(25)00015-9. [Epub ahead of print]128 181-211

Glut-1 inhibition in breast cancer cells.

Ajeesh Babu Littleflower, Sulfath Thottungal Parambil, Gisha Rose Antony, Anju M S, Lakshmi Subhadradevi.

  Breast cancer is a widely prevalent and devastating morbidity that affects millions of women around the world. Conventional treatment options for breast cancer include surgery, chemotherapy, and radiotherapy. However, these therapies can frequently have adverse side effects and may not be effective for all patients. In recent years, there has been an increasing interest in the development of targeted therapies for breast cancer. Glut-1, a key glucose transporter that is often overexpressed in breast cancer cells, is a potential candidate for targeted therapies. Glut-1 is crucial for basal glucose transport into cancer cells and is necessary for their rapid growth and survival. Several Glut-1 inhibitors - both natural and synthetic small molecules - have been identified and used as anticancer agents. In this chapter, we summarize the different approaches of Glut-1 inhibition in breast cancer and the mode of inhibition used by various Glut-1 inhibitors. Further understanding of the mechanisms underlying the efficacy of Glut-1 inhibitors in breast cancer treatment may provide crucial insights that can lead to the advancement of current treatment strategies. The functional inhibition of Glut-1 by specific Glut-1 inhibitors is being explored as a potential treatment modality for breast cancer. This approach holds great promise for improving the therapeutic efficacy of breast cancer treatment and minimizing the side effects associated with conventional therapies.

Keywords:  Anticancer agents; Breast cancer; Glucose metabolism; Glut-1 inhibition; Natural and synthetic inhibitors

DOI:  https://doi.org/10.1016/bs.vh.2025.01.003
Clin Lymphoma Myeloma Leuk. 2025 Mar 01. pii: S2152-2650(25)00076-X. [Epub ahead of print]

Chemotherapy Trends in Acute Myeloid Leukemia: 2004 to 2020.

Aditya Ravindra, Bradley Loeffler, Luna Acharya, Avantika Pyakuryal, Vijaya Raj Bhatt, Prajwal Dhakal.

   BACKGROUND: Chemotherapy is crucial for treating acute myeloid leukemia (AML), as it improves survival and quality of life. However, prior studies have shown that many eligible patients in the United States do not receive chemotherapy due to demographic and socioeconomic disparities.
PATIENTS AND METHODS: We utilized the National Cancer Database to analyze chemotherapy utilization in 82,755 patients with AML from 2004 to 2020. We examined trends in 2 time periods, 2004 to 2010 and 2011 to 2019, with a separate analysis for 2020 to evaluate the impact of the COVID pandemic on chemotherapy use.
RESULTS: Among all patients with AML, 57.1% received multiagent chemotherapy, 20.5% received single-agent chemotherapy, and 22.4% received no chemotherapy. Chemotherapy use rose from 72.9% in 2004 to 81.3% in 2019, then slightly declined to 80.6% in 2020. The odds of receiving chemotherapy increased significantly in 2011 to 2019 compared to 2004 to 2010 based on age (P = .02), race (P < .01), and AML subtype (P = .03). Patients aged 18 to 40 consistently had higher chemotherapy utilization rates, with treatment odds rising across all age groups. While Black patients were less likely than White patients to receive chemotherapy from 2004 to 2010, their odds improved significantly in 2011 to 2019. Despite increased chemotherapy use across all AML subtypes, therapy-related AML consistently showed the lowest odds of treatment. Lower-income patients, those with more co-morbidities, and female patients had reduced chances of receiving chemotherapy, and these inequities remained largely consistent over time.
CONCLUSION: This large database study highlights improved but persistent disparities based on demographic and socioeconomic status, calling for innovative measures to expand chemotherapy use.

Keywords:  Healthcare disparities; Large Retrospective Analysis; Myeloid Malignancies; National Cancer Database; Trends in chemotherapy utilization

DOI:  https://doi.org/10.1016/j.clml.2025.02.014
Exp Physiol. 2025 Mar 19.

Increase in plasma succinate is associated with aerobic lactate production in a model of endotoxic shock.

Juan D Caicedo Ruiz, Jorge I Alvarado Sanchez, Juan J Diaztagle Fernández, Cándida Diaz Brochero, Luis E Cruz Martinez.

  The Krebs or tricarboxylic acid (TCA) cycle plays a key role in the regulation of immune responses and adaptations to hypoxia that occur during sepsis. Although the concentrations of some of these intermediates have been reported to be increased in large cohorts of septic patients, a detailed analysis of their changes during sepsis is still lacking. Here, we investigated the plasma concentrations of several TCA intermediates in a swine model of endotoxic shock and the relationship between these TCA cycle intermediates and lactate production. Nine female swine were administered lipopolysaccharide to induce endotoxic shock, while four females served as controls. Plasma samples were collected at three time points: baseline, 3 and 6 h after lipopolysaccharide administration. Control samples were collected at parallel time points. Quantification of TCA intermediates, lactate and pyruvate was performed by high-performance liquid chromatography. Oxygen-derived variables were obtained by gas analysis of arterial and venous samples. The endotoxic shock group showed a significant increase in lactate, accompanied by stability of oxygen-derived variables and a low lactate:pyruvate ratio, indicative of aerobic conditions. Of all the TCA intermediates analysed, only citrate and succinate showed significant increases compared with controls. Furthermore, the changes in lactate were determined, in part, by the changes in succinate concentration. The increase in succinate concentrations was associated with the increase in lactate in global aerobic conditions. Our results suggest a potential role for succinate as a biomarker of aerobic lactate production.

Keywords:  Krebs cycle; endotoxic shock; lactate; sepsis; succinate; translational research

DOI:  https://doi.org/10.1113/EP092109
Theranostics. 2025 ;15(8): 3655-3672

Plasma extracellular vesicles from recurrent GBMs carrying LDHA to activate glioblastoma stemness by enhancing glycolysis.

Xin Zhang, JunJie Li, Yiyao Huang, Anming Yang, Xiaoliu Liu, Yunhao Luo, Hao Tian, Minghui Wen, Chengzong Zhong, Bin Peng, Haitao Sun, Lei Zheng.

  Rationale: Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain tumor in adults, characterized by high invasiveness and poor prognosis. Glioma stem cells (GSCs) drive GBM treatment resistance and recurrence, however, the molecular mechanisms activating intracranial GSCs remain unclear. Extracellular vesicles (EVs) are crucial signaling mediators in regulating cell metabolism and can cross the blood-brain barrier (BBB). This study aimed to elucidate how EV cargo contributes to the intracranial GSC state and validate a non-invasive diagnostic strategy for GBM relapse. Methods: We isolated plasma extracellular vesicles (pl-EVs) from three groups: recurrent GBM patients post-resection, non-recurrent GBM patients post-resection, and healthy individuals. Newly diagnosed GBM patients served as an additional control. EVs were characterized and co-cultured with primary GBM cell lines to assess their effect on tumor stemness. EV cargo was analyzed using proteomics to investigate specific EV subpopulations contributing to GBM relapse. Based on these findings, we generated engineered LDHA-enriched EVs (LDHA-EVs) and co-cultured them with patient-derived organoids (PDOs). Metabolomics was performed to elucidate the underlying signal transduction pathways. Results: Our study demonstrated that pl-EVs from recurrent GBM patients enhanced aerobic glycolysis and stemness in GBM cells. Proteomic analysis revealed that plasma EVs from recurrent GBMs encapsulated considerable amounts of the enzyme lactate dehydrogenase A (LDHA). Mechanistically, LDHA-loaded EVs promoted glycolysis, induced cAMP/ATP cycling, and accelerated lactate production, thereby maintained the GSC phenotype. Concurrently, post-surgical therapy-induced stress-modulated hypoxia in residual tumors, promoted LDHA-enriched EV release. Clinically, high levels of circulating LDHA-positive EVs correlated with increased glycolysis, poor therapeutic response, and shorter survival in recurrent GBM patients. Conclusion: Our study highlights LDHA-loaded EVs as key mediators promoting GSC properties and metabolic reprogramming in GBM. These findings provide insights into recurrence mechanisms and suggest potential liquid biopsy approaches for monitoring and preventing GBM relapse.

Keywords:  EV-based liquid biopsy; GBM; LDHA-EVs; glioma stem cells; glycolysis; recurrence monitoring

DOI:  https://doi.org/10.7150/thno.102014
Cell Metab. 2025 Mar 13. pii: S1550-4131(25)00066-X. [Epub ahead of print]

Pyruvate metabolism enzyme DLAT promotes tumorigenesis by suppressing leucine catabolism.

Ning Wang, Sijia Lu, Ziyi Cao, Huimin Li, Junting Xu, Qian Zhou, Hanrui Yin, Qiqi Qian, Xianjing Zhang, Mijia Tao, Quanxin Jiang, Peihui Zhou, Liaoyuan Zheng, Liu Han, Hongtao Li, Limin Yin, Yunqing Gu, Xuefeng Dou, Haipeng Sun, Wei Wang, Hai-Long Piao, Fuming Li, Yingjie Xu, Weiwei Yang, Suzhen Chen, Junli Liu.

  Pyruvate and branched-chain amino acid (BCAA) metabolism are pivotal pathways in tumor progression, yet the intricate interplay between them and its implications for tumor progression remain elusive. Our research reveals that dihydrolipoamide S-acetyltransferase (DLAT), a pyruvate metabolism enzyme, promotes leucine accumulation and sustains mammalian target of rapamycin (mTOR) complex activation in hepatocellular carcinoma (HCC). Mechanistically, DLAT directly acetylates the K109 residue of AU RNA-binding methylglutaconyl-coenzyme A (CoA) hydratase (AUH), a critical enzyme in leucine catabolism, inhibiting its activity and leading to leucine accumulation. Notably, DLAT upregulation correlates with poor prognosis in patients with HCC. Therefore, we developed an AUHK109R-mRNA lipid nanoparticles (LNPs) therapeutic strategy, which effectively inhibits tumor growth by restoring leucine catabolism and inhibiting mTOR activation in vivo. In summary, our findings uncover DLAT's unexpected role as an acetyltransferase for AUH, suppressing leucine catabolism. Restoring leucine catabolism with AUHK109R-mRNA LNP effectively inhibits HCC development, highlighting a novel direction for cancer research.

Keywords:  DLAT; LNP-mRNA; acetylation; hepatocellular carcinoma; leucine catabolism

DOI:  https://doi.org/10.1016/j.cmet.2025.02.008