ArticleCell reports. Medicine2024
Combinatorial targeting of glutamine metabolism and lysosomal-based lipid metabolism effectively suppresses glioblastoma.
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Article in Cell reports. Medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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42 citing papers in PubMed.
- Gut microbial ammonia as a mediator of PFOS neurotoxicity and its remediation by the flavonoid Icaritin.Gut microbes · 2026Article
- Ammonia-induced cell death patterns in glioblastoma: Immune landscape, prognostic signature, and therapeutic target identification.Genes & diseases · 2026Article
- Cancer drug response and resistance: molecular mechanisms and combating strategies.Signal transduction and targeted therapy · 2026Review
- Dual action of pimozide through lysosome disruption and inhibition of STATs induces apoptosis in chronic lymphocytic leukemia (CLL).Blood advances · 2026Article
- CRISPR screening reveals NPC1L1 as a key driver of glioblastoma progression via cholesterol metabolic regulation.MedScience · 2026Article
- Beyond Glycolysis: Targeting Non-Glycolytic Metabolic Pathways in Brain Tumors for Therapeutic Innovation: A Narrative Review.Health science reports · 2026Article
- LncRNA SOX21-AS1 is associated with poor prognosis and immunomodulation in glioblastoma.Translational cancer research · 2026Article
- TP53 mutations in triple-negative breast cancer cells confer sensitivity to ASCT2 inhibition via arginine uptake.Cell death & disease · 2026Article
- Review
- GPR40 Attenuates Glioma TMZ-Resistance Through Ferroptosis Inhibition.Neurochemical research · 2026Article
- A novel microprotein MUCP1 promotes colorectal cancer metabolic reprogramming by regulating mitochondrial succinate transport.Neoplasia (New York, N.Y.) · 2026Article
- Article
- Targeting Metabolic Vulnerabilities in Glioblastoma: a Framework for Multi-node Combination Therapy.Current oncology reports · 2026Review
- Adaptaquin is selectively toxic to glioma stem cells through disruption of iron and cholesterol metabolism.Molecular oncology · 2026Article
- Ammonia metabolic reprogramming in the tumor microenvironment: emergence of an immunosuppressive niche.Frontiers in cell and developmental biology · 2026Review
- Crosstalk in the brain tumor microenvironment: mechanisms, therapeutic strategies, and clinical advances.Military Medical Research · 2026Review
- Metabolic remodeling and immune evasion in glioblastoma: a focus on serine and lipid networks.Frontiers in oncology · 2026Review
- Navigating the Lipid Landscape: The Role of Fatty Acid Synthase in Neural Stem Cell Fate and Central Nervous System Function.Molecular neurobiology · 2025Review
- Multifunctional nanoplatforms for tumor microenvironment remodeling: Toward precision and intelligent cancer therapy.Materials today. Bio · 2025Review
- Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review).International journal of molecular medicine · 2025Review
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Authors and funding
21 authors.
Yaogang ZhongDepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Feng GengDepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Logan MazikDepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Xinmin YinDepartment of Chemistry, Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY 40208, USA.
Aline Paixao BeckerDepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA.
Shabber MohammedDivision of Medicinal Chemistry & Pharmacognosy, College of Pharmacy at The Ohio State University, Columbus, OH 43210, USA.
Huali SuDepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Enming XingDivision of Medicinal Chemistry & Pharmacognosy, College of Pharmacy at The Ohio State University, Columbus, OH 43210, USA.
Yongjun KouDepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Cheng-Yao ChiangDepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Yunzhou FanDepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Yongchen GuoDepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Qiang WangDepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Pui-Kai LiDivision of Medicinal Chemistry & Pharmacognosy, College of Pharmacy at The Ohio State University, Columbus, OH 43210, USA.
Xiaokui MoCenter for Biostatistics, Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Etienne LefaiHuman Nutrition Unit, French National Research Institute for Agriculture, Food and Environment, University Clermont Auvergne, 63122 Clermont-Ferrand, France.
Liqing HeDepartment of Chemistry, Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY 40208, USA.
Xiaolin ChengDivision of Medicinal Chemistry & Pharmacognosy, College of Pharmacy at The Ohio State University, Columbus, OH 43210, USA; Translational Data Analytics Institute at The Ohio State University, Columbus, OH 43210, USA.
Xiang ZhangDepartment of Chemistry, Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY 40208, USA.
Arnab ChakravartiDepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA.
Deliang GuoDepartment of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and College of Medicine at The Ohio State University, Columbus, OH 43210, USA; Center for Cancer Metabolism, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. Electronic address: deliang.guo@osumc.edu.
Funding
Translational Therapeutics Research Program (TT)P30CA016058 · NCI · OHIO STATE UNIVERSITY · PI Daniel G. Stover · 1985 to 2026
$132.3MRole of oxidized linoleic acid metabolites in the pathogenesis of alcoholic liver diseaseP20GM113226 · NIGMS · UNIVERSITY OF LOUISVILLE · PI HOOD, JOSHUA L. · 2016 to 2025
$24.1MDetermining the role of lipid droplets in glioblastoma and their therapeutic potentialR01NS104332 · NINDS · OHIO STATE UNIVERSITY · PI Deliang Guo · 2018 to 2026
$4.2MDelineating how retinoic acids regulate lipid metabolism in glioblastoma and their resistance mechanismsR01CA240726 · NCI · OHIO STATE UNIVERSITY · PI GUO, DELIANG · 2020 to 2024
$2.2MIdentifying SREBP-1 activation mechanism in glioblastoma and its new role in regulating glutamine metabolismR01NS112935 · NINDS · OHIO STATE UNIVERSITY · PI GUO, DELIANG · 2020 to 2024
$1.8MDefining the molecular mechanisms regulating the hexosamine-N-glycosylation pathway in glioblastomaR01CA227874 · NCI · OHIO STATE UNIVERSITY · PI CHAKRAVARTI, ARNAB, GUO, DELIANG · 2019 to 2023
$1.5MNovel lipid and glutamine metabolism-based combination therapies for glioblastomaR01NS141312 · NINDS · OHIO STATE UNIVERSITY · PI Deliang Guo · 2025 to 2026
$1.2MUltra Performance Liquid Chromatography High Resolution High Mass Accuracy Mass SpectrometerS10OD020106 · OD · UNIVERSITY OF LOUISVILLE · PI ZHANG, XIANG · 2015 to 2015
$600kNCI NIH HHS P30 CA016058NCI NIH HHS R01 CA227874NCI NIH HHS R01 CA240726NIGMS NIH HHS P20 GM113226NIH HHS S10 OD020106NINDS NIH HHS R01 NS104332NINDS NIH HHS R01 NS112935NINDS NIH HHS R01 NS141312
Abstract
Antipsychotic drugs have been shown to have antitumor effects but have had limited potency in the clinic. Here, we unveil that pimozide inhibits lysosome hydrolytic function to suppress fatty acid and cholesterol release in glioblastoma (GBM), the most lethal brain tumor. Unexpectedly, GBM develops resistance to pimozide by boosting glutamine consumption and lipogenesis. These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo. Our findings underscore the promising therapeutic potential of effectively targeting GBM by combining glutamine metabolism inhibition with lysosome suppression.
Indexed as
GlioblastomaGlutamineLipid MetabolismLysosomesAmino Acid Transport System ASCAnimalsBrain NeoplasmsCell Line, TumorGlutaminaseHumansLipogenesisMiceMinor Histocompatibility AntigensMitochondriaOxidative StressSterol Regulatory Element Binding Protein 1Amino Acid Transport System ASCGlutaminaseGlutamineMinor Histocompatibility AntigensSLC1A5 protein, humanSREBF1 protein, humanSterol Regulatory Element Binding Protein 1ASCT2cholesterolfatty acidsglioblastomaGLSglutaminelipid dropletslysosomepimozideSREBP-1
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LicenceCC BY-NC-ND
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.