ArticleScience translational medicine2023
Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.
Article in Science translational medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 54 citations in OpenAlex.
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- One size does not fit all: An in vitro evaluation of the effects of bezafibrate and medroxyprogesterone acetate on human SH-SY5Y and U-87 MG cancer cells.FEBS open bio · 2026Article
- Molecular insights into DNA damage response plasticity in glioma stem cells.Communications biology · 2026Review
- LncRNA SOX21-AS1 is associated with poor prognosis and immunomodulation in glioblastoma.Translational cancer research · 2026Article
- Stiripentol induces ER stress and pyroptosis in pancreatic cancer cells under metabolic stress by dysregulating SFAs/UFAs homeostasis.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- Metabolic drivers of genome instability in cancer: mechanisms and therapeutic opportunities.Experimental hematology & oncology · 2026Review
- SCD1 and SCD5 modulate PARP-dependent DNA repair via fatty acid desaturation in glioblastoma.Cell reports · 2026Article
- Inhibiting stearoyl-CoA desaturase suppresses bone metastatic prostate cancer by modulating cellular stress, mTOR signaling, and DNA damage response.FEBS letters · 2026Article
- Metabolic rewiring of the tumor microenvironment: therapeutic intervention of multi-pathway adaptations to impede cancer metastasis.Frontiers in molecular biosciences · 2026Review
- Coupling proteostasis andTheranostics · 2026Article
- Desat1-mediated lipid homeostasis mitigates 20E-induced lipotoxicity in blood-fed mosquitoes.Nature communications · 2025Article
- Targeting bone marrow adipocyte-driven fatty acid metabolism to overcome drug resistance in lung cancer bone metastasis.Journal of nanobiotechnology · 2025Article
- Rewiring cancer metabolism: oncogenic signaling pathways and targeted therapeutics.Science China. Life sciences · 2025Review
- Cut the fat: targeting cholesterol and lipid metabolism in glioblastoma.Cell death & disease · 2025Review
- Targeting the crosstalk of metabolism reprogramming and replication stress: novel strategy to combat cancer.Medical oncology (Northwood, London, England) · 2025Review
- Near-infrared fatty acid molecular probe for image-guided surgery of glioblastoma.Npj imaging · 2025Article
- Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights.Acta neuropathologica communications · 2025Review
- Targeting Monounsaturated Fatty Acid Metabolism for Radiosensitization of KRAS Mutant 3D Lung Cancer Models.Molecular cancer therapeutics · 2025Article
- Targeting SCD triggers lipotoxicity of cancer cells and enhances anti-tumor immunity in breast cancer brain metastasis mouse models.Communications biology · 2025Article
- Lipid metabolic reprograming: the unsung hero in breast cancer progression and tumor microenvironment.Molecular cancer · 2025Review
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15 authors at 6 institutions in 3 countries.
Funding
Abstract
Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or in combination with temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological manipulation of key signaling nodes in gliomagenesis complemented with shotgun lipidomics, we show that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drive therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs resistant to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Together, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for the rational integration of DNLS-targeted GBM therapies.
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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 OpenQuestion graph.