ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2023
PERK-Mediated Cholesterol Excretion from IDH Mutant Glioma Determines Anti-Tumoral Polarization of Microglia.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 21 citations in OpenAlex.
- M2-like GAMs secreting CSTA drive glioblastoma progression via the ITGB4-TGFB1 feedback axis.Journal of translational medicine · 2026Article
- LARS promotes osteosarcoma proliferation through leucine-dependent PRIM2 translation and DNA replication activation.Journal of experimental & clinical cancer research : CR · 2026Article
- RAP-peptide functionalized biomimetic nanoformulation with pathological ROS/pH-responsive drug release for target immunotherapy in glioma.Journal of nanobiotechnology · 2026Article
- Targeting the unfolded protein response in cancer: mechanisms, small-molecule inhibitors, and translational challenges.Frontiers in immunology · 2026Review
- Crosstalk in the brain tumor microenvironment: mechanisms, therapeutic strategies, and clinical advances.Military Medical Research · 2026Review
- Progenitor cells, microglia, and non-coding RNAs: Orchestrators of glioblastoma pathogenesis and therapeutic resistance.Non-coding RNA research · 2025Review
- CircABCA1 promotes ccRCC by reprogramming cholesterol metabolism and facilitating M2 macrophage polarization through IGF2BP3-mediated stabilization of SCARB1 mRNA.Molecular cancer · 2025Article
- Non-Coding RNAs as Critical Modulators of Cholesterol Metabolism in Cancer.Biomedicines · 2025Review
- The role of SPI1/VSIG4/THBS1 on glioblastoma progression through modulation of the PI3K/AKT pathway.Journal of advanced research · 2025Article
- Article
- The Impact of Metabolic Rewiring in Glioblastoma: The Immune Landscape and Therapeutic Strategies.International journal of molecular sciences · 2025Review
- Endoplasmic reticulum stress orchestrates tumor metabolism and immunity: new insights into immunometabolic therapeutics.Frontiers in immunology · 2025Review
- Nontargeted metabolomics uncovering metabolite signatures in glioblastoma: a preliminary study on candidate biomarker discovery for IDH subtyping and survival prediction.Frontiers in oncology · 2025Article
- Cholesterol: The driving force behind the remodeling of tumor microenvironment in colorectal cancer.Heliyon · 2024Review
- Integration of histone modification-based risk signature with drug sensitivity analysis reveals novel therapeutic strategies for lower-grade glioma.Frontiers in pharmacology · 2024Article
- Spatial transcriptomics analysis identifies therapeutic targets in diffuse high-grade gliomas.Frontiers in molecular neuroscience · 2024Article
- PERK-Mediated Cholesterol Excretion from IDH Mutant Glioma Determines Anti-Tumoral Polarization of Microglia.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
Corrections and comments
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Authors and funding
21 authors at 6 institutions in 2 countries.
Funding
Abstract
Isocitrate dehydrogenase (IDH) mutation, a known pathologic classifier, initiates metabolic reprogramming in glioma cells and has been linked to the reaction status of glioma-associated microglia/macrophages (GAMs). However, it remains unclear how IDH genotypes contribute to GAM phenotypes. Here, it is demonstrated that gliomas expressing mutant IDH determine M1-like polarization of GAMs, while archetypal IDH induces M2-like polarization. Intriguingly, IDH-mutant gliomas secrete excess cholesterol, resulting in cholesterol-rich, pro-inflammatory GAMs without altering their cholesterol biosynthesis, and simultaneously exhibiting low levels of tumoral cholesterol due to expression remodeling of cholesterol transport molecules, particularly upregulation of ABCA1 and downregulation of LDLR. Mechanistically, a miR-19a/LDLR axis-mediated novel post-transcriptional regulation of cholesterol uptake is identified, modulated by IDH mutation, and influencing tumor cell proliferation and invasion. IDH mutation-induced PERK activation enhances cholesterol export from glioma cells via the miR-19a/LDLR axis and ABCA1/APOE upregulation. Further, a synthetic PERK activator, CCT020312 is introduced, which markedly stimulates cholesterol efflux from IDH wild-type glioma cells, induces M1-like polarization of GAMs, and consequently suppresses glioma cell invasion. The findings reveal an essential role of the PERK/miR-19a/LDLR signaling pathway in orchestrating gliomal cholesterol transport and the subsequent phenotypes of GAMs, thereby highlighting a novel potential target pathway for glioma therapy.
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