biostudies-literatureBurban AInstitut National Du Cancer (INCa)Agence Nationale de la Recherche (ANR)Agence Nationale de la RechercheInstitut National Du CancerCanceropole GSOFondation de FranceFondation de France (Foundation of France)Wellcome TrustARTC469-503https://www.ebi.ac.uk/biostudies/studies/S-EPMC11903783biostudies-literatureUnknown17(3)Glioblastoma is one of the most treatment-resistant and lethal cancers, with a subset of self-renewing brain tumour stem cells (BTSCs), driving therapy resistance and relapse. Here, we report that mubritinib effectively impairs BTSC stemness and growth. Mechanistically, bioenergetic assays and rescue experiments showed that mubritinib targets complex I of the electron transport chain, thereby impairing BTSC self-renewal and proliferation. Gene expression profiling and Western blot analysis revealed that mubritinib disrupts the AMPK/p27^Kip1 pathway, leading to cell-cycle impairment. By employing in vivo pharmacokinetic assays, we established that mubritinib crosses the blood-brain barrier. Using preclinical patient-derived and syngeneic models, we demonstrated that mubritinib delEMBO molecular medicineExploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile.PMC1190378300130896283008001308912274412023-E5241284ANR-21-CE19-0029Nicot NSharanek ATessier CNikolski MMathivet TBikfalvi AGuyon JDartigues BToujas MBurban ACappellen DDaubon TPinglaut MGeorget EGalvis JLarroquette MLuchman HALubiato CBrisson LWeiss SKlink BfalseExploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile.Glioblastoma is one of the most treatment-resistant and lethal cancers, with a subset of self-renewing brain tumour stem cells (BTSCs), driving therapy resistance and relapse. Here, we report that mubritinib effectively impairs BTSC stemness and growth. Mechanistically, bioenergetic assays and rescue experiments showed that mubritinib targets complex I of the electron transport chain, thereby impairing BTSC self-renewal and proliferation. Gene expression profiling and Western blot analysis revealed that mubritinib disrupts the AMPK/p27^Kip1 pathway, leading to cell-cycle impairment. By employing in vivo pharmacokinetic assays, we established that mubritinib crosses the blood-brain barrier. Using preclinical patient-derived and syngeneic models, we demonstrated that mubritinib del2025-01-01T00:00:00Z2025 Mar2026-04-08T19:46:53.061Z2025-04-22T07:22:03.195ZS-EPMC119037833990101910.1038/s44321-025-00195-6