ArticleCNS neuroscience & therapeutics2025
The HBP Pathway Inhibitor FR054 Enhances Temozolomide Sensitivity in Glioblastoma Cells by Promoting Ferroptosis and Inhibiting O-GlcNAcylation.
Article in CNS neuroscience & therapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Cross-talk between glycosylation pathways: Mechanistic insights and implications for human diseases.Molecular metabolism · 2026Review
- Distinct O-Linked Glycosylation Systems in Signaling and Immune Regulation.International journal of molecular sciences · 2026Review
- Decidual macrophage-mediated ferroptosis in trophoblasts leads to recurrent spontaneous abortion.iMeta · 2026Article
- Organoids as next-generation models for investigating intracranial tumours.Molecular brain · 2026Review
- O-GlcNAcylation in novel regulated cell death: ferroptosis, pyroptosis, and necroptosis.Cell death discovery · 2025Review
- The HBP Pathway Inhibitor FR054 Enhances Temozolomide Sensitivity in Glioblastoma Cells by Promoting Ferroptosis and Inhibiting O-GlcNAcylation.CNS neuroscience & therapeutics · 2025Article
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Authors and funding
10 authors.
Funding
Abstract
backgroundThe clinical efficacy of temozolomide (TMZ) in glioblastoma (GBM) patients is often limited by the development of resistance. To date, no clinically validated therapeutic strategies exist to restore sensitivity to TMZ treatment. In this study, we investigated the potential of FR054, a hexosamine biosynthesis pathway (HBP) inhibitor, to sensitize GBM cells to TMZ and elucidated its underlying molecular mechanism.
methodsTMZ-resistant U87-MG and A172 cell lines were generated through stepwise exposure to increasing concentrations of TMZ. Proteomics and bioinformatics analyses revealed HBP activation in these resistant cells. The effects of FR054 alone or in combination with TMZ were assessed using cell line models, GBM organoid models, and intracranial xenograft models. Transcriptomic analysis and validation experiments were further conducted to explore the molecular mechanisms involved.
resultsLong-term exposure to TMZ induced resistance in U87-MG and A172 GBM cells, which was associated with the activation of the HBP pathway. PGM3, a key enzyme in the HBP, was found to correlate with poor prognosis in GBM patients. The combination of FR054, a specific PGM3 inhibitor, with TMZ exhibited synergistic inhibitory effects in vitro and superior inhibitory efficacy in GBM organoid models. In vivo, this combination significantly suppressed tumor progression and prolonged survival in orthotopic xenograft mice with minimal side effects. Mechanistically, FR054 enhanced TMZ sensitivity by inhibiting protein O-GlcNAcylation and promoting ferroptosis via the upregulation of HMOX1 and downregulation of GPX4.
conclusionOur findings demonstrate that targeting the HBP pathway with FR054 can overcome TMZ resistance in GBM by reducing O-GlcNAc modification and inducing ferroptosis. This novel approach enhances the efficacy of TMZ, offering a promising therapeutic strategy for GBM patients with limited treatment options.
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