Glyoxalase 1 promotes glioma progression by modulating Sox2 transcriptional networks in glioma stem-like cells

BACKGROUND: Glioma stem-like cells (GSCs) contribute to tumor heterogeneity and are resistant to conventional therapies, making them a significant obstacle to achieving long-term treatment success. However, efforts to eliminate GSCs have been hindered by the lack of reliable markers that provide functional insight into these processes. Therefore, identifying GSC-associated markers is critical for understanding glioma tumorigenesis and for developing targeted therapeutic strategies that can effectively suppress tumor progression and recurrence. METHODS: We employed single-cell transcriptomics, functional genomics, in vitro assays, and preclinical glioblastoma (GBM) models, including patient-derived xenografts (PDXs) and in utero electroporation (IUE)-based models, to investigate the role of Glyoxalase 1 (Glo1) in GSCs and GBM. Manipulation of Glo1 was achieved through genetic overexpression, knockdown, and pharmacological inhibition. RESULTS: Glyoxalase 1 was initially identified through integrative single-cell transcriptomic analyses of human and mouse GBM models, where it is enriched in GSC populations defined by stemness markers. Genetic manipulation of Glo1 indicates that it promotes GSC proliferation and tumor progression, while also being associated with poor prognosis. In addition, pharmacological inhibition of Glo1 significantly reduced GSC viability and tumor growth, and prolonged survival in both PDX and IUE-GBM models. Mechanistically, Glo1 modulation disrupted transcriptional programs associated with GSC maintenance, in part by modulating Sox2 activity. CONCLUSIONS: These findings demonstrate Glo1 as a key regulator of GSC biology and highlight its potential as a therapeutic target for GSC-directed intervention in GBM. Targeting Glo1 may offer a novel strategy to impair GSC-driven tumor progression and improve GBM treatment outcomes.