PTBP1 knockdown reprograms glioma stem cells into neuronal-like cells and suppresses tumorigenesis via the DUSP5-ERK1/2 signaling pathway

Background Glioblastoma (GBM), the most prevalent and aggressive primary brain tumor in adults, has a median survival of merely 14 months. Current therapeutic approaches, including maximal safe resection, radiotherapy, and temozolomide-based chemotherapy, have limited efficacy owing to resistance and the high rate of recurrence. Methods We analyzed H&E-stained specimens from 65 patients with glioma using deep learning-based morphological classification and analyzed a mouse model through tissue clearing and 3D imaging. Integrated transcriptomic and single-cell RNA-seq analyses identified PTBP1 as a morphology regulator. We validated the function of PTBP1 through lentiviral knockdown in vitro and in orthotopic models and performed structure-based drug screening against PTBP1 with experimental validation. Results We detected a clinically significant association between glioma cell morphology and patient survival times. Mechanistically, PTBP1, an RNA-binding protein abundantly expressed in glioma cells, regulated dual-specificity phosphatase 5 (DUSP5) expression post-transcriptionally and modulate ERK1/2 phosphorylation dynamics, thus reducing glioma stem cell proliferation and enhancing differentiation into neuronal-like cells to suppress tumor growth. Importantly, we developed a nanotherapeutic strategy using A2-PLGA/venetoclax; this strategy repurposes venetoclax, a known clinical drug for leukemia, as a PTBP1-targeting agent that effectively suppresses glioma progression in mouse models. Conclusion Our findings establish a novel PTBP1/DUSP5/ERK1/2 axis governing glioma stem cell proliferation and differentiation and identify the A2-PLGA/venetoclax nanoparticle as a mechanistically justified therapeutic candidate for glioblastoma.