PTBP1: A Key Hub and a Potential Therapeutic Target in High-Grade Glioma

High-grade gliomas (HGGs) are lethal primary brain tumors with poor prognosis despite multimodal therapy. Polypyrimidine tract-binding protein 1 (PTBP1) is an RNA-binding protein that regulates alternative splicing, mRNA stability, and translation. In HGGs, PTBP1 is overexpressed and correlates with tumor grade, IDH mutation status, and patient survival, supporting it as a candidate prognostic biomarker and therapeutic target. Structurally, PTBP1 contains four RNA recognition motifs connected by flexible linkers, conferring conformational plasticity for diverse RNA interactions. In glioma cells, upstream regulators—including non-coding RNAs and post-translational modifications—dysregulate PTBP1, converting it from a physiological regulator into a predominantly oncogenic driver. Multiple lines of evidence suggest that PTBP1 drives malignancy through three interconnected mechanisms: oncogenic splicing switching, stabilization of oncogenic mRNAs, and IRES-dependent translation. Although no selective, direct small-molecule inhibitor of PTBP1 has yet been clinically validated, repurposed compounds (e.g., venetoclax) and indirect modulators have shown preliminary antitumor activity in preclinical models. However, direct target engagement, in vivo efficacy, and blood–brain barrier penetration remain insufficiently established. This review summarizes PTBP1’s structure, upstream networks, downstream mechanisms, and therapeutic potential, highlighting the need for further validation of PTBP1-centered strategies prior to clinical translation.