PTBP1 acts as a tumor suppressor in glioma by promoting HMOX1-dependent ferroptosis.

Glioblastoma (GBM) is the most common glioma with a 5-year relative survival rate of only 5%. Gliomas progress diffusely despite treatment, and all glioblastomas eventually progress or recur following traditional radiotherapy and chemotherapy. Therefore, targeted therapy is particularly important for gliomas. Several studies have shown that the expression of polypyrimidine tract-binding protein 1 (PTBP1) is critical for glioma development. However, the exact molecular mechanisms remain unknown. Here, we performed transcriptome sequencing in glioma cells with or without inhibiting PTBP1 to uncover the underlying mechanisms, followed by in vitro and in vivo functional validation. We found that PTBP1 knockdown (KD) promotes ferroptosis by upregulating the expression of heme oxygenase 1 (HMOX1), while ferrostatin-1 (Fer-1), deferoxamine (DFOM) or si-HMOX1 effectively block PTBP1 deletion-mediated ferroptosis pathway activation. Importantly, we also use high-grade glioma cells for orthotopic transplantation aimed at validating PTBP1/ HMOX1 pathway in vivo, and confirmed that PTBP1 knockdown induced ferroptosis in glioma cells through the upregulation of HMOX1. This study uncovers a novel mechanistic understanding of the role of PTBP1 in glioma development, which constitutes a novel biomarker and target for GBM.