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<p>Glioblastoma (GBM) is the most aggressive primary brain tumor with a dismal prognosis. Ferroptosis is implicated in GBM pathogenesis. Heat shock protein B1 (HSPB1) is associated with tumor progression, yet its precise function and regulatory mechanism in GBM ferroptosis remain elusive. Differentially expressed genes were identified from the GSE151352 dataset. WGCNA was employed to identify GBM-associated modules, which were then intersected with genes from the FerrDb V2 database. HSPB1 expression and prognostic value were validated using TCGA and GEPIA databases, and clinical specimens. Functional assays (EdU, TUNEL, and Transwell) and ferroptosis indicators (lipid ROS, Fe<sup>2+</sup>, GSH) were assessed following HSPB1 modulation. Bioinformatics tools predicted METTL1-mediated m7G modification of HSPB1, and results were validated by RIP, dual-luciferase reporter assay, and mRNA stability assays. Transcriptional regulation of HSPB1 by HOXA5 was predicted and confirmed. A subcutaneous xenograft model was used to evaluate the METTL1-HSPB1 axis in vivo. Analysis revealed 2985 DEGs. WGCNA identified a GBM-correlated “red” module; intersection with ferroptosis genes pinpointed HSPB1. HSPB1 was significantly overexpressed in GBM, correlating with poor patient survival. HSPB1 knockdown suppressed GBM cell proliferation, migration, invasion, and induced ferroptosis. Mechanistically, METTL1 mediated m7G modification to HSPB1 mRNA to enhance its stability. Concurrently, HOXA5 bound to the HSPB1 promoter to activate its transcription. Silencing either METTL1 or HOXA5 downregulated HSPB1, inhibiting GBM malignant phenotypes. In vivo, the METTL1-HSPB1 axis promoted tumor growth. METTL1 stabilizes HSPB1 mRNA through m7G methylation, and HOXA5 transcriptionally activates HSPB1 expression. This regulation promotes GBM malignant progression.</p> Graphical Abstract <p></p> <p>Bioinformatic screening identifies HSPB1 as a ferroptosis-related hub gene in GBM: METTL1 stabilizes HSPB1 mRNA via m7G modification, while HOXA5 transcriptionally activates HSPB1 by binding its promoter. Elevated HSPB1 drives GBM proliferation, invasion, and resistance to apoptosis and ferroptosis, promoting tumor malignancy.</p>

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WGCNA-Based Identification of HSPB1 Reveals a HOXA5/METTL1-m7G Regulatory Axis that Promotes Malignant Progression and Suppresses Ferroptosis in Glioblastoma

  • 期刊论文

  • 发表日期：

    2026年5月27日

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  • Hongchao Li,
  • Yusheng Chen,
  • Yanyan Zhu,
  • Shanbao Ke,
  • Danting Wu

摘要

Glioblastoma (GBM) is the most aggressive primary brain tumor with a dismal prognosis. Ferroptosis is implicated in GBM pathogenesis. Heat shock protein B1 (HSPB1) is associated with tumor progression, yet its precise function and regulatory mechanism in GBM ferroptosis remain elusive. Differentially expressed genes were identified from the GSE151352 dataset. WGCNA was employed to identify GBM-associated modules, which were then intersected with genes from the FerrDb V2 database. HSPB1 expression and prognostic value were validated using TCGA and GEPIA databases, and clinical specimens. Functional assays (EdU, TUNEL, and Transwell) and ferroptosis indicators (lipid ROS, Fe2+, GSH) were assessed following HSPB1 modulation. Bioinformatics tools predicted METTL1-mediated m7G modification of HSPB1, and results were validated by RIP, dual-luciferase reporter assay, and mRNA stability assays. Transcriptional regulation of HSPB1 by HOXA5 was predicted and confirmed. A subcutaneous xenograft model was used to evaluate the METTL1-HSPB1 axis in vivo. Analysis revealed 2985 DEGs. WGCNA identified a GBM-correlated “red” module; intersection with ferroptosis genes pinpointed HSPB1. HSPB1 was significantly overexpressed in GBM, correlating with poor patient survival. HSPB1 knockdown suppressed GBM cell proliferation, migration, invasion, and induced ferroptosis. Mechanistically, METTL1 mediated m7G modification to HSPB1 mRNA to enhance its stability. Concurrently, HOXA5 bound to the HSPB1 promoter to activate its transcription. Silencing either METTL1 or HOXA5 downregulated HSPB1, inhibiting GBM malignant phenotypes. In vivo, the METTL1-HSPB1 axis promoted tumor growth. METTL1 stabilizes HSPB1 mRNA through m7G methylation, and HOXA5 transcriptionally activates HSPB1 expression. This regulation promotes GBM malignant progression.

Graphical Abstract

Bioinformatic screening identifies HSPB1 as a ferroptosis-related hub gene in GBM: METTL1 stabilizes HSPB1 mRNA via m7G modification, while HOXA5 transcriptionally activates HSPB1 by binding its promoter. Elevated HSPB1 drives GBM proliferation, invasion, and resistance to apoptosis and ferroptosis, promoting tumor malignancy.