HSPB1 silencing enhances ferroptosis in glioma cells by suppressing BAG3 expression.

To investigate the role of heat shock protein family B (small) member 1 (HSPB1) in regulating ferroptosis in glioma and to explore the underlying molecular mechanisms. HSPB1 expression was analyzed in glioma cell lines. U251 glioma cells were transfected with HSPB1-targeting short hairpin RNA (shRNA). Cell proliferation, invasion, ferroptosis markers (iron accumulation, oxidative stress), and expression of BCL2-associated athanogene 3 (BAG3) were assessed using molecular and biochemical assays. BAG3 was further silenced or overexpressed to evaluate its interaction with HSPB1 in regulating ferroptosis. HSPB1 was markedly overexpressed in glioma cell lines. HSPB1 knockdown significantly suppressed U251 cell proliferation and invasion, while promoting ferroptosis via increased intracellular Fe2+ levels and lipid peroxidation. BAG3 was identified as a downstream target of HSPB1. Silencing BAG3 replicated the anti-tumor and pro-ferroptotic effects of HSPB1 knockdown. Moreover, BAG3 overexpression partially rescued the effects of HSPB1 silencing, confirming its role in the HSPB1-mediated ferroptosis pathway. HSPB1 inhibits ferroptosis and promotes glioma cell survival, at least in part through BAG3 upregulation. Targeting the HSPB1-BAG3 axis may represent a novel therapeutic strategy and prognostic approach in glioma treatment.