Procyanidin B1 Promotes PSMC3-NRF2 Ubiquitination to Induce Ferroptosis in Glioblastoma

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• NRF2 signaling is a key antioxidant pathway vital for tumor survival and resistance to ferroptosis.
• Targeting NRF2 is a promising strategy for cancer therapy, but effective inhibitors are needed.
• Traditional Chinese medicine components are potential sources for novel NRF2 inhibitors.

Purpose of the Study:

• To investigate the anti-tumor effects of procyanidin B1 on glioblastoma (GBM).
• To determine if procyanidin B1 acts as an NRF2 inhibitor and induces ferroptosis in GBM cells.
• To elucidate the molecular mechanism underlying procyanidin B1's action, including its interaction with NRF2 and PSMC3.

Main Methods:

• Established an intracranial GBM orthotopic model.
• Utilized protein-small-molecule docking, confocal imaging, SPR, immunoprecipitation, mass spectrometry, and western blotting.
• Assessed procyanidin B1's impact on GBM cell proliferation, survival, NRF2 degradation, and ferroptosis.

Main Results:

• Procyanidin B1 suppressed GBM cell proliferation and prolonged survival in bearing mice.
• Procyanidin B1 binds to NRF2 and promotes its ubiquitin-dependent degradation via PSMC3.
• This degradation induced ferroptosis and enhanced H₂O₂ accumulation in GBM cells.

Conclusions:

• Procyanidin B1 functions as a novel NRF2 inhibitor with anti-glioblastoma activity.
• The anti-tumor effect is mediated by PSMC3-dependent degradation of NRF2, leading to ferroptosis.
• Procyanidin B1 shows potential as an adjuvant therapeutic agent for glioblastoma.