Brusatol enhances ferroptosis susceptibility in nasopharyngeal carcinoma by downregulating Nrf2 expression

Area of Science:

• Oncology
• Cell Biology
• Pharmacology

Background:

• Nasopharyngeal carcinoma (NPC) presents significant therapeutic challenges due to its high metastatic potential.
• Current treatments for NPC are limited, necessitating the development of novel therapeutic strategies.
• Ferroptosis, a regulated cell death pathway, is implicated in tumorigenesis, but its role in NPC remains unexplored.

Purpose of the Study:

• To investigate the effects of brusatol on ferroptosis in NPC cells.
• To elucidate the underlying mechanisms by which brusatol regulates ferroptosis in NPC.
• To assess the therapeutic potential of brusatol in NPC models.

Main Methods:

• NPC cell lines were treated with brusatol to assess cell growth inhibition and Nrf2 expression.
• Combination therapy with brusatol and RSL3 was used to evaluate ferroptosis induction.
• Cellular reactive oxygen species (ROS) and lipid peroxidation levels were measured.
• NPC xenograft mouse models were utilized to confirm in vivo efficacy, assessing tumor volume, Ki-67, Nrf2, and COX2 expression.

Main Results:

• Brusatol significantly inhibited NPC cell growth and downregulated nuclear factor erythroid-2-related factor 2 (Nrf2) expression.
• The combination of brusatol with RSL3 markedly enhanced ferroptosis in NPC cells, increasing ROS and lipid peroxidation.
• In vivo studies demonstrated reduced tumor volumes, decreased Nrf2 and Ki-67 staining, and increased COX2 expression in NPC xenografts treated with brusatol.

Conclusions:

• Brusatol promotes ferroptotic cell death in nasopharyngeal carcinoma by inducing Nrf2 degradation and enhancing lipid peroxidation.
• These findings highlight brusatol's potential as a therapeutic agent for NPC.
• Targeting ferroptosis pathways represents a promising strategy for overcoming therapeutic limitations in NPC treatment.