Brusatol enhances ferroptosis susceptibility in nasopharyngeal carcinoma by downregulating Nrf2 expression.

Nasopharyngeal carcinoma (NPC) is characterized by high metastatic potential and invasiveness, posing significant therapeutic challenges. Existing treatment methods remain limited, and new therapeutic strategies are urgently needed. Brusatol, a natural quinoline-derived compound, exhibits broad pharmacological activities, including anti-cancer effects. Ferroptosis is a unique mode of regulated cell death and is closely associated with tumorigenesis. However, the effects of brusatol on ferroptosis in NPC cells have not been reported. This study aimed to investigate how brusatol regulates ferroptosis in NPC and its underlying mechanisms. Our results showed that brusatol inhibited NPC cell growth and downregulated the expression of nuclear factor erythroid-2-related factor 2 (Nrf2). The combination of brusatol with RAS-selective lethal 3 (RSL3) significantly enhanced ferroptosis in NPC cells, accompanied by increased levels of cellular reactive oxygen species (ROS) and lipid peroxidation. These effects were further confirmed in NPC xenograft mouse models, as demonstrated by reduced tumor volumes, decreased Ki-67 and Nrf2 staining, and increased expression of cyclooxygenase-2 (COX2). In conclusion, brusatol promotes ferroptotic cell death in NPC cells by inducing Nrf2 degradation and enhancing lipid peroxidation, suggesting its promising therapeutic potential for the treatment of NPC.