Brusatol modulates the Nrf2/GCLC pathway to enhance ferroptosis in the treatment of oral squamous cell carcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: Oral squamous cell carcinoma is one of the most common malignant tumors in the oral and maxillofacial region, with insidious morbidity, high mortality rate, and limited therapeutic methods at present, so there is an urgent need for the development of new therapeutic drugs in the clinic. AIM OF THE STUDY: This study aims to investigate the therapeutic potential of brusatol (BRT)-a natural compound isolated from Brucea javanica (L.) Merr.-for treating oral squamous cell carcinoma, with a focus on evaluating its antitumor efficacy and deciphering the underlying molecular mechanisms. MATERIALS AND METHODS: We conducted in vitro and in vivo experiments respectively. Firstly, we found that brusatol (BRT) can effectively inhibit the growth rate of the nude mouse heterotopic transplantation tumor model constructed with Cal-27 cells. Secondly, it was proved that brusatol (BRT) can promote the ferroptosis of Cal-27 cells, reduce their survival rate, and inhibit their growth and migration capabilities. Further research revealed that Nrf2, as a key factor in facilitating ferroptosis by brusatol (BRT), can suppress the expression of its downstream target genes GCLC and SLC7A11, leading to depletion of intracellular GSH, accumulation of Fe(2+) and ROS, and the occurrence of ferroptosis in Cal-27 cells. RESULTS: In summary, our study confirms that brusatol (BRT) can promote ferroptosis and improve oral squamous cell carcinoma by inhibiting the Nrf2/GCLC pathway. CONCLUSION: This discovery makes brusatol (BRT) a promising therapeutic agent for the treatment of oral squamous cell carcinoma.