INHIBITION OF TETRAHYDROBIOPTERIN AS A STRATEGY TO SENSITIZE TO FERROPTOSIS AND BLOCK THE PROGRESSION OF METASTATIC MELANOMA

Dysregulation of redox metabolism associated with activation of the 
MAPK/ERK pathway promotes melanoma progression and therapeutic resistance. 
Tetrahydrobiopterin (BH4) contributes to maintaining redox homeostasis, acting 
as an antioxidant and regulator of ferroptosis, a form of cell death dependent on 
lipid peroxidation and iron accumulation. In metastatic melanoma, increased BH4 
levels promote cell survival and growth through ERK activation, suggesting a pro
tumoral function. Inhibition of BH4 increases reactive oxygen species, which may 
favor ferroptosis. Thus, the BH4 pathway emerges as a promising therapeutic 
target to sensitize metastatic melanoma to ferroptosis.