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 protumoral 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.