Through the RNA-sequencing technology and a panel of biochemical assays, it was evidenced that MITF was significantly involved in the regulation of melanoma cell ferroptosis downstream of Wnt/β-catenin signaling, and pharmacological suppression of MITF by nelfinavir was effective in exacerbating ferroptosis, which could be considered a promising strategy with relatively high translational potential. Here, MITF is linked to melanoma.