In this study, we also observed that sorafenib treatment resulted in Arg2 but not Arg1 downregulation at the mRNA and protein expression levels, leading to ferroptosis, and overexpression of Arg2 blocked lipid peroxidation by activating the Akt/GPX4 signaling pathway, which negatively regulates sorafenib-induced ferroptosis in murine melanoma cells. This evidence concerns the gene ARG1 and melanoma.