Deubiquitination by USP7 Stabilizes JunD and Activates AIFM2 (FSP1) to Inhibit Ferroptosis in Melanoma

Abstract

Ferroptosis resistance in melanoma cells is a key factor in melanoma progression, influenced by the tumor microenvironment. This study investigates the regulatory mechanisms of the USP7–JunD–AIFM2 pathway, which contributes to ferroptosis resistance in melanoma cells. We identified USP7 as a critical deubiquitinase that stabilizes the transcription factor JunD. Stabilized JunD, in turn, promotes the expression of AIFM2 (also known as FSP1), enhancing ferroptosis resistance in melanoma. Inhibition of USP7 led to JunD degradation and reduced AIFM2 levels, effectively sensitizing melanoma cells to ferroptosis both in vitro and in murine xenograft models. These findings underscore the role of the USP7–JunD–AIFM2 pathway in ferroptosis resistance and suggest that targeting USP7 could provide a potential therapeutic strategy against resistant melanoma.