Vemurafenib Activates PSMB9 to Induce Ferroptosis via Free Iron Accumulation and Inhibits Melanoma Progression

Melanoma is a highly lethal skin cancer with increasing incidence, underscoring the need for novel therapeutic strategies. Ferroptosis, a noncanonical programmed cell death pathway, has emerged as a promising target for cancer intervention. This study investigates the role of vemurafenib in melanoma therapy by targeting PSMB9 to modulate free iron levels and induce ferroptosis. Single-cell transcriptomics analysis identified a subset of malignant melanoma cells with low ferroptosis scores, while prognostic analysis of TCGA data revealed ferroptosis-related genes correlated with poor prognosis. Network pharmacology identified PSMB9 as a key target of vemurafenib, and expression analysis confirmed its underexpressed in melanoma. Functional assays demonstrated that vemurafenib treatment promoted PSMB9 expression, inhibited melanoma cell growth, motility, and invasiveness, and increased free iron levels, thereby inducing ferroptosis. Silencing PSMB9 reversed these effects, which were restored by ferroptosis activator Erastin. In vivo experiments confirmed that vemurafenib treatment enhanced PSMB9 expression, increased iron ion accumulation, and suppressed tumor growth via ferroptosis induction. These findings establish a novel mechanism by which vemurafenib exerts anti-melanoma effects through PSMB9-mediated ferroptosis, offering potential therapeutic implications for melanoma management.