Cutaneous melanoma is an aggressive skin cancer characterized by high rates of recurrence and mortality, especially in its advanced stages. Ferroptosis, a distinct form of programmed cell death, has emerged as a promising therapeutic strategy for cancer. Nevertheless, the regulatory mechanisms underlying ferroptosis in melanoma remain poorly defined. In this study, we aimed to elucidate the role of USP36, a deubiquitinating enzyme that removes ubiquitin from substrate proteins, in the ferroptosis of melanoma cells. Using A375 and SK-MEL-28 melanoma cells treated with the ferroptosis inducer erastin, we analyzed USP36 expression and evaluated its functional role through both overexpression and knockdown experiments. Co-immunoprecipitation and ubiquitination assays demonstrated that USP36 stabilizes APEX1 through the cleavage of its K48-linked ubiquitin chains. We further employed USP36-deficient xenograft models to assess tumor growth and ferroptosis sensitivity. Our results indicate that erastin downregulates USP36, whereas overexpression of USP36 suppresses ferroptosis. Importantly, knockdown of APEX1 abolished the anti-ferroptotic effect of USP36. In addition, USP36-deficient tumors exhibited reduced proliferation and enhanced ferroptosis. Collectively, these findings establish USP36 as an oncogene in melanoma that inhibits ferroptosis through stabilization of APEX1. Therefore, targeting the USP36-APEX1 axis may represent a novel therapeutic approach for melanoma treatment.
Zhang et al. (2026) studied this question.