Discovery of a selenium-containing compound as a promising ferroptosis inducer attenuates prostate cancer progression.

Advanced prostate cancer (PCa) frequently progresses to metastatic castration-resistant prostate cancer (mCRPC), a stage characterized by limited therapeutic options and dismal prognosis. Emerging evidence has underscored ferroptosis induction as a promising therapeutic strategy for advanced PCa. Here, we synthesized and identified a selenium-containing compound, 8m, which significantly suppressing tumor cell proliferation, migration, and stemness in both in vitro and in vivo models. Mechanistic investigations revealed that 8m inhibits the deubiquitinase USP30, leading to enhanced ubiquitination and degradation of GPX4, a critical regulator of ferroptosis. This study not only establishes the USP30/GPX4 axis as a novel molecular mechanism governing ferroptosis in PCa using 8m as a chemical probe but also provides a promising therapeutic strategy and lead compound for the treatment of advanced PCa.