Bruceine A Suppresses Triple‐Negative Breast Cancer Growth and Metastasis by Inducing <scp>GPX4</scp> ‐Dependent Ferroptosis via Ubiquitin–Proteasome‐Mediated Degradation

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited targeted therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising strategy for treating refractory cancers. Here, we identify Bruceine A (BA), a natural quassinoid, as a potent inducer of GPX4-dependent ferroptosis in TNBC. BA suppressed proliferation, clonogenic survival, migration, and invasion of MDA-MB-231 and 4T1 cells and significantly reduced tumor growth and pulmonary metastasis in vivo. Mechanistically, BA induced iron accumulation, lipid peroxidation, and oxidative stress, consistent with ferroptotic activation. Genetic ablation of GPX4 resulted in elevated basal ferroptotic stress and abolished further BA-induced lipid peroxidation and ferroptotic amplification, indicating that BA-mediated ferroptosis requires functional GPX4. At the molecular level, BA reduced GPX4 expression at both transcriptional and post-translational levels. BA accelerated GPX4 protein turnover through ubiquitin-proteasome-mediated degradation, accompanied by enhanced ubiquitination. Molecular docking and dynamics simulations supported a stable interaction between BA and GPX4, providing structural insight into its destabilization. Collectively, these findings establish BA as a GPX4-dependent ferroptosis inducer that suppresses TNBC growth and metastasis, highlighting targeting of GPX4 stability as a potential therapeutic strategy in TNBC.