TRIM39-mediated deubiquitination upregulates RNF168 to evade autophagy-ferroptosis in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and due to the lack of robust therapeutic targets, treatment options remain limited to conventional cytotoxic chemotherapy and surgical resection. Autophagy, a lysosome-dependent degradation process, is typically regarded as a survival mechanism. However, excessive degradation of ferritin may indirectly lead to Fe²⁺ accumulation, thereby facilitating ferroptosis. In this study, we reveal for the first time the existence of a TRIM39-RNF168 ubiquitination axis in the TNBC model that targets autophagy-dependent ferroptosis in TNBC cells. The high expression of TRIM39 in TNBC cells confers resistance to ferroptosis and enhances cell survival. Regulation of the TRIM39-RNF168 axis, achieved by knocking down TRIM39 or RNF168, can activate autophagy-coupled ferroptosis in TNBC cells. The activated autophagy-ferroptosis pathway effectively suppresses TNBC progression in vivo, presenting a promising potential therapeutic approach.