CD55 glycosylation promotes ferroptotic stress tolerance in CD55-high triple-negative breast cancer

Triple-negative breast cancer (TNBC) lacks effective targeted therapies and is characterized by pronounced metabolic reprogramming and redox adaptation. Identifying key regulators of its antioxidant defense system therefore holds important therapeutic potential. Ferroptosis-an iron-dependent, lipid peroxidation-driven form of regulated cell death-represents a promising anticancer strategy; however, TNBC frequently exhibits altered antioxidant defense characteristics under ferroptotic stress, although the underlying mechanisms remain unclear. Analysis of GEO datasets and oxidative stress-related gene sets identified the highly glycosylated membrane protein CD55 as markedly upregulated in TNBC models. CD55 expression was associated with reduced sensitivity to Erastin and RSL3. Compared with the non-TNBC comparator MCF-7 cells, TNBC cells showed modestly stronger survival, migration, and clonogenic capacity under ferroptotic stress. These variations were quantitative rather than exclusive, indicating a more pronounced, CD55-associated dependence in TNBC. Genetic suppression of CD55 or pharmacological inhibition of glycosylation with tunicamycin enhanced the effects of ferroptosis inducers, leading to increased ROS and Fe²⁺ accumulation, glutathione depletion, lipid peroxidation, and mitochondrial dysfunction, thereby promoting ferroptotic damage. Ferrostatin-1 partially restored cell viability under Erastin or RSL3 treatment, including tunicamycin co-treatment conditions, further supporting the ferroptosis-dependent nature of the observed cytotoxicity. Combined treatment (tunicamycin plus CD55 siRNA) produced similar sensitizing effects without significant additivity, suggesting that disruption of CD55 glycosylation is a major contributor to this response. Collectively, these findings indicate that glycosylated CD55 is an important regulator of ferroptotic stress tolerance in TNBC and represents a potential target for therapeutic sensitization strategies.