A novel circular RNA confers trastuzumab resistance in human epidermal growth factor receptor 2‐positive breast cancer through regulating ferroptosis.

HER2‐positive breast cancer is an aggressive subtype of breast cancer, characterized by high malignancy and poor prognosis. Trastuzumab, the first HER2‐targeted monoclonal antibody therapy, has a crucial role in a curative setting in HER2‐positive breast cancer. However, frequent drug resistance inhibits its clinical efficacy. Herein, by performing circular RNA (circRNA) profiling, we identified a novel circRNA, circ‐BGN, as a key contributor in trastuzumab resistance. Circ‐BGN was evidently increased in trastuzumab‐resistant breast cancer cells and tissues, linking to poor overall survival. Knockdown of circ‐BGN inhibited breast cancer cell viability and notably restored its sensitivity to trastuzumab. Further, we found that circ‐BGN could directly bind to OTUB1 and SLC7A11, enhancing OTUB1‐mediated SLC7A11 deubiquitination and thereby inhibiting ferroptosis, a newly recognized form of cell death that is distinct from apoptosis, necrosis, and autophagy. Moreover, erastin, a small‐molecule ferroptosis inducer, could effectively restore the anti‐tumor effect of trastuzumab. Pre‐clinically, the orthotopic tumor model showed that erastin significantly reduced tumor volume generated by trastuzumab‐resistant breast cancer cells, which was more pronounced after combined circ‐BGN knockdown. Collectively, our data reveal a novel circRNA controlling trastuzumab resistance via regulation of ferroptosis, providing a promising therapeutic strategy for trastuzumab‐resistant breast cancer patients. [ABSTRACT FROM AUTHOR]