4-Hydroxyderricin from Angelica keiskei promotes the stability of BRCA1 in triple-negative breast cancer cells through inhibition of cathepsin S.

Breast cancer susceptibility gene 1 (BRCA1), a tumor suppressor protein, is closely associated with ovarian and breast cancers. Previously, cathepsin S (CTSS) was reported to prevent BRCA1-mediated apoptosis, contributing to chemoresistance in TNBC. In this study, we screened the CTSS inhibitory activity of 107 pure compounds derived from plant materials and identified 4-hydroxyderricin (12) from Angelica keiskei as a potent CTSS inhibitor. Compound 12 increased BRCA1 stability in TNBC cells in a CTSS-dependent manner. In an in vivo TNBC xenograft mouse model, combination treatment with paclitaxel and compound 12 significantly increased BRCA1 stability, reduced the final tumor weight, and decreased the number of Ki-67-positive proliferative cells. Our findings suggest that combination therapy with compound 12 can enhance BRCA1 function and improve chemotherapeutic efficacy. This study highlights CTSS inhibition as a promising therapeutic strategy for TNBC patients with wild-type BRCA1.