Raddeanin A induces ferroptosis by targeting VEPH1 in a cisplatin-resistant epithelial ovarian cancer cell line

Ovarian cancer (OC) is a fatal female malignancy, and cisplatin resistance severely impacts the clinical management of epithelial ovarian cancer (EOC), the most prevalent histological subtype accounting for over 90% of cases. Exploration of novel effective targets and drugs for treatment of cisplatin-resistant EOC is urgently needed to address the tremendous challenge. In this study, we screened a Traditional Chinese Medicine (TCM) library including 978 monomers and found that Raddeanin A (RA) extracted from Anemone raddeana Regel displayed the powerful cytotoxic effect on cisplatin-resistant EOC cells. Further investigations revealed that RA had potential of inducing ferroptosis via binding to an evolutionarily conserved scaffold protein, VEPH1. Bioinformatics analysis combined with RA-sepharose pull-down assay and immunoprecipitation confirmed that RA interacted with two sites of VEPH1, site 1 (S1) at 212-217 aa and site 2 (S2) at 579-651 aa, and S1 was also involved in VEPH1 binding to and promoting lats1 activation. Moreover, RA bound to and enhanced VEPH1 degradation through the proteasome pathway, and meanwhile inhibited the interaction between VEPH1 and lats1, which in turn suppressed lats1 activation, promoted YAP nuclear translocation to up-regulate the expression of ferroptosis-driven proteins, TFRC and ACSL4, resulting in an imbalance of intracellular iron homeostasis, as well as promotion of lipid peroxidation, and thus inducement of ferroptosis in cisplatin-resistant EOC cells. Importantly, the in vivo results confirmed that RA induced ferroptosis and dramatically suppressed the growth of A2780/DDP transplanted tumours. Taken together, we revealed for the first time that VEPH1 is the direct target for RA, and ferroptosis contributes to RA-triggered anti-tumour effect on cisplatin-resistant EOC, which provides new insights into the therapeutic application of RA against EOC chemoresistance.