Tripterygium glycosides reverse cisplatin resistance in epithelial ovarian cancer by activating ferroptosis via two different pathways
In our previous study, tripterygium glycosides (TG) demonstrated to combine with cisplatin (DDP) in reversing DDP resistance in A2780/DDP cells by exacerbating ferroptosis via downregulation of glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter (System Xc-) expression. However, the regulation of ferroptosis-related proteins alone is insufficient to explain the reversal of DDP resistance in epithelial ovarian cancer (EOC), suggesting the involvement of additional mechanisms. This study focused on the underlying mechanisms through which TG contributes to reversing DDP resistance in EOC. In this study, using DDP-resistant A2780/DDP cells and a nude mouse xenograft model, we comprehensively investigated the underlying mechanisms by which TG reverses DDP resistance via ferroptosis regulation through combined animal and cellular research. The results demonstrated that TG can induce ferroptosis in A2780/DDP cells. Mechanistic studies confirmed that TG induces ferroptosis through a dual-pathway mechanism involving both Keap1/Nrf2/ARE and HIF-1α/ACSL4 signaling. Furthermore, TG combined with DDP co-regulates the p53/Bax/Bcl-2 pathway to enhance apoptosis, thereby strengthening the inhibitory effect of DDP on drug-resistant EOC. Animal studies confirmed that the combination of TG and DDP significantly suppressed tumor growth compared to DDP monotherapy, with no observed increase in toxicity, indicating favorable treatment safety. In conclusion, our findings reveal for the first time that the TG combined with DDP reverses EOC drug resistance through the simultaneous induction of ferroptosis (HIF-1α/ACSL4 and Keap1/Nrf2/ARE) and apoptosis (p53/Bax/Bcl-2). These results provide experimental evidence supporting the clinical application of TG in overcoming DDP chemotherapy resistance in EOC.