Corosolic acid increases the therapeutic effect of cisplatin on gastric cancer by regulating Gpx4-dependent ferroptosis.

Aim: Cisplatin serves as a primary chemotherapeutic agent in the treatment of gastric cancer (GC), but resistance to cisplatin-based chemotherapeutic regimens hampers its clinical application. Corosolic acid (CA), a natural triterpenoid, exhibits both anti-inflammatory and anti-cancer activities. However, the effect of CA on improving cisplatin resistance in GC remains unclear. The study primarily aimed to evaluate whether CA increases the therapeutic efficacy of cisplatin against GC and to reveal its underlying mechanism. Methods: Cisplatin and CA were used to treat GC cells or cisplatin-resistant AGS cells (AGS-CR), and then cell viability, apoptosis, and growth were assessed using Cell Counting Kit-8, TdT-mediated dUTP nick end labeling, and clone formation assays, respectively. Glutathione peroxidase 4 (Gpx4) expression was measured through quantitative real-time PCR and western blotting assays. Results: CA treatment induced a dose-dependent reduction in GC cell viability. The combination of cisplatin and CA resulted in enhanced cytotoxicity and pro-apoptotic effects compared to treatment with cisplatin alone. The effect of CA as a chemosensitizer in GC cells was damaged by a ferroptosis inhibitor, suggesting that CA decreased cisplatin chemoresistance by accelerating cancer cell ferroptosis. CA triggered cell ferroptosis by repressing Gpx4 expression in GC cells. Furthermore, elevated Gpx4 expression was significantly associated with poorer overall and disease-free survival. Conclusion: CA has the potential to increase cisplatin chemosensitivity in GC, and Gpx4 may represent a promising therapeutic target for its treatment.