CircHIPK3 contributes to cisplatin resistance in gastric cancer by blocking autophagy-dependent ferroptosis

Cisplatin is the first-line chemotherapy for gastric cancer (GC). However, its efficacy is dampened by the development of chemoresistance, which leads to poor prognosis in GC patients. Recently, evidence has revealed that circular RNAs (circRNAs) and dysregulation of autophagy-dependent ferroptosis play critical roles in cancer chemoresistance. Herein, for the first time we report that circHIPK3 has a vital role in GC cisplatin resistance. CircHIPK3 regulated cisplatin resistance by targeting autophagy and ferroptosis. In brief, knockdown circHIPK3 decreased GC cell cisplatin resistance by enhancing ferroptosis via the miR-508-3p/Bcl-2/beclin1/SLC7A11 axis. Taken together, our results demonstrate that ferroptosis is a promising strategy to ameliorate cisplatin resistance. Importantly, serum exosomal circHIPK3 could also be a noninvasive indicator to evaluate cisplatin resistance in GC.

Automated summary

In this study, the crucial role of circular RNAs (circRNAs) in cisplatin resistance in gastric cancer (GC) was reported for the first time. CircHIPK3 regulated cisplatin resistance by targeting autophagy and ferroptosis. Inhibition of circHIPK3 enhanced ferroptosis through the miR-508-3p/Bcl-2/beclin1/SLC7A11 axis, leading to decreased cisplatin resistance in GC cells. The results demonstrate that ferroptosis is a promising strategy to alleviate cisplatin resistance. Importantly, serum exosomal circHIPK3 could serve as a noninvasive indicator to evaluate cisplatin resistance in GC.