Icariside II induces ferroptosis in renal cell carcinoma cells by regulating the miR-324-3p/GPX4 axis

Icariside II (ICS II) is an active flavonoid having anti-tumor properties. However, the role of ICS II in renal cell carcinoma (RCC) and its underlying mechanisms have not been investigated to date. In this study, we demonstrated that ICS II inhibited proliferation, migration, and invasion of RCC cells. Furthermore, ferroptosis, a novel form of cell death, induced in RCC cells by ICS II, accompanied by accumulation of Fe2+, MDA (lipid peroxidation), and ROS (reactive oxygen species), and reduced GSH levels. The underlying mechanism was found to be the downregulation of GPX4, independent of p53, that occurs during ICS II-induced ferroptosis. Overexpression of GPX4 reversed the ferroptosis induced by ICS II. Moreover, ICS II treatment resulted in the upregulation of miR-324-3p, which directly targets GPX4. Overall, our results suggested that ICS II-induced ferroptosis via the miR-324-3p/GPX4 axis in RCC cells could be a promising therapeutic agent for RCC.