5-Fluorouracil induces ferroptosis in breast cancer cells via targeting SLC7A11

Breast cancer (BC) is one of the major causes of cancer mortality worldwide among women. 5-Fluorouracil (5-FU) is a widely used chemotherapy drug to treat breast cancer, which is unclear that the mechanism of inhibiting BC. Ferroptosis is a mode of programmed cell death determined by iron-dependent lipid peroxidation. The aim of the study was to investigate whether ferroptosis is involved in 5-FU-induced BC cell injury. In the current study, we found that iron metabolism and SLC7A11/GPX4 signaling may play a key role in cell death of BC induced by 5-FU in vitro. In vitro experiments, we found that 5-FU exposure significantly increased the levels of iron and reactive oxygen species (ROS) in MCF-7 and MDA-MB-231 cells. Furthermore, ferrostatin-1, the ferroptosis inhibitor, inhibited cell death induced by 5-FU. Subsequent western blotting, qRT-PCR, and measurement of various kits, fluorescence staining as well as cellular thermal shift assay, confirmed the results that 5-FU induces ferroptosis by targeting SLC7A11 in BC cells. In conclusion, the results in our study reveals that 5-FU exposure leads to ferroptosis in BC cells via targeting inhibition of SLC7A11/GPX4 signaling pathway, which offers novel insight in pharmacodynamic effect and mechanism of 5-FU in therapeutic avenues of BC.