Butyrate enhances erastin‐induced ferroptosis of lung cancer cells via modulating the ATF3/SLC7A11 pathway

Abstract Ferroptosis is a novel form of programmed cell death triggered by iron‐dependent lipid peroxidation and has been associated with various diseases, including cancer. Erastin, an inhibitor of system Xc‐, which plays a critical role in regulating ferroptosis, has been identified as an inducer of ferroptosis in cancer cells. In this study, we investigated the impact of butyrate, a short‐chain fatty acid produced by gut microbiota, on erastin‐induced ferroptosis in lung cancer cells. Our results demonstrated that butyrate significantly enhanced erastin‐induced ferroptosis in lung cancer cells, as evidenced by increased lipid peroxidation and reduced expression of glutathione peroxidase 4 (GPX4). Mechanistically, we found that butyrate modulated the pathway involving activating transcription factor 3 (ATF3) and solute carrier family 7 member 11 (SLC7A11), leading to enhanced erastin‐induced ferroptosis. Furthermore, partial reversal of the effect of butyrate on ferroptosis was observed upon knockdown of ATF3 or SLC7A11. Collectively, our findings indicate that butyrate enhances erastin‐induced ferroptosis in lung cancer cells by modulating the ATF3/SLC7A11 pathway, suggesting its potential as a therapeutic agent for cancer treatment.