NCOA4-mediated ferroptosis conducive to EMT inhibition in colorectal cancer cells was achieved through the PI3K/AKT/mTOR pathway.

The link of epithelial-mesenchymal transition (EMT) program with metastasis is well documented. However, the role of ROS in EMT process is self-contradictory. DpdtpA was a dithiocarbamate derivative (an iron chelator) that exhibits excellent growth and wound healing inhibitory effects in colorectal cancer (CRC) cell lines, but the underlying mechanism of action was not fully determined. The present data in this study revealed that the ROS derived from autophagic degradation of ferritin were conducive to EMT repression. Genetically knockdown of NCOA4 promoted expression of mesenchymal characteristics, supporting that NCOA4 involved EMT regulation. In addition, DpdtpA treatment also caused depletion of Gpx4 and xCT, triggering ferroptosis as Erastin acted. The causal relationship analysis demonstrated that depletion of Gpx4 and xCT, (or ferroptosis) contributed to the EMT inhibition. Moreover, there seemed to be a feedback loop between Gpx4 and xCT, knockdown of Gpx4 led to upregulation of xCT, but knockdown of xCT brought about downregulation of Gpx4. Further study demonstrated that the depletion of Gpx4 and xCT was due to enhanced autophagy. In addition, PI3K/AKT/mTOR/pathway was showed involving EMT and ferroptosis regulation. In short, our data suggested that the status of EMT and ferroptosis largely was dominated by the continuous NCOA4-mediated ROS production.