Our results showed that CPX directly induces both mitochondrial and cellular ROS production, which leads to the activation of ER stress and UPRER, which leads to activation of the PERK-eIF2α-ATF4 pathway, promoting ER stress-associated cell death in both chemoresistant (HCT-8/5-FU) and chemosensitive (HCT-8 and DLD-1) CRC cells. This evidence concerns the gene ATF4 and colorectal carcinoma.