In the present study, we found that shikonin induced the cell apoptosis of colorectal cancer cells by activating the ER stress through the PERK/elF2α/ATF4/CHOP and IRE1α/JNK signaling pathways, up-regulating the anti-apoptotic protein Bcl-2 and increasing the expression of caspase-3/9. Here, ERN1 is linked to colorectal cancer.