ATF4 and breast cancer: Consistent with previous studies in H1299 non-small cell lung cancer (NSCLC) cells, breast cancer cells and normal human fibroblasts [9, 44], our study also found that methionine deprivation induces ISR, characterized by upregulation of Atf4, Chac1 and Trib3. As a pro-apoptotic molecule, CHAC1 induces programmed cell death characterized primarily by ferroptosis by degrading glutathione, affecting calcium signaling, and impairing mitochondrial respiratory function [45, 46].