In this study, we found that GRP75 is redistributed outside of mitochondria as a result of its increased phosphorylation and protects cancer cells from ferroptosis by directly binding with Kelch-like ECH-associated protein 1 (Keap1), at MAMs and in the cytosol, leading to reduced Keap1-mediated transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2).