In conclusion, the current study demonstrates that COPS5, which is overexpressed in HCC in an amplification‐ and ATF4‐dependent manner, stabilizes MK2 through deubiquitination and, in turn, induces HSPB1 activation, protecting HCC cells from ferroptosis, thus promoting sorafenib resistance and tumor progression (Figure S14, Supporting Information). Here, COPS5 is linked to hepatocellular carcinoma.