Mechanistically, COPS5 stabilized mitogen‐activated protein kinase 2 (MK2) through deubiquitination and, in turn, induced the activation of heat shock protein beta‐1 (HSPB1), a ferroptosis repressor, thereby protecting HCC cells from ferroptosis and consequently leading to sorafenib resistance and tumor progression, while its own expression could be induced by sorafenib treatment via activating transcription factor 4 (ATF4)‐activated transcription. This evidence concerns the gene COPS5 and hepatocellular carcinoma.