Indeed, we observed that targeting MK2 with small‐molecule inhibitors (MK2 Inhibitor III and PF3644022) or targeting COPS5 with curcumin strongly impaired the basal activation of the MK2‐HSPB1 signaling pathway, and the feedback activation of this pathway induced by sorafenib, augmented ferroptosis and synergized with sorafenib to attenuate the growth of HCC cells. Here, MAPKAPK2 is linked to hepatocellular carcinoma.