Based on these data, we prioritized a common hit COP9 signalosome subunit 5 (COPS5), which is the catalytic subunit of the COP9 signalosome complex that inactivates Cullin‐RING E3 ubiquitin ligases through deneddylation of the ubiquitin‐like activator NEDD8,[12] for validation as a critical mediator of sorafenib resistance in HCC, and to determine its negative regulation of ferroptosis. The gene discussed is COPS5; the disease is hepatocellular carcinoma.