Abstract
Sorafenib, which is proven to serve as a potent ferroptosis inducer, is used as a first-line treatment for patients with advanced hepatocellular carcinoma (HCC), but it has limited clinical benefits, mainly due to drug resistance. Herein, using genome-wide CRISPR/Cas9 knockout screening and multiple functional studies, this work identifies COP9 signalosome subunit 5 (COPS5) as a driver of sorafenib resistance and a suppressor of ferroptosis in HCC. Consistently, the amplification and overexpression of COPS5 are frequently observed in clinical HCC samples, which are associated with poor patient prognosis and might predict patient response to sorafenib therapy. 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. Furthermore, pharmacological inhibition of COPS5/MK2 synergize with sorafenib to induce ferroptosis and suppress HCC progression. This data reveals the crucial role of COPS5 in triggering ferroptosis defense and sorafenib resistance through the activation of the MK2-HSPB1 axis in HCC and highlights the potential of targeting COPS5/MK2 combined with sorafenib as a promising strategy for treating HCC.