COPS5 Triggers Ferroptosis Defense by Stabilizing MK2 in Hepatocellular Carcinoma.

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 activa

SUBMITTER: Luo AL 

PROVIDER: S-EPMC12165036 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature