Targeting USP18 overcomes acquired resistance in hepatocellular carcinoma by regulating NCOA4 deISGylation and ferroptosis

Targeted therapy resistance has become a major challenge for hepatocellular carcinoma (HCC) treatment. Triggering ferroptosis emerges as a promising strategy to overcome therapeutic resistance. Here, we have identified ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating enzyme family, contributing to HCC resistance by inhibiting sorafenib-induced ferroptosis. Nuclear receptor coactivator 4 (NCOA4), a crucial regulator of ferroptosis, turned out to be a novel downstream effector of USP18 and is posttranslationally suppressed. Such regulation is based on the USP18-mediated deISGylation and degradation process. Additionally, we have demonstrated that sorafenib promotes USP18 accumulation in HCC via the STING/IRF3/ISG15 axis. Importantly, we screened and identified hyperoside (HYP) as a new USP18 enzyme activity inhibitor, which sensitizes cancer cells to existing targeted therapies (sorafenib and regorafenib) by inhibiting USP18 and following deISGylation of NCOA4. Collectively, our study has uncovered a novel mechanism of acquired sorafenib resistance and offers a promising combination therapy strategy for overcoming therapeutic resistance in HCC.