Fig. 8: A schematic illustration of the working model.

Sorafenib treatment-induced STING/IRF3/ISG15 axis activation contributes to USP18 accumulation, which promotes NCOA4 deISGylation and degradation. USP18-mediated NCOA4 deficiency impairs sorafenib-induced ferroptosis and leads to subsequent drug resistance. Hyperoside (HYP), a USP18 inhibitor, effectively enhances the sensitivity of cancer cells to sorafenib by specifically targeting the IBB1 domain and inhibiting the deISGylation process of NCOA4.