URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers. HEK293T cells were transfected with His-URI plasmid before anti-His immunoprecipitation and gel cutting. LC-MS/MS was performed to identify URI potential binding proteins.

URI keeps low levels of p53 in a TRIM28-MDM2 dependent manner, maintains SCD1 activity and accumulation of MUFAs, and subsequently promotes resistance to TKIs in cancer cell. URI-p53-SCD1 axis mediates resistance of TKIs and may explain why p53-wild type HCC still showed intrinsic resistance to TKIs. Moreover, the combination therapy identified here may represent a promising strategy for the approximately 41% of patients with advanced HCC who have wild-type p53 and high levels of URI/SCD1.