Tyrosine kinase inhibitor (TKI) resistance limits therapy for hepatocellular carcinoma (HCC). Integrating RNA-seq and public cohort data, we found consistent downregulation of the bile salt export pump (BSEP/ABCB11) in TKI-resistant HCC associated with poorer prognosis and reduced clinical response. Functional in vitro and xenograft studies, using BSEP overexpression/knockdown and TKI-resistant cell lines plus targeted metabolomics, showed BSEP expression deficiency leads to intracellular accumu...