Potentiating BSEP-mediated bile acid efflux reverses first-line tyrosine kinase inhibitor resistance in hepatocellular carcinoma

Cancer Lett. 2026 Jun 28:648:218453. doi: 10.1016/j.canlet.2026.218453. Epub 2026 Mar 26.

Abstract

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 accumulation of primary conjugated bile acids (BAs)-especially glycocholic acid (GCA)-which activates EGFR signaling and drives resistance; restoring BSEP enhances BA efflux and resensitizes cells and tumors to TKIs. Mechanistic assays revealed that ursodeoxycholic acid (UDCA) upregulated BSEP and reversed resistance via an FXR-independent mechanism: UDCA directly binds cortactin (CTTN), reduces its PRMT1-dependent mono-methylation, and promotes CTTN degradation via chaperone-mediated autophagy (CMA), thereby enabling YY1 nuclear translocation and transcriptional activation of BSEP. Clinical specimen analyses corroborated an inverse BSEP-CTTN relationship and UDCA modulation. These findings identify impaired BSEP-mediated BA efflux and GCA accumulation as metabolic features of TKI resistance and support targeting the CTTN/YY1/BSEP axis, including UDCA, to overcome resistance.

Keywords: BSEP; Bile acid; HCC; TKI-Resistance; UDCA.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11* / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 11* / metabolism
  • Animals
  • Bile Acids and Salts* / metabolism
  • Carcinoma, Hepatocellular* / drug therapy
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm* / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Liver Neoplasms* / drug therapy
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Mice
  • Mice, Nude
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Signal Transduction
  • Tyrosine Kinase Inhibitors
  • Xenograft Model Antitumor Assays

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • Protein Kinase Inhibitors
  • Bile Acids and Salts
  • ABCB11 protein, human
  • Tyrosine Kinase Inhibitors