2. Academic Validation
  3. Potentiating BSEP-mediated bile acid efflux reverses first-line tyrosine kinase inhibitor resistance in hepatocellular carcinoma

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.
Zong Wu 1,  Yixiu Wang 1,  Bingran Yu 2,  Ruobing Yu 1,  Mo Chen 3,  Zhiwen Chen 1,  Jijun Shan 1,  Zhiwen Ding 1,  Jiaxi Li 4,  Xin Jin 1,  Yixin Chen 1,  Longrong Wang 1,  Hongxu Zhu 1,  Weiping Zhu 1,  Qi Pan 1,  Ti Zhang 1,  Yongfa Zhang 1,  Lei Lv 5,  Lu Wang 6,  Yiming Zhao 7
Affiliations

Affiliations

  • 1 Department of Hepatic Surgery, Fudan University, Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Shanghai 200032, China.
  • 2 Department of Pediatric Surgery, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Birth Defects, Shanghai 201102, China.
  • 3 Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 4 MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 5 MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 6 Department of Hepatic Surgery, Fudan University, Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Shanghai 200032, China. Electronic address: [email protected].
  • 7 Department of Hepatic Surgery, Fudan University, Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Shanghai 200032, China. Electronic address: [email protected].
PMID: 41903671 DOI: 10.1016/j.canlet.2026.218453
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.

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