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
  • 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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