FXR splicing by SF3B3 promotes MYC-driven hepatocarcinogenesis

BACKGROUND AND AIMS: Dysregulation of the MYC oncogene is a major genetic event in hepatocellular carcinoma (HCC). Farnesoid X receptor (FXR), a bile acid (BA) receptor, has emerged as a promising therapeutic target for various liver diseases. Both BA composition and FXR isoforms have been shown to be significantly altered in human HCCs. This study aimed to investigate their potential roles in MYC-driven hepatocarcinogenesis. APPROACH AND RESULTS: HCC was induced in mice by hydrodynamic injection with MYC and MCL1 oncogenes. UPLC-MS/MS analysis revealed elevated BA levels, particularly primary conjugated BAs, in both serum and livers of MYC-driven HCC mice. qPCR and western blot analyses demonstrated suppression of BSEP and dysregulation of FXR splicing in the livers of these mice. Using RNA antisense purification coupled with mass spectrometry (RAP-MS), the splicing factor SF3B3 was identified as a regulator of FXR splicing. Both in silico and in vitro studies confirmed that SF3B3 is a direct downstream target of MYC in mice and humans. Functionally, overexpression of Fxrα2 and Fxrα4 or deletion of Sf3b3 significantly impeded MYC-driven hepatocarcinogenesis in mice. Moreover, combination treatment with a SF3B inhibitor and an FXR agonist synergistically suppressed proliferation of HCC cells. Analysis of clinical HCC samples revealed a positive correlation between SF3B3 and the relative expression of FXRα2. Conclusions: SF3B3 is a key downstream effector of MYC-driven hepatocarcinogenesis and a critical regulator of FXR splicing. Both SF3B3 and FXR represent druggable vulnerabilities in MYC-amplified HCC.