WTAP resists cholestatic liver injury by m 6 A-IGF2BP1-dependent regulation of the nuclear receptor FXR

Background Cholestatic liver injury is characterised by bile acid accumulation, hepatocyte damage and inflammatory response, leading to fibrosis and potential cirrhosis. Wilms’ tumour-1 associated protein (WTAP), a key regulator of N6-methyladenosine (m6A) modification, plays a crucial role in various diseases. However, the role of WTAP-mediated m6A modification in cholestatic liver diseases has been rarely studied. Objective This research aims to demonstrate the crucial function and underlying mechanism of WTAP in cholestasis, providing a novel therapeutic target. Design Hepatic WTAP expression was analysed in cholestatic patients and mice. Hepatocyte-specific WTAP knockout mice were generated via CRISPR/Cas9. Liver pathophysiological and immune-metabolic changes were assessed by multi-omics and molecular assays. Mechanistic experiments including m6A profiling, nucleic acid immunoprecipitation and dual-luciferase reporter assays were performed to explore WTAP function. Rescue experiments were conducted with adeno-associated virus-mediated farnesoid X receptor (FXR) overexpression and FXR agonists. Results WTAP was upregulated in cholestatic patients and correlated with disease severity. WTAP knockout exacerbated cholestasis and liver injury, with increased bile acid accumulation, inflammation and fibrosis, whereas WTAP overexpression alleviated these phenotypes. Mechanistically, bile acids induced WTAP transcription in a STAT3-dependent manner. WTAP depletion reduced m6A modification and transcript stability of FXR, a key bile acid metabolism regulator, in an IGF2BP1-dependent manner. FXR overexpression partially reversed liver injury in WTAP knockout mice. Conclusions Hepatocyte WTAP regulates the function of FXR in cholestasis through an m6A-IGF2BP1-dependent mechanism. Targeting WTAP may be a crucial strategy for treating cholestatic liver diseases.