Senkyunolide A interrupts TRAF6-HDAC3 interaction to epigenetically suppress c-MYC and attenuate cholestatic liver injury

Cholestatic liver diseases are highly prevalent and lack effective treatment, ultimately progressing to end-stage liver diseases. Our recent study indicates that the interplay between c-MYC and lncRNA H19 exacerbates the ductular reaction during cholestasis. However, the underlying mechanisms and their potential as therapeutic targets remain unclear. In this study, we demonstrate that senkyunolide A (SenA) effectively mitigates cholangiocyte hyperproliferation by epigenetically suppressing c-MYC expression and disrupting the downstream H19/Let-7a/Lin28a axis. Through comprehensive characterization using CHIP analysis, protein truncation, amino acid mutation or deletion, and the development of SenA derivatives, we identified a potential interaction between the carbonyl group in SenA and Arg483 in TRAF6, disrupting the TRAF6-HDAC3 complex. This dissociation facilitates the binding of HDAC3 to the MYC promoter region, resulting in enhanced histone deacetylation and transcriptional suppression. Here, we highlight the therapeutic potential of SenA in cholestatic liver diseases by elucidating its role in epigenetic regulation.