Discovery of Novel Schisandrol B Simplification Derivatives as PXR Agonists to Promote Liver Regeneration

Abstract Partial hepatectomy (PHx) and liver transplantation are the most effective interventions for end-stage liver diseases, yet druggable targets that promote donor or remnant liver regeneration are critically lacking. Pregnane X receptor (PXR), a key regulator of liver regeneration, is a promising therapeutic target. Previously, we identified the natural product Schisandrol B (SolB) as a PXR agonist to promote liver regeneration. To further improve its PXR activity and selectivity, the present study performed structural simplification of SolB and identified BZZ-034, a ring-opened analogue with an isobutyl amide side chain, as a novel PXR agonist. BZZ-034 exhibited higher PXR binding affinity and stronger transcriptional efficacy than SolB, along with greater selectivity against related nuclear receptors. In vivo, BZZ-034 significantly promoted hepatomegaly and accelerated liver regeneration after PHx in mice. These findings identify BZZ-034 as a promising lead compound and demonstrate that structural simplification is an effective strategy for optimizing complex natural products.