Schisandrin B targets cannabinoid 2 receptor in Kupffer cell to ameliorate CCl4-induced liver fibrosis by suppressing NF-κB and p38 MAPK pathway.

BACKGROUND: Lignans, the major bioactive components of Schisandra chinensis, displays an anti-liver fibrosis effect. However, which one is the most effective lignan and what is its molecular mechanisms are still unclear. PURPOSE: This research aimed to screen the most effective components of lignans, identify and verify its pharmacological target, and investigate its molecular mechanism against liver fibrosis. METHODS: First, the most effective lignans were screened by a comprehensive RAW264.7/CMC system and LPS-induced RAW264.7. Second, the potential targets were predicted by a liver fibrosis domain-specific chemo-genomics knowledgebase and further verified by competition binding assay. Third, the effect of anti-liver fibrosis was evaluated by employing RAW264.7, co-cultured hepatic stellate cells (HSC) and CCl4-induced liver fibrosis CB2-/- mice. The qPCR, ELISAs, western blot analyses, and immunofluorescence were used to evaluate the expression of main inflammatory factors and key proteins in NF-κB and p38 MAPK pathway. RESULTS: Schisandrin B was identified as the most effective component for attenuating liver fibrosis, and CB2 was proven to be a potential target for anti-liver fibrosis. The in vitro and in vivo assays indicated that schisandrin B ameliorated CCl4-induced liver fibrosis through suppressing NF-κB and p38 MAPK pathway in Kupffer cells by targeting CB2 receptor CONCLUSION: Schisandrin B targets CB2 receptor to inhibit Kupffer cell polarization by downregulating the NF-κB and p38 MAPK signaling pathways for ameliorating liver fibrosis.