Picroside II promotes HSC apoptosis and inhibits the cholestatic liver fibrosis in Mdr2^-/- mice by polarizing M1 macrophages and balancing immune responses

Liver fibrosis is characterized by chronic inflammatory responses and progressive fibrous scar formation. Macrophages are central characters of the pathogenesis of hepatic fibrosis by reconstructing the immune microenvironment. Picroside II (PIC II) is extracted from the Picrorhizae rhizoma and has been reported to exert a therapeutic potential on multiple liver damage. However, the mechanisms by which macrophage polarization initiates immune cascades and further contributes to the development of liver fibrosis and whether this process can be influenced by PIC II remains unclear. In the current study, RNA-sequencing and multiple molecular approaches were applied for exploring the underlying mechanism of PIC II against liver fibrosis in multidrug-resistance protein 2 knockout (Mdr2^-/-) mice. We found that PIC II activated M1-polarized macrophage to recruit NK cells, which might be dependent on the CXCL16-CXCR6 axis. Also, PIC II facilitated the apoptosis of activated hepatic stellate cells (aHSCs) accompanied by the enhanced cytotoxic effects of NK cells and attenuated formation of neutrophil extracellular traps (NETs). Notably, these PIC II-associated anti-hepatic fibrosis effects were largely reversed by macrophage depletion in Mdr2^-/- mice. Collectively, our research suggests that PIC II is a potential candidate for halting the progression of liver fibrosis.