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Liver fibrosis is the most common pathway in most types of chronic liver damage, characterized by an imbalance of ECM degradation and synthesis. Saikosaponin-d (SSd) possesses anti-inflammatory and anti-fibrotic effects. However, the underlying mechanism by which SSd represses hepatic stellate cell (HSC) activation remains unclear. Here, we found that SSd remarkably alleviated carbon tetrachloride (CCl 4 )-induced liver fibrosis, as evidenced by decreased collagen levels and profibrotic marker (COl1a1 and α-smooth muscle actin (SMA)) expression. SSd repressed CCl 4 -induced NOD-like receptor family pyrin-domain-containing-3 (NLRP3) activation in fibrotic livers, as suggested by decreased levels of NLRP3, IL-18, and IL-β. The primary HSCs of CCl 4  mice exhibited a significant increase in profibrotic marker expression and NLRP3 activation, but SSd treatment reversed this effect. SSd also repressed TGF-β-induced profibrotic marker expression and NLRP3 activation in vitro. Mechanistically, TGF-β decreased the expression of estrogen receptor-β (ERβ) in HSCs, whereas SSd treatment reversed this effect. ERβ inhibition enhances NLRP3 activation in HSCs. More importantly, ERβ or NLRP3 inhibition partially destroyed the function of SSd in liver fibrosis. In summary, the current data suggest that SSd prevents hepatic fibrosis by regulating the ERβ/NLRP3 inflammasome pathway and suggests SSd as a potential agent for treating liver fibrosis.

Saikosaponin-d protects against liver fibrosis by regulating the estrogen receptor-β/NLRP3 inflammasome pathway