Schisandrin B Promotes Hepatic Stellate Cell Ferroptosis via Wnt Pathway-Mediated Ly6C^lo Macrophages

A key event in liver fibrosis is the activation of the hepatic stellate cell (HSC). Schisandrin B (Sch B), a major component extracted from Schisandra chinensis, has been shown to inhibit HSC activation. Recently, ferroptosis (FPT) has been reported to be involved in HSC activation. However, whether Sch B has an effect on the HSC FPT remains unclear. Herein, we explored the effects of Sch B on liver fibrosis in vivo and in vitro and the roles of Wnt agonist 1 and ferrostatin-1 in the antifibrotic effects of Sch B. Sch B effectively alleviated CCl₄-induced liver fibrosis, with decreased collagen deposition and α-SMA level. Additionally, Sch B resulted in an increase in lymphocyte antigen 6 complex locus C low (Ly6C^lo) macrophages, contributing to a reduced level of TIMP1 and increased MMP2. Notably, the Wnt pathway was involved in Sch B-mediated Ly6C macrophage phenotypic transformation. Further studies demonstrated that Sch B-treated macrophages had an inhibitory effect on HSC activation, which was associated with HSC FPT. GPX4, a negative regulator of FPT, was induced by Sch B and found to be involved in the crosstalk between macrophage and HSC FPT. Furthermore, HSC inactivation as well as FPT induced by Sch B-treated macrophages was blocked down by Wnt pathway agonist 1. Collectively, we demonstrate that Sch B inhibits liver fibrosis, at least partially, through mediating Ly6C^lo macrophages and HSC FPT. Sch B enhances Wnt pathway inactivation, leading to the increase in Ly6C^lo macrophages, which contributes to HSC FPT. Sch B may be a promising drug for liver fibrosis treatment.