Targeting FGG alleviates cholestatic fibrosis by inhibiting hepatic stellate cell activation and regulating macrophage homeostasis.

BACKGROUND &

aimsCholestatic liver injury is a serious pathological process with limited treatment options. The function of fibrinogen gamma chain (FGG) in the liver is not well defined. This study aims to explore the role of FGG in the progression of cholestatic liver fibrosis, and to find a new target for the treatment of cholestatic liver fibrosis.

resultsA BDL induced mouse model and LX2 cell line, as well as a co-culture system of LX2 and THP-1, were used. Gene expression, cell activation and polarization were evaluated by qRT-PCR, Western Blot, RNA-seq, and immunofluorescence. 4-Octyl itaconate (OI) was used to block the M2 polarization, and an AEAA-modified lipid nanoparticle (LNP) was developed as a platform for targeted delivery of siFGG, and its therapeutic efficacy was evaluated in vitro and in vivo. In the BDL mouse, FGG expression was significantly increased and mainly localized to activated hepatic stellate cells (HSCs). In vitro experiments confirmed that FGG directly regulated the activation state of HSCs. Overexpression of FGG in mice significantly promoted the development of liver fibrosis. Further studies revealed that FGG specifically promoted macrophage polarization toward the M2 phenotype. Co-culture experiments demonstrated that FGG was a key factor driving M2 polarization of macrophages. The siFGG delivered by AEAA-LNP effectively knocked down the expression of FGG, thereby inhibiting HSC activation, disrupting the crosstalk between HSC and M2 macrophages, and ultimately significantly alleviating BDL induced liver fibrosis in vitro and in vivo.

conclusionsThis study identifies FGG as a key fibrosis promoter that acts through simultaneous HSC activation and M2 macrophage polarization. Targeting FGG with a novel AEAA-LNP system offers a potent dual-mechanism therapy for liver fibrosis.