Work

Vincamine ameliorates hepatic fibrosis via inhibiting S100A4‐mediated farnesoid X receptor activation: based on liver microenvironment and enterohepatic circulation dependence

Year: 2025

Type: article

Abstract: BACKGROUND AND PURPOSE: Vincamine has extensive biological and pharmaceutical activity. We examined the hepatoprotective effects and mechanisms by which vincamine suppresses hepatic fibrosis. EXPERIMENTAL APPROACH: Hepatic stellate cells (HSCs), TGF-β stimulated, were cultured with either vincamine, farnesoid X receptor (NR1H4; FXR) agonist or antagonist. Further, C57BL/6 mice were given thioacetamide (TAA) to induce hepatic fibrosis and subsequently treated with vincamine or curcumin. KEY RESULTS: Vincamine regulated the deposition of extracellular matrix (ECM), inflammatory factors and S100A4, and up-regulated FXR and TGR5 (GPBA receptor) in activated HSCs, by activating FXR. FXR deficiency blocked vincamine effect on FXR, TGR5, α-smooth muscle actin (α-SMA) and IL1R1 in activated LX-2 cells. Vincamine corrected ECM imbalance, inflammatory secretion and FXR/TGR5 down-regulation in activated LX-2 cells with stimulating medium from LPS-primed THP-1 cells. S100A4 deficiency increased FXR and TGR5, and decreased IL-1β expression in activated THP-1. Further, S100A4 deficiency in activated macrophages could elevate FXR and TGR5 expression in activated LX-2, strengthening the impact of vincamine on α-SMA and IL-1β expression. Further, vincamine reduced serum ALT/AST levels, liver and intestinal histopathological changes, and caused ECM accumulation and protected the intestinal barrier in thioacetamide-induced hepatic fibrosis mice. Vincamine decreased inflammatory factors e.g. caspase 1 and IL-1β, and inhibited the S100A4-mediated FXR-TGR5 pathway. CONCLUSION AND IMPLICATIONS: Vincamine significantly reverses hepatic fibrosis via inhibiting S100A4 involved in the crosstalk between macrophages and HSCs, and by activating the FXR-TGR5 pathway. Targeting the S100A4-mediated FXR dependence on modulating the liver environment may be the key target of vincamine in inhibiting hepatic fibrosis.

Source: British Journal of Pharmacology

DOI: 10.1111/bph.17471