Salvianolic acid C attenuates liver fibrosis and inhibites hepatic stellate cell activation by targeting FAP/TβRI/SMAD axis.

Liver fibrosis remains a major clinical challenge with limited effective therapeutic options. Salvianolic acid C (SAC), a major water-soluble compound derived from Salvia miltiorrhiza, has shown anti-fibrotic activity in various disease models; however, its role and underlying mechanisms in liver fibrosis remain unclear. A CCl4-induced mouse model was used to assess the in vivo anti-fibrotic activity of SAC. LX-2 hepatic stellate cells (HSCs) were used to investigate the underlying mechanisms in vitro. Network pharmacology, machine learning, molecular docking and molecular dynamics simulations were integrated to identify potential targets. Western blotting and immunohistochemistry were used to validated the key findings in vitro and in vivo. SAC significantly reduced collagen deposition and alleviated hepatic injury in CCl4-induced murine models. It also inhibited the expression of Col1a1, α-SMA, and Timp1 both in vivo and in vitro. FAP was implicated as a potential target of SAC, and SAC promotes FAP degradation in HSCs, thereby reducing FAP protein levels and inhibiting HSC activation in a FAP-dependent manner. SAC treatment significantly downregulated TβRI expression and inhibited SMAD phosphorylation, and these effects were attenuated by FAP overexpression. SAC attenuated liver fibrosis and inhibited HSC activation by targeting FAP to suppress the TβRI/SMAD signaling pathway. This finding underscores its potential as a therapeutic agent for liver fibrosis and provides a basis for further drug development.