Tanshinone IIA alleviates liver fibrosis by suppressing hepatic stellate cell proliferation via ERK/cyclin D۱/p-Smad۳L signaling axis

Objective(s): Liver fibrosis (LF) is a critical stage in chronic liver disease progression, and effective therapeutic drugs are currently lacking. Tanshinone IIA (Tan IIA), a monomer extracted from Salvia miltiorrhiza, shows potential in treating LF. This research aims to discuss the antifibrotic efficacy and underlying pharmacological mechanism of Tan IIA. Materials and Methods: The in vivo model was induced with CCl۴ to form a LF model in mice, and the in vitro model was induced by TGF-β۱ in LX-۲ and HSC-T۶ cells. Liver pathology was characterized by HE, Masson, and Sirius red staining, and serum levels of ALT, AST, LDH, and γ-GT were examined. Cell viability and proliferation were detected by Cell Counting Kit-۸ and colony formation assays. Cell cycle distribution was detected by flow cytometry. The protein levels of p-ERK, cyclin D۱, CDK۴, and p-Smad۳L were assessed through Western blot, immunohistochemistry, or immunofluorescence assays.Results: Tan IIA markedly decreased serum levels of ALT, AST, LDH, and γ‐GT. Collagen I and α-SMA were reduced, as shown by in vitro and in vivo models. Moreover, while arresting HSCs in the G۱ phase was increased, Tan II A markedly inhibited cell viability and colony formation. Mechanistically, Tan IIA decreased the expression of p-ERK, cyclin D۱, CDK۴, and p-Smad۳L proteins in TGF-β۱-activated cells and CCl۴-induced mice.Conclusion: Tan IIA may improve LF by regulating the signaling axis of ERK/cyclin D۱/p-Smad۳L, thereby blocking activated HSCs in the G۱ phase and inhibiting their proliferation.

کلیدواژه ها:

ERK/cyclin D۱/p-Smad۳L - signaling ، Hepatic stellate cells ، Liver fibrosis ، Tanshinone IIA ، TGF-β۱