Liver fibrosis (LF) is the result of a vicious cycle between inflammation‐induced chronic hepatocyte injury and persistent activation of hepatic stellate cells (HSCs). Mesenchymal stem cell (MSC)‐based therapy may represent a potential remedy for treatment of LF. However, the fate of transplanted MSCs in LF remains largely unknown. In the present study, the fate and antifibrotic effect of MSCs were explored in a LF model induced by CCl4 in mouse. Additionally, MSCs were stimulated in vitro with LF‐associated factors, tumor necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ), and transforming growth factor‐β1 (TGF‐β1), to mimic the LF microenvironment. We unveiled that MSCs exhibited autophagy in response to the LF microenvironment through Becn1 upregulation both in vivo and in vitro. However, autophagy suppression induced by Becn1 knockdown in MSCs resulted in enhanced antifibrotic effects on LF. The improved antifibrotic potential of MSCs may be attributable to their inhibitory effects on T lymphocyte infiltration, HSCs proliferation, as well as production of TNF‐α, IFN‐γ, and TGF‐β1, which may be partially mediated by elevated paracrine secretion of PTGS2/PGE2. Thus, autophagy manipulation in MSCs may be a novel strategy to promote their antifibrotic efficacy.

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