Let-7 suppresses liver fibrosis by inhibiting hepatocyte apoptosis and TGF-I3 production

Objective: FAS-mediated apoptosis of hepatocytes and aberrant TGF-I3 signaling are major drivers of liver fibrosis. Decreased miRNA let-7 expression in the livers of patients and animals with fibrosis suggests a mechanistic link of let-7 to hepatic fibrogenesis. Methods: Using transient transfection we tested the effects of let-7 overexpression and TET3 siRNA knockdown on FAS and TGF-I31 expression and FAS-mediated apoptosis in human and mouse primary hepatocytes. We assessed the therapeutic activity of let-7 miRNA delivered via adeno-associated viral vectors in mouse models of carbon tetrachloride (CCl4)-induced and bile duct ligation (BDL)-induced liver fibrosis. Results: Let-7 decreased TGF-I31 production from hepatocytes through a negative feedback loop involving TET3. On the other hand, let-7 post-transcriptionally inhibits FAS expression, thereby suppressing hepatocyte apoptosis. Hepatic-specific delivery of let-7 miRNA mitigated liver fibrosis in both CCl4 and BDL mouse models. Conclusions: Let-7 is a crucial node in the signaling networks that govern liver fibrosis progression. Let-7 and/or its derivatives may be used as therapeutic agents for liver fibrosis. (c) 2023 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).