MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression

TLDR

Hedgehog signaling drives hepatic fibrogenesis, yet the role of microRNAs in liver fibrosis remains poorly understood. The study aims to characterize how miRNAs are regulated in chronically damaged, fibrotic liver. Smoothened suppresses miR‑378a‑3p transcription by activating the p65 subunit of NF‑κB. Reduced miR‑378a‑3p in CCl₄‑treated livers and its overexpression, which lowers Gli3 and profibrotic genes while inducing the HSC inactivation marker GFAP, demonstrate that miR‑378a‑3p targets Gli3 and holds therapeutic promise for liver fibrosis.

Abstract

Abstract Hedgehog (Hh) signalling regulates hepatic fibrogenesis. MicroRNAs (miRNAs) mediate various cellular processes; however, their role in liver fibrosis is unclear. Here we investigate regulation of miRNAs in chronically damaged fibrotic liver. MiRNA profiling shows that expression of miR-378 family members (miR-378a-3p, miR-378b and miR-378d) declines in carbon tetrachloride (CCl 4 )-treated compared with corn-oil-treated mice. Overexpression of miR-378a-3p, directly targeting Gli3 in activated hepatic stellate cells (HSCs), reduces expression of Gli3 and profibrotic genes but induces gfap , the inactivation marker of HSCs, in CCl 4 -treated liver. Smo blocks transcriptional expression of miR-378a-3p by activating the p65 subunit of nuclear factor-κB (NF-κB). The hepatic level of miR-378a-3p is inversely correlated with the expression of Gli3 in tumour and non-tumour tissues in human hepatocellular carcinoma. Our results demonstrate that miR-378a-3p suppresses activation of HSCs by targeting Gli3 and its expression is regulated by Smo-dependent NF-κB signalling, suggesting miR-378a-3p has therapeutic potential for liver fibrosis.