Mammalian cleavage factor 25 targets KLF14 to inhibit hepatic stellate cell activation and liver fibrosis

Liver fibrosis is primarily caused by the activation of hepatic stellate cells (HSCs), which results from chronic liver damage. Understanding the pathogenesis of HSC activation could identify new therapeutic targets to treat liver fibrosis. In this study, we examined the protective role of the mammalian cleavage factor I 25 kD subunit (CFIm25, NUDT21) in inhibiting hepatic stellate cell activation. CFIm25 expression was measured in liver cirrhosis patients and a CCl4-induced mouse model. Adeno-associated viruses and adenoviruses were used to alter hepatic CFIm25 expression in vivo and in vitro to investigate how CFIm25 functions in liver fibrosis. The underlying mechanisms were explored using RNA-seq and co-IP assays. Here, we found that CFIm25 expression was drastically decreased in activated murine HSCs and fibrotic liver tissues. CFIm25 overexpression down -regulated the expression of genes involved in liver fibrosis, inhibiting the progression of HSC activation, migration and proliferation. These effects resulted from direct activation of the KLF14/PPAR & gamma; signaling axis. KLF14 inhibition abrogated the CFIm25 overexpression-mediated reduction in antifibrotic effects. These data reveal that hepatic CFIm25 regulates HSC activation through the KLF14/PPAR & gamma; pathway as liver fibrosis pro-gresses. CFIm25 may be a novel therapeutic target for liver fibrosis.

Automated summary

Liver fibrosis is caused by the activation of hepatic stellate cells (HSCs) due to chronic liver damage. This study investigates the protective role of CFIm25 in inhibiting HSC activation and its underlying mechanisms. CFIm25 expression was found to be decreased in activated murine HSCs and fibrotic liver tissues. CFIm25 overexpression down-regulated fibrosis-related genes, inhibiting HSC activation, migration, and proliferation through the KLF14/PPARγ signaling axis. These findings suggest that CFIm25 may be a potential therapeutic target for liver fibrosis.