Targeting X-box-binding protein-1 by Decoy oligodeoxynucleotide modulates fibrogenic features of activated hepatic...

Because of their pivotal role in liver fibrosis, activated hepatic stellate cells (aHSCs) may serve as a promising target for innovative medical treatments. Endoplasmic reticulum stress activation through inositol-requiring enzyme1 (IRE1)-X-box-binding protein-1 (XBP1) is a significant event associated with hepatic stellate cells (HSC) activation. We evaluated the potential impact of treatment with XBP1-specific decoy oligodeoxynucleotide (ODN) on modulation of aHSC. To activate HSCs, LX-2 cells were treated with transforming growth factor β (5 ng/mL). Meanwhile, the sequence of XBP1-specific decoy ODN was designed using the JASPAR (open-access transcription factor binding profile data base) and CLC Main Workbench (Qiagen) software. The outcome of treatment with ODN on aHSC was analyzed using quantitative reverse transcription polymerase chain reaction, immunoblotting, scratch assay, and ELISA. Transfection of activated LX-2 cells with 1 μg XBP1 decoy ODN downregulated the expression level of lysyl oxidase, tissue inhibitor of matrix metalloproteinase, α-smooth muscle actin, and fibronectin genes. In addition, the immunoblotting analysis and ELISA assay showed that XBP1 decoy ODN significantly reduced protein expression of α-smooth muscle actin and collagen secretion, respectively, compared to control cells. Our research may lead to innovative treatments for liver fibrosis, providing hope for better outcomes for patients with this chronic condition. SIGNIFICANCE STATEMENT: This study applied a novel decoy oligodeoxynucleotide targeting X-box-binding protein-1 to suppress the activation of hepatic stellate cells, a key driver of liver fibrosis. By modulating endoplasmic reticulum stress and fibrogenic gene expression, this strategy offers a promising therapeutic avenue for chronic liver diseases.