Hepatic fibrosis (HF) is the process of fibrous scar formation caused by chronic liver injury of different etiologies. Previous studies have hypothesized that the activation of hepatic stellate cells (HSCs) is the central process in HF. The interaction between HSCs and surrounding cells is also crucial. Additionally, hepatic sinusoids capillarization, inflammation, angiogenesis and fibrosis develop during HF. The process involves multiple cell types that are highly connected and work in unison to maintain the homeostasis of the hepatic microenvironment, which serves a key role in the initiation and progression of HF. The current review provides novel insight into the intercellular interaction among liver sinusoidal endothelial cells, HSCs and Kupffer cells, as well as the hepatic microenvironment in the development of HF.

MicroRNAs (miRNAs) are a class of short non-coding RNAs that play a crucial role in the post-transcriptional regulation of gene expression. They are associated with various biological processes related to tumors. Among the numerous miRNAs, miR-29 has garnered attention for its role in regulating tumor angiogenesis. In numerous human tumors, miR-29 has been demonstrated to negatively correlate with the capacity for angiogenesis and the degree of malignancy, as well as with the expression levels of pro-angiogenic factors such as vascular endothelial growth factor vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and matrix metalloproteinase (MMP)-2. Multiple studies, utilizing techniques like dual-luciferase reporter assays, have confirmed that miR-29 directly targets the 3'-untranslated region (UTR) of mRNAs for VEGF, PDGF, and MMP-2. Extensive investigations involving tumor cell lines and animal models have shown that the overexpression of miR-29, achieved through miRNA transfection or the introduction of miRNA mimics, effectively inhibits angiogenesis by upregulating these pro-angiogenic factors. Conversely, downregulation of miR-29 using specific inhibitors promotes angiogenesis. While small molecule inhibitors and antibodies targeting VEGF constitute a primary strategy in anti-angiogenesis therapies, miR-29's ability to target multiple pro-angiogenic molecules positions it as a promising candidate for future therapeutic interventions, especially with ongoing advancements in nucleic acid drug design and delivery systems.

Targeted therapeutics for liver fibrosis (LF) are unavailable. PU.1 is a pioneer transcription factor (TF) that promotes hepatic stellate cell (HSC) activation and LF. PU.1 decoy oligodeoxynucleotides (ODNs) can potentially repress LF by capturing PU.1. In this study, we used Apt-Tan, a hepatic stellate cell (HSC)-internalizing DNA aptamer selected through the cell systematic evolution of ligands by exponential enrichment (Cell-SELEX), and validated the anti-LF effect of a combination of Apt-Tan and PU.1 decoy ODN in mice. Furthermore, intravenous injection of Apt-Tan- PU.1 decoy ODN repressed the expression of PU.1 downstream pro-fibrotic genes such as TIMP1, alleviated liver injury, and reduced extracellular matrix deposition in mice model of LF induced by CCL₄. Apt-Tan- PU.1 decoy ODN demonstrated anti-fibrosis potential and warranted further investigation.

The excessive accumulation of extracellular matrix of hepatic fibrosis is positively correlated with tissue inhibitors of metalloproteinase 1 (TIMP1). Here we aimed to investigate whether TIMP1 may be down-regulated by Decoy ODNs strategy to capture transcriptional factor upstream TIMP1 element 1 (UTE1) and specificity protein 1(SP1). By luciferase reporter assays, we confirmed that these Decoy ODNs could influence the promoter activation of TIMP-1, α-SMA and Collagen Iα2 (COLΙα2) genes as well as the enhancer activation of TRE in HSC-T6 cells, and the combination tended to be more effective than SP1 or UTE1 Decoy ODN alone. Western blot analysis also demonstrated down-regulation of the expression of those target genes except for TGF-β. Furthermore, we observed that the viability of HSC-T6 cells at 72 h was significantly in decline in combination group. The combination of SP1 and UTE1 Decoy ODNs treatments inhibit the activation and proliferation of HSCs more effectively than one of the Decoy ODNs through co-regulation of TIMP1 and TGF-β signal pathway but not the expression of TGF-β itself.