Liver Fibrosis Resolution: From Molecular Mechanisms to Therapeutic Opportunities

Abstract

The liver is a critical system for metabolism in human beings, which plays an essential role in an abundance of physiological processes and is vulnerable to endogenous or exogenous injuries. After the damage to the liver, a type of aberrant wound healing response known as liver fibrosis may happen, which can result in an excessive accumulation of extracellular matrix (ECM) and then cause cirrhosis or hepatocellular carcinoma (HCC), seriously endangering human health and causing a great economic burden. However, few effective anti-fibrotic medications are clinically available to treat liver fibrosis. The most efficient approach to liver fibrosis prevention and treatment currently is to eliminate its causes, but this approach's efficiency is too slow, or some causes cannot be fully eliminated, which causes liver fibrosis to worsen. In cases of advanced fibrosis, the only available treatment is liver transplantation. Therefore, new treatments or therapeutic agents need to be explored to stop the further development of early liver fibrosis or to reverse the fibrosis process to achieve liver fibrosis resolution. Understanding the mechanisms that lead to the development of liver fibrosis is necessary to find new therapeutic targets and drugs. The complex process of liver fibrosis is regulated by a variety of cells and cytokines, among which hepatic stellate cells (HSCs) are the essential cells, and their continued activation will lead to further progression of liver fibrosis. It has been found that inhibiting HSC activation, or inducing apoptosis, and inactivating activated hepatic stellate cells (aHSCs) can reverse fibrosis and thus achieve liver fibrosis regression. Hence, this review will concentrate on how HSCs become activated during liver fibrosis, including intercellular interactions and related signaling pathways, as well as targeting HSCs or liver fibrosis signaling pathways to achieve the resolution of liver fibrosis. Finally, new therapeutic compounds targeting liver fibrosis are summarized to provide more options for the therapy of liver fibrosis.

Keywords: fibrosis regression; hepatic stellate cells; liver fibrosis; therapeutic compounds.

Figure 1

Hepatic stellate cells in the progression and regression of liver fibrosis. Quiescent hepatic stellate cells are activated when the liver is damaged. Many cells, including hepatocytes, liver sinusoidal endothelial cells, macrophages, TGF-β, and PDGF signal pathways, are involved in this process, which leads to the proliferation of aHSCs, and excessive secretion of ECM proteins, and eventually cirrhosis. Inhibition of HSC proliferation, induction of HSC death, or inactivation of HSCs can reverse hepatic fibrosis. qHSCs: quiescent hepatic stellate cells. TGF-β: transforming growth factor-β. PDGF: platelet-derived growth factor. DAMPs: damage-associated molecular patterns. ROS: reactive oxygen species. aHSCs: activated hepatic stellate cells. LSEC: liver sinusoidal endothelial cell. MMPs: matrix metalloproteinases. TIMPs: tissue inhibitors of matrix metalloproteinases. ECM: extracellular matrix. iHSC: inactivated hepatic stellate cell.

Figure 2

Therapeutic compounds for liver fibrosis resolution. Inhibition of HSC proliferation, induction of HSC death, or inactivation of HSCs and inhibition of liver fibrosis-related signal pathways can reverse liver fibrosis. Various compounds, including natural and synthetic compounds, have been found to have therapeutic effects in various animal models of liver fibrosis. Meanwhile, in order to improve the utilization rate of therapeutic drugs, a variety of nano-drug delivery systems are also used in the treatment of liver fibrosis. aHSC: activated hepatic stellate cell. HSC: hepatic stellate cell. TGF-β: transforming growth factor-β. TAA: thioacetamide. CCl₄: carbon tetrachloride. BDL: bile duct ligation. DEN: diethylnitrosamine. DMN: dimethylnitrosamine.