Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy

Abstract

Liver fibrosis is an abnormal wound repair response caused by a variety of chronic liver injuries, which is characterized by over-deposition of diffuse extracellular matrix (ECM) and anomalous hyperplasia of connective tissue, and it may further develop into liver cirrhosis, liver failure or liver cancer. To date, chronic liver diseases accompanied with liver fibrosis have caused significant morbidity and mortality in the world with increasing tendency. Although early liver fibrosis has been reported to be reversible, the detailed mechanism of reversing liver fibrosis is still unclear and there is lack of an effective treatment for liver fibrosis. Thus, it is still a top priority for the research and development of anti-fibrosis drugs. In recent years, many strategies have emerged as crucial means to inhibit the occurrence and development of liver fibrosis including anti-inflammation and liver protection, inhibition of hepatic stellate cells (HSCs) activation and proliferation, reduction of ECM overproduction and acceleration of ECM degradation. Moreover, gene therapy has been proved to be a promising anti-fibrosis method. Here, we provide an overview of the relevant targets and drugs under development. We aim to classify and summarize their potential roles in treatment of liver fibrosis, and discuss the challenges and development of anti-fibrosis drugs.

Keywords: drug therapy; extracellular matrix; hepatic stellate cells; liver fibrosis; targets.

FIGURE 1

Pathogenesis of liver fibrosis. Activation of HSCs is a crucial step of the occurrence and progression of liver fibrosis. Quiescent HSCs are activated to fibrogenic phenotype by DAMPs released by injured hepatocytes. Activated HSCs are continuously activated and proliferated by paracrine and autocrine. They secret abundant fibrogenic cytokines and produce excessive ECM, which causes the break of the balance of pro-fibrosis/anti-fibrosis mechanism. The pro-fibrosis mechanism leads to the abnormal formation of scar and eventually induces liver fibrosis (Tacke and Weiskirchen, 2012; Roehlen et al., 2020).

FIGURE 2

Therapeutic approaches of liver fibrosis. The liver fibrosis is induced when the balance of pro-inflammatory/anti-inflammatory, or apoptosis/proliferation of hepatocyte and HSCs, or production and deposition/degradation of ECM is destroyed (Campana and Iredale, 2017; Roehlen et al., 2020).