Molecular Mechanisms and Potential New Therapeutic Drugs for Liver Fibrosis

Abstract

Liver fibrosis is the pathological process of excessive extracellular matrix deposition after liver injury and is a precursor to cirrhosis, hepatocellular carcinoma (HCC). It is essentially a wound healing response to liver tissue damage. Numerous studies have shown that hepatic stellate cells play a critical role in this process, with various cells, cytokines, and signaling pathways engaged. Currently, the treatment targeting etiology is considered the most effective measure to prevent and treat liver fibrosis, but reversal fibrosis by elimination of the causative agent often occurs too slowly or too rarely to avoid life-threatening complications, especially in advanced fibrosis. Liver transplantation is the only treatment option in the end-stage, leaving us with an urgent need for new therapies. An in-depth understanding of the mechanisms of liver fibrosis could identify new targets for the treatment. Most of the drugs targeting critical cells and cytokines in the pathogenesis of liver fibrosis are still in pre-clinical trials and there are hardly any definitive anti-fibrotic chemical or biological drugs available for clinical use. In this review, we will summarize the pathogenesis of liver fibrosis, focusing on the role of key cells, associated mechanisms, and signaling pathways, and summarize various therapeutic measures or drugs that have been trialed in clinical practice or are in the research stage.

Keywords: cytokines; extracellular matrix; hepatic stellate cells; liver fibrosis; traditional Chinese medicine.

FIGURE 1

Mechanisms of liver fibrosis. Liver injury is caused by a variety of stimuli that result in hepatocyte damage and the release of substances such as ROS; in response to persistent hepatocyte injury, HSCs and macrophages (including Kupffer cells) are activated, activated myofibroblasts increase and excessive ECM is produced, leading to the progression of liver fibrosis. The activation of hepatic stellate cells is a key step in the process of liver fibrosis. Many influential factors regulating HSC activation, proliferation, function, and survival have emerged as important therapeutic targets; likewise, protection of hepatocytes from damage and degradation of excessive ECM deposition provide therapeutic options. HSCs: Hepatic stellate cells CCL2:C-C chemokine ligands types 2; LPS: Lipopolysaccharide LSEC： Liver sinusoidal endothelial cells TIMP: inhibitors of matrix metalloproteinase; MMP: matrix metalloproteinase; DAMPS:damage-associated molecular patterns; ECM: extracellular matrix; ROS: reactive oxygen species.