The liver is a complex heterogeneous organ made up of various cell types. In the hepatic architecture, parenchymal cells known as hepatocytes and different nonparenchymal cells, such as immune cells and stromal cells, are dispersed. These cells compose the liver microenvironment regulating liver homeostasis and liver function in a normal state. However, chronic liver disease shifts the character of the liver microenvironment by resulting in a change of activities and characteristics of liver cells. In the early stage of liver disease, nonparenchymal cells sensitively respond to liver damage by secreting cytokines and induce the transition of the liver microenvironment to the proinflammatory characteristic. Chronic hepatitis supports tumor growth by reducing antitumor immunity, recruiting stromal cells, and causing the differentiation of hepatocytes. Ultimately, a formed proinflammatory microenvironment is converted into a protumoral microenvironment promoting the development of hepatocellular carcinoma.
Phosphorylation and dephosphorylation are reversible posttranslational modifications of proteins that generally regulate the activation and inhibition of intracellular signaling pathways. According to recent studies, phosphatases can regulate hepatocellular carcinoma progression by determining the characteristics of the liver microenvironment via the regulation of intracellular signaling pathways in liver cells. Therefore, this review highlights the importance of protein phosphatases in regulating the cellular components of the liver microenvironment and their significance as therapeutic targets.