Iron as a therapeutic target in chronic liver disease

Abstract

It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.

Keywords: Iron overload, Liver disease, Ferroptosis, Ferritinophagy, Ferroptosis modulators

Core Tip: Iron overload may damage the liver in a variety of liver diseases such as cirrhosis and hepatocellular carcinoma affecting patient survival. In this review, we present the evidence, both experimental and clinical, of the detrimental effects of iron deposition in hepatocytes and other liver sinusoidal cells. Moreover, we examine the mechanism and implications of the recently described ferroptosis in the evolution of liver disease. Ferroptosis is a form of regulated hepatocyte death caused by excess iron and lipid peroxidation. Inhibition or induction of ferroptosis may profoundly improve the course of many liver diseases as demonstrated by a large number of experimental studies as well as a small number of clinical trials.