Caspase inhibitors for the treatment of liver disease: friend or foe?

Because of the liver’s function in the body as both a filter for toxins and an innate immune organ, the liver is predisposed to cellular turnover. Under healthy conditions, this occurs through the removal of aging and damaged hepatocytes by apoptosis. However, in a diseased liver, pathological cell death often occurs. In the previous 20 years, there has been considerable discussion in the research community over the different types of cell death. Apoptosis has a complex signaling pathway that prototypically results in activation of caspases in hepatocytes, resulting in the degradation of cellular proteins and activation of DNases, which cleave nuclear DNA and induce cell death. As such, inhibition of caspases has routinely been tested in multiple models of liver disease as a potential means for reducing cell death. However, caspase inhibitors have failed to protect in many of these experiments. One reason discussed extensively was the fact that apoptosis was not the major mode of cell death in these models [1]. In addition, recent studies have indicated caspase inhibition can have profound effects outside of just inhibition of apoptotic cell death and may not always interrupt the cell death process in a sustainable fashion. The purpose of this editorial is to discuss caspase inhibition both as a clinical therapeutic option and as a component of the wider accepted mechanisms of hepatocyte cell death.