Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH)

Introduction: Cyclophilins are a family of diverse regulatory enzymes that have been studied for over 30 years; they participate in many pathophysiological processes. Genetic deletion or pharmacologic inhibition of cyclophilins has shown therapeutic effects in a wide spectrum of disease models, including liver disorders, and hence may be beneficial in treating nonalcoholic steatohepatitis (NASH).Areas Covered: This articles briefly describes cyclophilin isomerases and the main classes of cyclophilin antagonists; it then summarizes data showing cyclophilin participation in the major pathophysiological activities that occur in NASH.Expert Opinion: Optimization of therapeutic outcomes in the treatment of NASH may be best realized by targeting multiple pathologic pathways, especially when treating advanced stages of the disease. A preferred approach for achieving this goal is to use compounds such as cyclophilin inhibitors that simultaneously target multiple disease processes. The pleiotropic benefits of this drug class derive from the extraordinary functionality of prolyl isomerization as a regulatory mechanism and its evolutionary diversification into many biochemical pathways. Nonimmunosuppressive analogs of cyclosporine A are the most thoroughly characterized cyclophilin inhibitors and show significant potential to attenuate several of the major pathophysiological events in NASH - mitochondrial dysfunction, cellular injury and death, inflammation, and in particular, fibrosis.