Hepatocyte iron suppresses liver fibrosis via fibrolytic neutrophil recruitment in cholestasis.

Background & Aims: Although it is well documented that iron promotes hepatocyte death in chronic liver disease, recent studies have suggested that iron in hepatocytes also has a protective role against such disease. However, the mechanisms underlying this beneficial role of iron remain poorly understood. Methods: F-box and leucine-rich repeat protein 5 (FBXL5) is a substrate recognition component of the SCF E3 ligase complex that restricts intracellular iron levels. To investigate the role of hepatic iron in the pathogenesis of cholestatic liver disease, liver-specific FBXL5-deficient or control mice were fed a diet supplemented with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (n = 3-12). Moreover, matrix metalloproteinase (MMP)-9 expression and liver fibrosis were analyzed in liver specimens obtained from 37 patients with primary biliary cholangitis (PBC). Results: Liver-specific FBXL5-deficient mice, which exhibit hepatic iron overload, were protected against liver fibrosis in cholestatic liver disease (Sirius red Conclusions: Our data link hepatocyte iron with fibrolysis pathways in the setting of chronic liver disease. Thus, the present study provides insights into the pro-resolving roles of neutrophils in cholestatic liver disease. Impact and implications: In this study, we show that hepatocyte iron suppresses liver fibrosis in cholestatic liver disease. Mechanistically, hepatocyte iron epigenetically upregulates CXCL5 expression, thereby promoting hepatic recruitment of MMP9