Chronic liver diseases (CLDs) are a heterogeneous group of disorders that involve progressive damage to the liver cells, leading to inflammation, metabolic disorders, and fibrosis. There is increasing evidence that abnormal iron metabolism is an important contributing factor in CLDs that intersects with immune, metabolic, and microbial pathways. At the core of systemic iron metabolism is the hepcidin–ferroportin pathway, whereby hepatic hepcidin regulates iron export and distribution. Hepcidin signaling is abnormal in CLDs with varying etiology‐specific patterns of iron overload or functional iron sequestration. In parallel with these advances in iron metabolism is the gut–liver axis in microbiota‐driven iron metabolism and hepatic inflammation. Gut microbiota imbalance affects iron absorption in the gut, inflammatory pathways, and hepatic hepcidin signaling through microbial metabolites, immune activation through endotoxin, and bile acid pathways. Another key player in CLDs is the iron‐dependent form of programmed cell death called ferroptosis through lipid peroxidation pathways. Ferroptosis is an important pathway in CLDs that links abnormal iron metabolism with hepatocyte damage, immune activation, and fibrosis progression. Ferroptosis pathways are cell‐type specific; although they cause damage to hepatocytes, they may also prevent fibrosis through the killing of activated hepatic stellate cells. In this review article, we will explore the current evidence on the interaction between abnormal iron metabolism through the hepcidin–ferroportin pathway, gut microbiota imbalance, and the new player in CLDs, the ferroptosis pathway. Although many of these pathways are still in the preclinical or early clinical stages of intervention, an understanding of the iron–microbiota–ferroptosis triad provides an important platform for understanding CLDs through the identification of new targets for intervention.
Dash et al. (Thu,) studied this question.