Iron‐related intercellular communication in the liver: Main players and mechanisms

BACKGROUND: The liver is widely recognized as a central hub for metabolic processes. Additionally, it plays critical roles in immune responses and in the regulation of iron homeostasis. Liver disorders have a profound impact on overall health and often involve iron dysregulation. Different cell types contribute to the completion of the plethora of different liver functions, including iron homeostasis. METHODS: A comprehensive literature search was conducted to identify recent advances in the understanding of the main mechanisms of intercellular communication in the liver that determine iron regulation and flow in health and disease. RESULTS: Hepatocytes are crucial to secure proper and safe iron storage and to regulate systemic iron distribution. For that, they contribute with the production of key proteins, such as ferritin, transferrin and hepcidin. Hepcidin production by hepatocytes is regulated by other liver cell types, including endothelial cells and macrophages. Macrophages significantly contribute to iron homeostasis by recycling iron from erythrocytes. Moreover, they modulate the physiology of other liver cells through the production of cytokines. Paracrine communication, involving soluble factors, extracellular vesicles or mitochondrial transfer, has been described as important mechanisms of iron regulation in the liver, critically contributing to its pathophysiology. Juxtacrine communication involving gap junctions or tunnelling nanotubes are mechanisms under investigation. This review highlights the recent advances in our understanding of the main mechanisms of intercellular communication in the liver that determine iron regulation and flow in health and disease. CONCLUSIONS: Iro-nrelated communication between different liver cell types is fundamental to maintaining its proper function.