Non-alcoholic Steatohepatitis: Pathophysiologic Role of Iron in Liver Fibrosis

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Nonalcoholic steatohepatitis, recently redefined as metabolic dysfunction-associated steatohepatitis (MASH), is a progressive form of fatty liver disease characterized by chronic inflammation and tissue fibrosis, potentially leading to liver cirrhosis and cancer. The “multiple parallel hit” hypothesis offers a possible pathogenic mechanism of MASH, where metabolic alterations, including excessive lipid and iron accumulation, with inflammatory stimuli, contribute to its development. Although the liver is crucial for the regulation of iron metabolism, no treatments targeting iron metabolism have been developed for MASH. In addition to the well-studied mechanisms in hepatocytes, such as ferroptosis, we recently demonstrated that macrophages accumulate iron, leading to proinflammatory and profibrotic changes that drive MASH progression. Iron accumulation predominantly occurs in a unique histological structure, in which macrophages aggregate around dead hepatocytes. Advances in single-cell RNA sequencing have highlighted the diversity of macrophages, challenging the belief that only one type exists. Based on the localization and metabolic state of MASH livers, we identified a novel iron-rich macrophage subtype that promotes hepatic inflammation and fibrosis. Further studies, particularly on the detailed molecular mechanisms, will pave the way for the development of diagnostic and therapeutic strategies focusing on iron metabolism.

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