The research team of Professor Chang-Yeop Han (School of Pharmacy), Jeonbuk National University (JBNU), and the collaborative research team led by Professor Won Kim of Boramae Hospital, Seoul National University College of Medicine, have identified a new pathogenic mechanism of metabolic dysfunction-associated steatotic liver disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease. Its prevalence has been steadily increasing worldwide, including in Korea, alongside rising rates of obesity. However, current pharmacological treatment options are very limited, making it important to understand the mechanisms of disease onset and progression and to discover new therapeutic strategies.

As the name implies, MASLD is closely associated with metabolic disorders such as obesity and diabetes. However, the specific molecular mechanisms by which these conditions influence each other are not yet fully understood.

The researchers focused on iron accumulation within tissues, which is commonly observed in chronic liver disease and metabolic disorders. Although clinical studies have reported correlations between iron accumulation and disease, it remained unclear how cell- and tissue-specific dysregulation of iron homeostasis contributes to the pathological processes of these diseases.

The study found increased iron accumulation in hepatocytes of patients with MASLD, which was associated with reduced expression of the iron transporter protein ferroportin (FPN). Using hepatocyte-specific ferroportin-deficient mice and a high-fat diet model, the researchers demonstrated that iron accumulation within hepatocytes directly contributes to weight gain, insulin resistance, and the development of diabetes.

Notably, the team was the first to demonstrate that this phenomenon is mediated by hepatokines—endocrine factors secreted by the liver that affect other tissues. Iron accumulated in hepatocytes increased expression of Fetuin-A and LECT2, and these hepatokines were shown to induce insulin resistance and metabolic disturbances in adipose tissue and skeletal muscle.

The results were recently published in the Journal of Clinical Investigation (IF 13.6, JCR top 2.3%).

Hye-Jin Cho, a doctoral candidate in the School of Pharmacy at JBNU and the first author of the study, said, 'Through this research we confirmed that dysregulated iron metabolism within hepatocytes can be importantly linked to systemic metabolic disturbances in patients with fatty liver. Although the research faced many challenges over a long period, I am pleased that it produced meaningful results.'

Professor Chang-Yeop Han added, 'This study is significant because it explains the mechanism linking fatty liver disease and metabolic dysfunction from a new perspective involving iron metabolism and hepatokines. It may lead to the identification of new therapeutic targets for MASLD and metabolic disorders in the future.'

The study was conducted by multiple domestic and international collaborative research teams centered on the JBNU School of Pharmacy. It was carried out with support from the National Research Foundation of Korea, including grants from the Outstanding Early Career Research Program, Core Research Program, and the Bio·Medical Technology Development Program.