TFR2 p.A75V mutation aggravates liver iron overload in alcoholic liver disease via ERK pathway.

Abstract

Liver iron overload, a contributing factor to liver damage, is frequently observed in advanced alcoholic liver disease (ALD). Genetic factors may influence the progression of ALD. This study explored the involvement of hemochromatosis-related genes in liver iron deposition among ALD patients. Clinical data from 97 ALD patients revealed that those with liver iron overload had worse liver function and prognosis. Among 43 patients who underwent exon sequencing of the HFE, HJV, HAMP, TFR2, and SLC40A1 genes, the TFR2 p.A75V mutation emerged as a potential contributor to iron overload. To further investigate, we developed a novel mouse model of ALD with liver iron overload. Administration of recombinant AAV carrying the wild-type TFR2 gene significantly reduced iron deposition in hepatocytes, whereas the TFR2 p.A75V mutation did not alleviate hepatic iron overload. This mutation impairs HAMP induction by disrupting the ERK pathway, likely due to abnormal cytoplasmic localization of the TFR2 protein. In conclusion, the TFR2 p.A75V mutation in ALD may decrease hepatocyte sensitivity to iron stimulation by inhibiting HAMP expression via the ERK pathway, thereby exacerbating iron overload both in vivo and in vitro. KEY MESSAGES: The study identifies the TFR2 p.A75V mutation as a key genetic factor worsening liver iron overload in ALD patients, linked to poorer liver function and prognosis. A novel ALD mouse model with iron overload demonstrates that the TFR2 p.A75V mutation impairs iron regulation. TFR2 p.A75V mutant disturbs the ERK pathway in HAMP induction and causes abnormal cytoplasmic localization of the TFR2 Protein.