In a groundbreaking study, scientists from Japan have identified a gene signature known as iFerroptosis, associated with iron overload-induced hepatic ferroptosis. This discovery, published in Hepatology Communications on May 29, 2025, could pave the way for new therapeutic targets for liver diseases.
Led by Professor Toshiro Moroishi of the Institute of Science Tokyo and Dr. Takashi Matsumoto from Kumamoto University, the research team evaluated the associated genes in both mice and human liver injury systems. Their findings suggest that iFerroptosis could serve as a biomarker for liver injuries, offering insights into unique therapeutic targets.
The Mechanism of Ferroptosis
Ferroptosis is a form of cell death triggered by excess intracellular iron, which leads to the production of highly reactive oxygen species. These species rapidly oxidize phospholipids, causing cellular damage. While ferroptosis has been linked to various diseases, recent evidence implicates it in liver pathologies such as fibrosis, cirrhosis, liver cancer, and hepatic ischemia-reperfusion injuries (HIRI).
The Japanese team addressed a significant gap in the field: the lack of a reliable model for iron overload-induced ferroptosis. By developing an innovative mouse model, they were able to identify specific gene expression patterns that may inform potential therapeutic interventions.
Development of the Mouse Model
To create the model, researchers developed liver-specific FBXL5 knockout (FBXL5 liver-KO) mice. FBXL5 is a protein that helps regulate cellular iron levels. The knockout mice were then fed a high iron diet to induce ferroptosis. “In the present study, we used this FBXL5 liver-KO to establish an iron overload-induced ferroptosis model and identify commonly regulated genes in the hepatic response to ferroptosis using a transcriptome-wide approach,” explains Moroishi.
Compared to control mice, the FBXL5 liver-KO mice exhibited increased levels of liver damage and high levels of lipid peroxidation, characteristic of ferroptosis. These findings confirmed that FBXL5 liver-KO mice were ideal models for studying hepatic ferroptosis.
Identifying the iFerroptosis Gene Signature
Through transcriptomic comparison, the researchers identified a marked difference in gene expression profiles between control and FBXL5 liver-KO mice. This led to the identification of 100 commonly upregulated genes, establishing an integrated ferroptosis gene signature for hepatic ferroptosis, termed iFerroptosis.
The gene expression profiles of this model were also compared with those of a redox potential reduction-induced ferroptosis model, further validating the iFerroptosis signature.
Implications for Human Health
To understand the impact of ferroptosis on postoperative recovery, the researchers examined preoperative serum iron levels in 174 patients undergoing hepatic resections. Patients with high preoperative serum iron levels showed significant enrichment of iFerroptosis gene signatures and had sustained postoperative liver damage compared to those with lower iron levels.
“Utilizing the iFerroptosis gene set may help to further understand ferroptosis-related hepatic disorders and offer insights into potential therapeutic strategies targeting ferroptosis to improve outcomes in patients with liver diseases,” concludes Moroishi.
This study not only identified a gene signature characteristic of hepatic ferroptosis but also highlighted how high serum iron levels may predict delayed postoperative recovery in patients with liver disorders.
The findings underscore the potential of iFerroptosis as a biomarker and therapeutic target, offering a new avenue for research and treatment in liver diseases. As the medical community continues to explore the implications of ferroptosis, this study provides a crucial foundation for future work.
