The Therapeutic Potential of Ferroterminator1 in Treating Metabolic Dysfunction-Associated Steatohepatitis

Hepatobiliary System Oncology Life Sciences Gastroenterology Medicine Biochemistry
Iron Overload Ferroterminator1 MASH Therapeutic Strategies Biomarkers

Comprehensive Clinical and Preclinical Studies Reveal the Therapeutic Potential of Ferroterminator1 (FOT1) for Metabolic-Associated Fatty Liver Disease (MAFLD)

Background: Research Needs on MAFLD and Iron Overload Issues

Metabolic-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a common chronic liver disease with a significantly increasing prevalence globally, presenting a rising trend year by year. One of the pathological subtypes of MAFLD is metabolic dysfunction-associated steatohepatitis (MASH), which not only has the features of fatty liver but is also accompanied by liver inflammation and fibrosis. In severe cases, it can progress to cirrhosis or even liver cancer, posing a significant public health threat. In recent years, the pathogenesis of MASH has gradually been uncovered, bringing hope for developing effective treatment regimens. However, due to the complexity of the pathological mechanisms of this disease, only one drug has been approved by the FDA for the clinical treatment of MASH, highlighting the importance of further exploring the critical mechanisms in the progression of MAFLD.

Objective and Significance of the Study: Explore the Relationship Between Hepatic Iron Overload and MASH Progression and Its Treatment Strategies

Recent studies have found that hepatic iron overload may play an important role in the progression of MASH. Iron is an essential trace element in various biological processes, and excess iron can generate toxic reactive oxygen species (ROS) via the Fenton reaction, leading to lipid peroxidation. This process is known as ferroptosis and is considered one of the potential mechanisms of MAFLD’s pathological progression. However, existing iron chelation therapies have limited effectiveness in treating MASH. Therefore, there is an urgent need to develop innovative therapies for MAFLD to alleviate or reverse disease progression through iron chelation strategies.

Research Methods: Integrated Clinical and Animal Model Studies

This study, conducted by Tao et al. and published in the journal “Cell Metabolism” in 2024, combines several clinical and preclinical models to investigate the impact of hepatic iron overload on MASH progression and to test the potential efficacy of a new iron chelator, FOT1, in treating MASH. The study employed the following research methods and models:

  1. Clinical Sample Analysis: Analysis of liver biopsy samples from 494 Asian patients revealed a positive correlation between iron overload and MASH severity, particularly more significant in male patients. Further biomarker analysis proposed that serum ferritin could potentially serve as a biomarker for assessing MASH severity and predicting treatment efficacy.

  2. Animal Model Studies: MASH was induced in various animal models, including methionine-choline deficient diet (MCD), high-fat high-cholesterol diet (HFHC), and Western diet + low dose carbon tetrachloride (WD+CCl4) models. Results showed significant iron overload in the livers of mice across these models, accompanied by hepatocyte apoptosis, lipid accumulation, and liver fibrosis.

  3. Drug Comparative Trials: Comparative trials were conducted between the new iron chelator FOT1 and FDA-approved iron chelators such as deferoxamine (DFO) and deferasirox (DFX). Results indicated that FOT1 significantly reduced hepatic iron content and improved liver function and lipid metabolism disorders in animal models more effectively than DFO and DFX, which showed limited effects in inhibiting liver fibrosis and had higher toxicity.

Key Findings: Significant Efficacy of FOT1 in MASH and Its Mechanisms of Action

The study results demonstrated that FOT1 had superior therapeutic effects on MASH compared to existing iron chelators, especially in mitigating hepatic iron overload and inhibiting ferroptosis, showing good therapeutic potential. The main mechanisms are as follows:

  1. Inhibition of Iron Overload and Ferroptosis: FOT1 significantly reduced non-heme iron content in the liver of mouse models and effectively inhibited ferroptosis-related indicators such as lipid peroxides accumulation. Further multi-omics analysis showed that FOT1 inhibits hepatic ferroptosis by blocking the c-myc-ACSL4 signaling pathway.

  2. Improvement in Liver Function and Metabolic Status: In the HFHC-MASH mouse models, the FOT1 treatment group showed significantly better liver function and lipid metabolic status compared to the control group, indicating that FOT1 effectively reduced lipid accumulation in hepatocytes and alleviated inflammation.

  3. Potential of Serum Ferritin as a Biomarker: The study found that serum ferritin levels correlated positively with hepatic iron overload and disease severity (such as NAS score and fibrosis score), and significantly decreased after FOT1 treatment. This suggests that serum ferritin could serve as a potential predictive marker for the efficacy of iron chelation therapy in MASH treatment.

Safety and Long-term Efficacy of FOT1

In safety assessments, FOT1 exhibited excellent safety at high doses (50 mg/kg/day). Compared to traditional iron chelators, FOT1 did not significantly affect normal iron homeostasis and did not cause abnormal changes in body weight or hemoglobin levels in mice. Additionally, after long-term treatment (16 weeks), FOT1 continued to significantly improve liver function and metabolic disorders, reducing liver inflammation and fibrosis degrees across various MASH models, demonstrating good long-term efficacy.

Potential Mechanisms of Ferroptosis and ACSL4

Research indicates that ACSL4 plays a critical role in MASH progression, and its upregulation significantly exacerbates lipid peroxidation and ferroptosis in hepatocytes. Under FOT1 treatment, the expression of ACSL4 in hepatocytes significantly decreased, and ferroptosis-related signaling was inhibited. Further molecular analysis showed that FOT1 downregulates c-myc expression, inhibiting the transcriptional activation of ACSL4, thereby reducing ferroptosis occurrence. This mechanism provides new insights into understanding FOT1’s action in treating MASH.

Clinical Translational Potential and Significance of FOT1

Based on these research findings, FOT1 shows great potential as a novel iron chelator in the treatment of MASH. Compared to traditional iron chelators, FOT1 has significant advantages in stability, safety, and efficacy. The study suggests further clinical trials to assess its application potential in various liver diseases, including MASH. Moreover, the potential role of serum ferritin as a biomarker warrants further exploration to more accurately select patient groups that may benefit from FOT1 treatment.

Research Limitations and Future Directions

There are some limitations to this study: first, the efficacy of FOT1 is limited to mouse models, and clinical translational studies are needed in the future; second, the impact of gender differences on FOT1’s efficacy requires further validation; third, the precise mechanisms of ferroptosis in different cell types need in-depth study. Future single-cell RNA sequencing and spatial transcriptomics may provide important information to reveal the exact mechanism by which FOT1 alleviates MASH.

Conclusion

This study integrates multiple clinical and preclinical evidence, revealing the critical role of hepatic iron overload in MASH progression and suggests that FOT1 alleviates liver damage by inhibiting the c-myc-ACSL4 signaling pathway and ferroptosis, offering new treatment strategies for MASH. This finding not only provides a new direction for MASH treatment but also lays the foundation for further understanding the role of iron overload in liver disease mechanisms.