Abstract：
The complex etiological factors associated with metabolic dysfunction-associated fatty liver disease (MAFLD), including perturbed iron homeostasis, and the unclear nature by which they contribute to disease progression have resulted in a limited number of effective therapeutic interventions. Here, we report that patients with metabolic dysfunction-associated steatohepatitis (MASH), a pathological subtype of MAFLD, exhibit excess hepatic iron and that it has a strong positive correlation with disease progression. FerroTerminator1 (FOT1) effectively reverses liver injury across multiple MASH models without notable toxic side effects compared with clinically approved iron chelators. Mechanistically, our multi-omics analyses reveal that FOT1 concurrently inhibits hepatic iron accumulation and c-Myc-Acsl4-triggered ferroptosis in various MASH models. Furthermore, MAFLD cohort studies suggest that serum ferritin levels might serve as a predictive biomarker for FOT1-based therapy in MASH. These findings provide compelling evidence to support FOT1 as a promising novel therapeutic option for all stages of MAFLD and for future clinical trials.
摘要：
与代谢功能障碍相关的脂肪肝（MAFLD）相关的复杂病因，包括扰动的铁稳态，它们对疾病进展的贡献性质不明确，导致有效的治疗干预措施数量有限。这里,我们报告代谢功能障碍相关脂肪性肝炎（MASH）患者，MAFLD的病理亚型,表现出过量的肝铁，它与疾病进展有很强的正相关。与临床批准的铁螯合剂相比，FerroTerminator1（FOT1）可有效逆转多种MASH模型的肝损伤，无明显的毒副作用。机械上,我们的多组学分析显示,在各种MASH模型中,FOT1同时抑制肝铁积累和c-Myc-Acsl4触发的铁细胞凋亡.此外，MAFLD队列研究表明，血清铁蛋白水平可能作为MASH中基于FOT1的治疗的预测性生物标志物。这些发现提供了令人信服的证据来支持FOT1作为MAFLD的所有阶段和未来临床试验的有希望的新型治疗选择。
