南华大学王福俤等研究人员合作发现，综合临床和前临床研究确定FerroTerminator1为治疗MASH的有效药物。2024年8月13日，《细胞—代谢》杂志在线发表了这项成果。

据研究人员介绍，与代谢功能障碍相关的脂肪肝病（MAFLD）的复杂病因因素，包括铁稳态紊乱，以及这些因素如何促使疾病进展尚不明确，因此有效的治疗干预措施有限。

研究人员报告了代谢功能障碍相关的脂肪性肝炎（MASH，MAFLD的一种病理亚型）患者表现出过量的肝脏铁，并且这种铁水平与疾病进展有强烈的正相关。与临床批准的铁螯合剂相比，FerroTerminator1（FOT1）在多个MASH模型中有效逆转肝脏损伤且无明显毒副作用。

从机制上讲，多组学分析揭示FOT1同时抑制了肝脏铁积累和c-Myc-Acsl4诱导的铁死亡。进一步的MAFLD队列研究表明，血清铁蛋白水平可能作为FOT1基础治疗MASH的预测生物标志物。这些发现为FOT1作为一种有前景的新型治疗选项用于所有阶段的MAFLD以及未来的临床试验提供了有力证据。

附：英文原文

Title: Integrative clinical and preclinical studies identify FerroTerminator1 as a potent therapeutic drug for MASH

Author: Liang Tao, Xinquan Yang, Chaodong Ge, Peng Zhang, Wenjian He, Xingbo Xu, Xin Li, Wenteng Chen, Yingying Yu, Huai Zhang, Sui-Dan Chen, Xiao-Yan Pan, Yunxing Su, Chengfu Xu, Yongping Yu, Ming-Hua Zheng, Junxia Min, Fudi Wang

Issue&Volume: 2024-08-13

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.

DOI: 10.1016/j.cmet.2024.07.013

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00284-5