Integrative clinical and preclinical studies identify FerroTerminator1 as a potent therapeutic drug for MASH
Liang Tao, Xinquan Yang, Chaodong Ge, Peng Zhang, Wenjian He, Xingbo Xu, Xin Li, Wenteng Chen, Yingying Yu, Huai Zhang, Sui‐Dan Chen, Xiaoyan Pan, Yunxing Su, Chengfu Xu, Yongping Yu, Ming‐Hua Zheng, Junxia Min, Fudi Wang
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.