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

Autor:	Tao L; School of Basic Medical Sciences, School of Public Health, School of Pharmaceutical Science, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China; The Second Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China., Yang X; The Second Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China; School of Public Health, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China., Ge C; The Second Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China; School of Public Health, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China., Zhang P; School of Basic Medical Sciences, School of Public Health, School of Pharmaceutical Science, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China., He W; School of Basic Medical Sciences, School of Public Health, School of Pharmaceutical Science, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China., Xu X; The Second Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China., Li X; School of Basic Medical Sciences, School of Public Health, School of Pharmaceutical Science, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China., Chen W; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang Province, China., Yu Y; The Second Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China., Zhang H; Department of Biostatistics and Medical Record, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China., Chen SD; Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China., Pan XY; Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China., Su Y; The Second Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China., Xu C; Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China., Yu Y; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang Province, China., Zheng MH; MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China. Electronic address: zhengmh@wmu.edu.cn., Min J; The Second Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: junxiamin@zju.edu.cn., Wang F; School of Basic Medical Sciences, School of Public Health, School of Pharmaceutical Science, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China; The Second Affiliated Hospital, The First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China; School of Public Health, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China. Electronic address: fwang@zju.edu.cn.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2024 Oct 01; Vol. 36 (10), pp. 2190-2206.e5. Date of Electronic Publication: 2024 Aug 13.
DOI:	10.1016/j.cmet.2024.07.013
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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