机构：[1]Department of Pathophysiology, West China College of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan, P.R. China[2]Horae Gene Therapy Center, UMass Chan Medical School, Worcester, MA, USA.[3]Viral Vector Core, UMass Chan Medical School, Worcester, MA, USA[4]Department of Genetics and Cellular Medicine, UMass Chan Medical School, Worcester, MA, USA.[5]Li Weibo Institute for Rare Diseases Research, UMass Chan Medical School, Worcester, MA, USA[6]Department of Microbiology, UMass Chan Medical School, Worcester, MA, USA.[7]Department of Breast Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.外科中心乳腺外科中心四川省肿瘤医院[8]Department of Emergency Medicine, Laboratory of Emergency Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China.四川大学华西医院[9]Department of Population and Quantitative Health Science, UMass Chan Medical School, Worcester, MA, USA.
Acetaminophen (APAP) overdose is a leading cause of acute liver failure (ALF), primarily through the excessive production of N-acetyl-p-benzoquinone imine (NAPQI). N-acetylcysteine (NAC) is the Food and Drug Administration-approved treatment for APAP overdose, but there is a growing interest in microRNAs as potential therapeutic agents. We delivered miR-375 ectopically via a liver-tropic adeno-associated virus serotype 8 (AAV8) and demonstrated its potent protection in a murine model of APAP overdose-induced ALF. Slc16a2, Cyb5b, and Acsl5 were identified as critical targets acting synergistically to mitigate toxicity. Liver transcriptome revealed that miR-375 overexpression or silencing of the targets of miR-375 increased Gstm3 expression in mice. AAV8-mediated Gstm3 expression protects against APAP-ALF, and the protection was further enhanced by disrupting the expression of Cyp2e1. Additionally, CYP2E1 and GSS, which contribute to APAP detoxification, were down- and upregulated by miR-375, respectively. These findings suggest that miR-375 prevents APAP-ALF by orchestrating the expression of pharmacogenes and enhancing glutathione synthesis. We conclude that miR-375 and its targets are promising therapeutic targets for APAP-ALF.Published by Elsevier Inc.
基金：
This research was sponsored by an internal grant to G.G. from the University of Massachusetts
Chan Medical School, United States. Y.W. was supported by The Science and
Technology Bureau Fund of Sichuan Province, China (2021YFS0051/2024YFFK0209).
语种：
外文
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PubmedID：
中科院(CAS)分区：
出版当年[2025]版：
大类|1 区医学
小类|1 区生物工程与应用微生物1 区遗传学1 区医学：研究与实验
最新[2025]版：
大类|1 区医学
小类|1 区生物工程与应用微生物1 区遗传学1 区医学：研究与实验
JCR分区：
出版当年[2024]版：
Q1BIOTECHNOLOGY & APPLIED MICROBIOLOGYQ1GENETICS & HEREDITYQ1MEDICINE, RESEARCH & EXPERIMENTAL
最新[2024]版：
Q1BIOTECHNOLOGY & APPLIED MICROBIOLOGYQ1GENETICS & HEREDITYQ1MEDICINE, RESEARCH & EXPERIMENTAL
第一作者机构：[1]Department of Pathophysiology, West China College of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan, P.R. China[2]Horae Gene Therapy Center, UMass Chan Medical School, Worcester, MA, USA.
共同第一作者：
通讯作者：
通讯机构：[2]Horae Gene Therapy Center, UMass Chan Medical School, Worcester, MA, USA.[3]Viral Vector Core, UMass Chan Medical School, Worcester, MA, USA[4]Department of Genetics and Cellular Medicine, UMass Chan Medical School, Worcester, MA, USA.[5]Li Weibo Institute for Rare Diseases Research, UMass Chan Medical School, Worcester, MA, USA[6]Department of Microbiology, UMass Chan Medical School, Worcester, MA, USA.
推荐引用方式(GB/T 7714)：
Wang Yi,Liu Jinghua,Zhu Sha,et al.miR-375 protects against acetaminophen-induced acute liver failure by orchestrating pharmacogene expression[J].Molecular Therapy : The Journal Of The American Society Of Gene Therapy.2025,33(10):4874-4888.doi:10.1016/j.ymthe.2025.06.038.
APA：
Wang Yi,Liu Jinghua,Zhu Sha,Hu Shiliang,Chen Xiupeng...&Xie Jun.(2025).miR-375 protects against acetaminophen-induced acute liver failure by orchestrating pharmacogene expression.Molecular Therapy : The Journal Of The American Society Of Gene Therapy,33,(10)
MLA：
Wang Yi,et al."miR-375 protects against acetaminophen-induced acute liver failure by orchestrating pharmacogene expression".Molecular Therapy : The Journal Of The American Society Of Gene Therapy 33..10(2025):4874-4888
医学