波形蛋白
肝损伤
小RNA
肝再生
癌症研究
生物
小干扰RNA
肝细胞
调节器
细胞凋亡
再生(生物学)
药理学
医学
细胞生物学
免疫学
细胞培养
基因
免疫组织化学
转染
体外
生物化学
遗传学
作者
Xiaoyan Lu,Lingqi Yu,Jie Zheng,Anyao Li,Junying Li,He Lou,Wentao Zhang,Hui Guo,Yuzhen Wang,Xuemei Li,Pan Shen,Xiaohui Fan,Jürgen Borlak
出处
期刊:MedComm
[Wiley]
日期:2024-08-21
卷期号:5 (9)
摘要
Abstract Understanding the endogenous mechanism of adaptive response to drug‐induced liver injury (arDILI) may discover innovative strategies to manage DILI. To gain mechanistic insight into arDILI, we investigated exosomal miRNAs in the adaptive response to toosendanin‐induced liver injury (TILI) of mice. Exosomal miR‐106b‐5p was identified as a specific regulator of arDILI by comprehensive miRNA profiling. Outstandingly, miR‐106b‐5p agomir treatment alleviated TILI and other DILI by inhibiting apoptosis and promoting hepatocyte proliferation. Conversely, antagomir treatments had opposite effects, indicating that miR‐106b‐5p protects mice from liver injury. Injured hepatocytes released miR‐106b‐5p‐enriched exosomes taken up by surrounding hepatocytes. Vim (encodes vimentin) was identified as an important target of miR‐106b‐5p by dual luciferase reporter and siRNA assays. Furthermore, single‐cell RNA‐sequencing analysis of toosendanin‐injured mouse liver revealed a cluster of Vim + hepatocytes; nonetheless declined following miR‐106b‐5p cotreatment. More importantly, Vim knockout protected mice from acetaminophen poisoning and TILI. In the clinic, serum miR‐106b‐5p expression levels correlated with the severity of DILI. Indeed, liver biopsies of clinical cases exposed to different DILI causing drugs revealed marked vimentin expression among harmed hepatocytes, confirming clinical relevance. Together, we report mechanisms of arDILI whereby miR‐106b‐5p safeguards restorative tissue repair by targeting vimentin.
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