MiR-126-3p and MiR-195-5p as Novel Therapeutic Attenuators of Liver Fibrosis by Targeting the IRS1/PI3K Signalling Pathway

IF 5.2 2区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Liver International Pub Date : 2025-09-01 DOI:10.1111/liv.70302

Xia Yuan, Kun Zhang, Dan Wang, Jie Li, Peng Lyu, Xuemei Zhao, Kang Zhang, Hongting Li, Bo Liu, Liping Ma

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Abstract

Background & Aims

Hepatic fibrosis is a progressive response to chronic liver injury. A key event in the development of hepatic fibrosis is the activation of hepatic stellate cells (HSCs); emerging research indicates that microRNAs play crucial roles in regulating HSCs activation. However, the specific roles of miR-126-3p (miR-126) and miR-195-5p (miR-195) in liver fibrosis remain inadequately understood.

Methods

We examined the expression of miR-126 and miR-195 in activated HSCs, fibrotic liver tissues from animal models, and blood samples from patients with liver disease. The effects on cell proliferation and migration were investigated by MTT, colony formation assay, cell wound healing assay, and Transwell assay. Finally, we evaluated the effect of miR-126 and miR-195 on the progression of liver fibrosis in mice.

Results

We revealed that miR-126 and miR-195 were markedly downregulated in activated HSCs, fibrotic liver tissues from animal models, and blood samples from patients with liver diseases. Functional experiments demonstrated that the overexpression of miR-126 and miR-195 significantly inhibited the proliferation, migration, and fibrotic markers expression in HSCs. Conversely, silencing miR-126 and miR-195 produced the opposite effects. Further mechanistic studies showed that miR-126 and miR-195 downregulate insulin receptor substrate 1 (IRS1) or phosphoinositide 3-kinase regulatory subunit 2 (PIK3-R2), respectively, thereby inhibiting the pro-fibrotic signalling pathway (IRS1/PI3K) and regulating the functions of HSCs. Importantly, in vivo experiments demonstrated that miR-126 and miR-195 markedly alleviated CCL₄-induced hepatic fibrosis in mice.

Conclusions

Our results unravel that miR-126 and miR-195 inhibit liver fibrosis by suppressing the IRS/PI3K pathway.

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靶向IRS1/PI3K信号通路的MiR-126-3p和MiR-195-5p作为肝纤维化的新型治疗减毒剂

背景和目的肝纤维化是慢性肝损伤的进行性反应。肝纤维化发展的一个关键事件是肝星状细胞（hsc）的激活；新兴研究表明，microrna在调节造血干细胞活化中起着至关重要的作用。然而，miR-126-3p （miR-126）和miR-195-5p （miR-195）在肝纤维化中的具体作用仍未充分了解。方法我们检测了miR-126和miR-195在活化的造血干细胞、动物模型纤维化肝组织和肝病患者血液样本中的表达。采用MTT法、菌落形成法、细胞创面愈合法和Transwell法研究其对细胞增殖和迁移的影响。最后，我们评估了miR-126和miR-195对小鼠肝纤维化进展的影响。结果我们发现，miR-126和miR-195在活化的hsc、动物模型的纤维化肝组织和肝脏疾病患者的血液样本中明显下调。功能实验表明，过表达miR-126和miR-195可显著抑制造血干细胞的增殖、迁移和纤维化标志物的表达。相反，沉默miR-126和miR-195产生相反的效果。进一步的机制研究表明，miR-126和miR-195分别下调胰岛素受体底物1 （IRS1）或磷酸肌苷激酶调节亚基2 (PIK3-R2)，从而抑制促纤维化信号通路（IRS1/PI3K），调节造血干细胞的功能。重要的是，体内实验表明，miR-126和miR-195可显著减轻ccl4诱导的小鼠肝纤维化。我们的研究结果揭示了miR-126和miR-195通过抑制IRS/PI3K途径抑制肝纤维化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Liver International 医学-胃肠肝病学

CiteScore

13.90

自引率

4.50%

发文量

348

审稿时长

2 months

期刊介绍： Liver International promotes all aspects of the science of hepatology from basic research to applied clinical studies. Providing an international forum for the publication of high-quality original research in hepatology, it is an essential resource for everyone working on normal and abnormal structure and function in the liver and its constituent cells, including clinicians and basic scientists involved in the multi-disciplinary field of hepatology. The journal welcomes articles from all fields of hepatology, which may be published as original articles, brief definitive reports, reviews, mini-reviews, images in hepatology and letters to the Editor.