白细胞介素-22通过Nrf2-ARE信号改善酒精相关肝纤维化：机制见解和临床相关性

IF 2.6 4区医学 Q2 GASTROENTEROLOGY & HEPATOLOGY

Clinics and research in hepatology and gastroenterology Pub Date : 2025-07-01 DOI:10.1016/j.clinre.2025.102617

Xiaojuan Xu , Heping Zhao , Jie Zhang , Hongyou Yan , Xing Liu , Junyan Huo , Lijuan Huo

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引用次数: 0

摘要

背景与目的：酒精相关性肝纤维化（ALF）是导致酒精相关性肝硬化的关键、潜在可逆阶段，但缺乏有效的治疗方法。本研究探讨肝细胞生存因子白细胞介素(IL)-22是否通过调节Nrf2-ARE抗氧化途径在ALF中发挥抗纤维化作用。方法：将IL-22和Nrf2-ARE抑制剂ML385给予暴露于乙醛的大鼠肝星状细胞（hsc）。研究细胞增殖、细胞周期分布和Nrf2-ARE活化情况。采用ALF小鼠模型评价IL-22和ML385对肝功能、纤维化和Nrf2-ARE通路激活的影响。同时检测IL-22和Nrf2-ARE通路在ALF/肝硬化患者中的表达，以及与肝功能和肝纤维化程度的相关性。结果：IL-22在体外可上调Nrf2-ARE通路，抑制乙醛诱导的HSC增殖和活化。在ALF小鼠中，IL-22促进Nrf2-ARE通路激活，降低氧化应激水平和血清转氨酶，改善纤维化。ALF患者IL-22、IL-22R1、Nrf2-ARE通路表达升高，与Child-Pugh评分和纤维化严重程度呈正相关，提示存在代偿反应。结论：IL-22通过激活Nrf2抗氧化应激途径缓解ALF，可能为ALF/肝硬化患者提供一个有希望的治疗选择。

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Interleukin-22 ameliorates alcohol-associated liver fibrosis via Nrf2-ARE signaling: mechanistic insights and clinical correlations

Background & Aims

Alcohol-associated liver fibrosis (ALF) is a key, potentially reversible stage leading to alcohol-associated liver cirrhosis, but effective treatments are lacking. This study explored whether interleukin (IL)-22, a hepatocyte survival factor, plays an anti-fibrotic role in ALF by modulating the Nrf2-ARE antioxidant pathway.

Methods

IL-22 and Nrf2-ARE inhibitor, ML385, were administered to rat hepatic stellate cells (HSCs) exposed to acetaldehyde. Cell proliferation, cell cycle distribution, and Nrf2-ARE activation were investigated. An ALF mouse model was used to evaluate the effects of IL-22 and ML385 on liver function, fibrosis, and Nrf2-ARE pathway activation. The expression of IL-22 and Nrf2-ARE pathway in ALF/cirrhosis patients was also examined, along with correlations to liver function and liver fibrosis degree.

Results

In vitro, IL-22 upregulated the Nrf2-ARE pathway, and inhibited acetaldehyde-induced HSC proliferation and activation. In ALF mice, IL-22 promoted Nrf2-ARE pathway activation, reduced oxidative stress levels and serum transaminases, and ameliorated fibrosis. The ALF patients showed increased expression of IL-22, IL-22R1, and Nrf2-ARE pathway, positively correlating with the Child-Pugh score and fibrosis severity, suggesting a compensatory response.

Conclusions

IL-22 alleviates ALF by activating the Nrf2 antioxidant stress pathway, and may offer a promising therapeutic option for ALF/cirrhosis patients.

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来源期刊

Clinics and research in hepatology and gastroenterology GASTROENTEROLOGY & HEPATOLOGY-

CiteScore

4.30

自引率

3.70%

发文量

198

审稿时长

42 days

期刊介绍： Clinics and Research in Hepatology and Gastroenterology publishes high-quality original research papers in the field of hepatology and gastroenterology. The editors put the accent on rapid communication of new research and clinical developments and so called "hot topic" issues. Following a clear Editorial line, besides original articles and case reports, each issue features editorials, commentaries and reviews. The journal encourages research and discussion between all those involved in the specialty on an international level. All articles are peer reviewed by international experts, the articles in press are online and indexed in the international databases (Current Contents, Pubmed, Scopus, Science Direct). Clinics and Research in Hepatology and Gastroenterology is a subscription journal (with optional open access), which allows you to publish your research without any cost to you (unless you proactively chose the open access option). Your article will be available to all researchers around the globe whose institution has a subscription to the journal.