Interleukin-22 ameliorates alcohol-associated liver fibrosis via Nrf2-ARE signaling: mechanistic insights and clinical correlations - 29/05/25

Doi : 10.1016/j.clinre.2025.102617

Xiaojuan Xu ^a,^b,^{^{1
Xiaojuan Xu and Heping Zhao equally contributed to this article as co-first authors.}}, Heping Zhao ^a,^{^{1
Xiaojuan Xu and Heping Zhao equally contributed to this article as co-first authors.}}, Jie Zhang ^a, Hongyou Yan ^b, Xing Liu ^b, Junyan Huo ^b, Lijuan Huo ^a,^⁎
^a Gastroenterology Department, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
^b Shanxi Medical University, Taiyuan, 030001, Shanxi, China

^⁎Correspondence: Lijuan Huo, Gastroenterology Department, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China. Tel: 86-351-4639511.Gastroenterology DepartmentFirst Hospital of Shanxi Medical UniversityTaiyuanShanxi030001China

En prensa. Manuscrito Aceptado. Disponible en línea desde el Thursday 29 May 2025
This article has been published in an issue click here to access

Highlights

•	IL-22 inhibited acetaldehyde-induced HSC proliferation and activation.
•	IL-22 ameliorated alcohol-associated liver fibrosis in mice via the Nrf2-ARE pathway.
•	ALF patients exhibited elevated IL-22, IL-22R1, and Nrf2-ARE pathway activity.
•	IL-22 may be a promising therapeutic option for patients with ALF/cirrhosis.

El texto completo de este artículo está disponible en PDF.

Abstract

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.

El texto completo de este artículo está disponible en PDF.

Keywords : alcohol-associated liver disease, alcohol-associated liver fibrosis, hepatic stellate cells, oxidative stress, interleukin-22, Nrf2-ARE pathway

Abbreviations : ACE, ALD, ALF, ALT, ARE, AST, α-SMA, CCL₄, CVF, GSH, HO-1, HSC, IL-22, MDA, NQO1, Nrf2, PI