Interleukin-22 ameliorates alcohol-associated liver fibrosis via Nrf2-ARE signaling: mechanistic insights and clinical correlations - 02/07/25
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. |
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.
Le texte complet de cet article est 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
Plan
Vol 49 - N° 7
Article 102617- juillet 2025 Retour au numéro
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