Abstract
Objective: This work aims to explore the potential targets and underlying therapeutic mechanisms of celastrol in autoimmune hepatitis (AIH) through network pharmacology and experiments on Laboratory Animals. Methods: A drug-target interaction network was constructed to predict the possible targets of celastrol and their potential relationship with the drug; docking studies were also performed for validation. This study used both acute and chronic rodent models of autoimmune hepatitis. Gross appearance of liver and spleen were obtained from murine models, hematoxylin-eosin staining and Sirius red staining were performed to examine hepatic inflammation and fibrosis respectively. By combining molecular docking and enrichment analysis results, the most prominent signaling pathway was selected and further confirmed by Western blot in AIH models administered with celastrol. Results: In total, 82 common targets of celastrol and AIH were obtained from databases, identified by network pharmacology, and adequately enriched. Among them, PIK3R1, SRC, MAPK1, AKT1, and HRAS were selected as the top 5 closely related targets to celastrol. They all performed effectively in molecular docking, with AKT1 and PIK3R1 exhibiting more-prominent binding energy. Subsequently, celastrol administration significantly ameliorated hepatitis and liver fibrosis by reducing AKT1 and PI3K phosphorylation in both acute liver injury and chronic models of autoimmune hepatitis. Conclusion: In summary, celastrol significantly attenuates autoimmune hepatitis by suppressing the PI3K/AKT signaling pathway, confirmed by validated animal models. These findings may help identify the mechanism involved in the anti-inflammatory action of celastrol in autoimmune hepatitis and provide ideas for future comprehensive studies.
Highlights
Autoimmune hepatitis (AIH) is a chronic inflammatory disorder of the liver, characterized by elevation of serum immunoglobulin G (IgG), presence of autoantibodies and interface hepatitis on liver histology (Webb et al, 2018)
Genes related to the term “autoimmune hepatitis” were extracted from the GeneCards database
We screened 292 targets of celastrol obtained from the above-mentioned databases
Summary
Autoimmune hepatitis (AIH) is a chronic inflammatory disorder of the liver, characterized by elevation of serum immunoglobulin G (IgG), presence of autoantibodies and interface hepatitis on liver histology (Webb et al, 2018). It occurs across the globe affecting individuals of all ages, with a higher prevalence among females (Mieli-Vergani et al, 2018). The use of corticosteroids with or without azathioprine is introduced as the first-line treatment, some patients obtain little benefit from standard of care, causing resistance or relapse. Identifying novel therapeutic approaches for patients not benefiting from first-line treatments is necessary (Taubert et al, 2018; van den Brand et al, 2019; Engel et al, 2020)
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