Therapeutic Potential and Mechanistic Insights of a Novel Synthetic α-Lactalbumin-Derived Peptide for the Treatment of Liver Fibrosis.

Abstract

Background: Liver fibrosis is a serious global health issue, but current treatment options are limited due to a lack of approved therapies capable of preventing or reversing established fibrosis.

Aim: This study investigated the antifibrotic effects of a synthetic peptide derived from α-lactalbumin in a mouse model of thioacetamide (TAA)-induced liver fibrosis.

Methods: In silico analyses were conducted to assess the physicochemical properties, pharmacophore features, and docking interactions of the peptide. Mice with induced fibrosis were treated with three different doses of the synthetic peptide (2.5, 5, or 10 μg/kg, twice weekly for 8 weeks). Immunohistochemistry, antioxidant enzyme levels, IGF-1 levels, and expression of fibrosis-related genes were assessed.

Results: Peptide interacted with human prothrombin's many sites with varying binding affinities. Besides, ligand similarity analysis identified 26 thrombin inhibitors with high Tanimoto scores. The peptide exhibited antifibrotic effects with dose-dependent improvements. The upregulated expression of IGF-1 in all treated groups compared with the pathological untreated group. In contrast, fibrotic markers such as TIMP, PDGF-α, and TGF-β were upregulated in the untreated pathological group but downregulated in the peptide-treated groups. The assessment of IGF-1 concentration in sera demonstrated that the peptide-treated groups exhibited an increase in IGF-1 levels. Histopathological examination of peptide-treated groups showed normal hepatic architecture with hepatocytes arranged in thin plates. Immunohistochemical results of high dose peptide-treated group showed a few numbers of positive αSMA with mild proliferating cell nuclear antigen expression.

Conclusion: The synthetic α-lactalbumin peptide shows promise as an antifibrotic therapy. Its safety and effectiveness are supported by in silico and in vivo analyses. The peptide's pharmacophore characteristics and potential as a thrombin inhibitor combine with its ability to downregulate fibrotic markers and maintain liver tissue integrity. These findings concluded the potential of this peptide as a promising therapeutic candidate for liver fibrosis, warranting further investigation.