International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3166 - 3166
Published: March 29, 2025
Metabolic-associated fatty liver disease (MAFLD) is a chronic condition with limited therapeutic options. To identify novel drug targets, we integrated bioinformatics, Mendelian randomization (MR), and colocalization analyses. Using the Gene Expression Omnibus (GEO) database, identified differentially expressed genes constructed protein–protein interaction (PPI) networks, pinpointing 10 hub genes. MR analyses revealed that Ubiquitin-like PHD ring finger domains 1 (UHRF1) causally associated MAFLD driven by same causal variant locus, suggesting its potential as target. Molecular docking disogenin candidate small-molecule targeting UHRF1. Drug affinity responsive target stability (DARTS) assays confirmed direct binding between UHRF1 disogenin. In vitro, significantly reduced mRNA protein levels induced free acids (FFA) in AML12 HepG2 cells, accompanied decreased cellular total cholesterol (TC) triglyceride (TG) levels. vivo, administration alleviated hepatic lipid accumulation, inflammation, fibrosis methionine/choline-deficient (MCD)-diet-fed mice. This study identifies promising for validates agent, providing foundation further investigation.
Language: Английский