Identification of Novel Therapeutic Targets for MAFLD Based on Bioinformatics Analysis Combined with Mendelian Randomization.

Metabolic-associated fatty liver disease (MAFLD) is a chronic liver 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, we identified differentially expressed genes and constructed protein-protein interaction (PPI) networks, pinpointing 10 hub genes. MR and colocalization analyses revealed that Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) is causally associated with MAFLD and driven by the same causal variant locus, suggesting its potential as a therapeutic target. Molecular docking identified disogenin as a candidate small-molecule drug targeting UHRF1. Drug affinity responsive target stability (DARTS) assays confirmed direct binding between UHRF1 and disogenin. In vitro, disogenin significantly reduced UHRF1 mRNA and protein levels induced by free fatty acids (FFA) in AML12 and HepG2 cells, accompanied by decreased cellular total cholesterol (TC) and triglyceride (TG) levels. In vivo, disogenin administration alleviated hepatic lipid accumulation, inflammation, and fibrosis in methionine/choline-deficient (MCD)-diet-fed mice. This study identifies UHRF1 as a promising therapeutic target for MAFLD and validates disogenin as a potential therapeutic agent, providing a foundation for further investigation.