A Systems Pharmacology Study on Lanifibranor for the Management of Non-Alcoholic Fatty Liver Disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a prevalent and progressive metabolic liver disorder with limited pharmacological treatment options. Lanifibranor, a pan-peroxisome proliferatoractivated receptor (pan-PPAR) agonist, has demonstrated promising therapeutic effects in clinical studies, yet its comprehensive mechanism of action remains unclear. This study employed a systems pharmacology approach integrating network pharmacology, protein–protein interaction (PPI) analysis, functional enrichment, and molecular docking to elucidate the multi-target actions of Lanifibranor in NAFLD. A total of 102 Lanifibranor-associated protein targets and 1,526 NAFLD-related genes were retrieved from public databases, with 37 overlapping targets identified. Network analysis revealed hub genes including PTGS2, MMP9, ESR1, and BCL2 as central regulators in the disease network. Gene Ontology and KEGG enrichment analysis indicated involvement in oxidative stress responses, lipid metabolism, inflammation, and fibrotic signalling pathways showing the involvement of PPAR and AGE– RAGE pathways. Molecular docking confirmed strong binding affinities of Lanifibranor to key targets, particularly PTGS2 (–8.2 kcal/mol) and BCL2 (–8.1 kcal/mol), suggesting anti-inflammatory and anti-apoptotic potential. These findings offer mechanistic insight into Lanifibranor’s pleiotropic actions and support its development as a multitargeted therapeutic agent for NAFLD management.