Integrated Network Pharmacology and Molecular Modeling Reveal Therapeutic Potential of Silybum marianum Compounds against NAFLD

He Wang; Yutong Li; Ling Guo; Jiqi Li; Yuedi Ni; Lianshan Chen; Dong Cai

doi:10.2174/0113816128428323251127043544

Integrated Network Pharmacology and Molecular Modeling Reveal Therapeutic Potential of Silybum marianum Compounds against NAFLD

Curr Pharm Des. 2026 Mar 13. doi: 10.2174/0113816128428323251127043544. Online ahead of print.

Authors

He Wang¹, Yutong Li¹, Ling Guo¹, Jiqi Li¹, Yuedi Ni², Lianshan Chen¹, Dong Cai¹

Affiliations

¹ College of Pharmacy, Jinzhou Medical University, Jinzhou 121001, China.
² First Clinical Medical College, Jinzhou Medical University, Jinzhou 121001, China.

PMID: 41832676
DOI: 10.2174/0113816128428323251127043544

Abstract

Introduction: Non-alcoholic fatty liver disease (NAFLD) is a global health burden lacking effective pharmacological treatments. Silybum marianum, a hepatoprotective herb, contains flavonolignans with potential therapeutic effects against NAFLD, yet its active components and mechanisms remain unclear.

Methods: Active compounds were screened using TCMSP and literature data based on oral bioavailability (OB ≥ 30%) and drug-likeness (DL ≥ 0.18). Putative targets were predicted via SwissTargetPrediction and intersected with NAFLD-related genes from GeneCards, OMIM, and DisGeNET. Key targets were identified through the PPI network and GO/KEGG enrichment analyses. Core compounds were further evaluated by molecular docking (Discovery Studio 2019) and molecular dynamics simulations (GROMACS 2021.4).

Results: A total of 33 active ingredients and 132 overlapping targets were identified. Network and pathway analysis revealed AKT1 and MTOR as central proteins involved in insulin signaling, autophagy, and lipid metabolism. Molecular docking showed strong binding affinities of silybin A and silandrin to AKT1 and MTOR, respectively. MD simulations confirmed superior structural stability and compactness of these complexes, with favorable RMSD, RMSF, Rg, SASA, and H-bond profiles.

Discussion: Silybin A and silandrin demonstrated stable interactions with key NAFLD targets, modulating lipid metabolism, oxidative stress, and autophagic pathways. These compounds outperformed other flavonolignans in network centrality, binding strength, and dynamic stability, highlighting their potential for further drug development.

Conclusion: This integrative study provides a mechanistic basis for the anti-NAFLD activity of Silybum marianum, identifying silybin A and silandrin as promising scaffolds for AKT1 and MTOR-targeted therapy.

Keywords: NAFLD; Silybum marianum; molecular docking; molecular dynamics; network pharmacology; silandrin.; silybin A.