Elucidating the molecular mechanisms of paeoniflorin intervention in oral lichen planus: a computational biology and bioinformatics–based research strategy

Abstract

Background Oral lichen planus (OLP) is a chronic inflammatory mucosal disease with a risk of malignant transformation and limited long-term therapeutic options. Paeoniflorin (PF), a natural monoterpene glycoside, exhibits multi-target anti-inflammatory and immunomodulatory properties, but its systematic mechanisms against OLP remain elusive. Methods We employed an integrative framework combining network pharmacology, transcriptomic cross-validation, molecular docking, and molecular dynamics (MD) simulations. Public databases were mined to identify PF targets and OLP-related genes. Core targets were prioritized via protein-protein interaction (PPI) network topology and further validated using OLP tissue transcriptomic datasets (GSE52130 and GSE213349). Functional enrichment analyses were performed, followed by structural validation of PF–target binding via molecular docking and 100-ns MD simulations. Results Sixty-eight overlapping targets between PF and OLP were identified. PPI network analysis and transcriptomic cross-validation pinpointed eight core targets: AKT1, IL6, MMP9, STAT3, TNF, IL1B, PTGS2, and PDE4B. Mechanistically, these targets converged on the TNF, PI3K–Akt, and MAPK signaling pathways, regulating inflammatory response, cell migration, apoptosis, and protease activity at membrane microdomain and extracellular matrix interfaces. Molecular docking showed PF binding affinities comparable to or exceeding reference inhibitors (e.g., STAT3: −9.27 vs. Stattic −9.16 kcal/mol). MD simulations confirmed stable conformational binding, with the STAT3 and PDE4B complexes exhibiting the most balanced rigidity and lowest ligand RMSD (0.09–0.10 nm). Conclusion This study provides a systems-level map of PF’s multi-target intervention in OLP, highlighting a composite anti-inflammatory–immune reprogramming–pro-repair axis centered on core inflammatory kinases and proteases. The structural validation of key targets establishes a mechanistic rationale for PF as a promising therapeutic candidate, warranting further preclinical and clinical development for OLP management.