Identification of tissue plasminogen activator (PLAT) as a potential target linking osteoarthritis and psoriasis: Integrated bioinformatics analysis and molecular dynamics simulation.

Abstract

BACKGROUND: Osteoarthritis (OA) and psoriasis (PSO), while distinct systemic diseases, both affect the joint system and share similar inflammatory factor expression profiles and immune cell infiltration patterns, suggesting potential common pathogenic mechanisms. Tissue plasminogen activator (PLAT), a pivotal fibrinolytic enzyme, may represent a candidate molecule associated with the molecular overlap between these two diseases. METHODS: This study applied an integrated multi-omics and experimental strategy, including Weighted Gene Co-expression Network Analysis (WGCNA), machine learning (LASSO, random forest, artificial neural network), immune infiltration analysis, single-cell RNA-seq, molecular docking, molecular dynamics simulation, MM/PBSA binding free-energy calculation, RT-qPCR, CCK-8 assay, and in vivo validation using an ACLT+MMx mouse OA model. RESULTS: WGCNA identified the OA-specific green module (r = 0.54) and the PSO-specific turquoise module (r = 0.91). Cross-analysis identified five core genes, with PLAT significantly upregulated in both diseases. PLAT expression positively correlated with M1 macrophage infiltration and immune dysregulation. ScRNA-seq showed high PLAT expression in chondrocytes (HTC/FC subpopulations). In vitro TNF-α stimulation and in vivo OA-model validation both showed elevated PLAT expression under degenerative-like conditions. Molecular docking identified Riboflavin as a candidate PLAT-binding compound, and subsequent MD simulation together with MM/PBSA analysis supported the stability and thermodynamic favorability of the Riboflavin-PLAT complex. In TNF-α-stimulated C28/I2 cells, Riboflavin also reduced the expression of PLAT and OA-related catabolic markers. CONCLUSION: PLAT was identified as a potential shared molecular target associated with OA and PSO comorbidity. Riboflavin, a predicted PLAT-binding compound, showed preliminary inhibitory effects in vitro and may warrant further investigation as a candidate lead for targeted intervention.