Single-Cell Transcriptomic Profiling of Psoriatic Arthritis Synovial Tissue Identifies Receptor Tyrosine Kinase Inhibitors and MMP Inhibitors as Repurposing Candidates

We applied a standardized single-cell RNA sequencing drug repurposing pipeline to publicly available synovial tissue transcriptomic data from psoriatic arthritis (PsA) and rheumatoid arthritis (RA) patients (GSE200815; n=5 PsA, n=4 RA; Floudas et al., Ann Rheum Dis 2022). After quality control filtering, 48,201 cells were analyzed using scVI dimensionality reduction, Leiden unsupervised clustering, and Wilcoxon differential expression analysis, identifying 11 synovial cell types and 467 genes upregulated in PsA. ChEMBL bioactivity screening identified 11,910 drug candidates prioritized by composite score (N_targets x 10 + max_pChEMBL); the top 2,000 were assessed for novelty via PubChem (all NOVEL). Top candidates include CHEMBL5653589 (score 79.24, pan-disease multi-target compound targeting HSPA5, ZMYND8, KPNA2, HSPB1, MAT2A), foretinib (50.03, AXL/DDR2/PDGFRA axis), nintedanib (38.72), prinomastat (30.52, MMP1/MMP3), and dasatinib (29.40, DDR2/PDGFRA). The AXL/DDR2/PDGFRA receptor tyrosine kinase axis and MMP1/MMP3 matrix metalloproteinase axis emerge as high-priority therapeutic targets coherent with the PsA transcriptomic signature. CHEMBL5653589 and dasatinib are confirmed cross-disease watchlist molecules spanning neurodegeneration and autoimmune scRNA-seq pipelines. Authors: Glen Charles Ritschel, Ritschel Research, Tega Cay SC; Claude, Anthropic, San Francisco CA.