Transcriptome-Guided Drug Repurposing for Calcinosis in Systemic Sclerosis: A Single-Cell RNA-seq and LINCS L1000 Analysis

Calcinosis cutis affects 20–40% of patients with systemic sclerosis (SSc) and has no approved disease-modifying treatment. We applied a scRNA-seq pipeline to GSE138669 (Tabib et al. 2021, n=22 SSc skin biopsies, 57,156 cells), performed scVI dimensionality reduction, Leiden clustering (resolution 0.8, 25 clusters), calcinosis signature scoring (osteogenic, calcification, hypoxia, fibrosis, inflammation), Wilcoxon differential expression, and Enrichr LINCS L1000 drug reversal scoring. Clusters 3 and 1 showed the highest osteogenic and fibrosis scores, identifying putative pro-calcinosis fibroblast subpopulations. LINCS L1000 reversal scoring identified 20 priority drug candidates, of which 14 were NOVEL_ALL. Top mechanistically prioritised candidates include LDN-193189 (BMP receptor ALK2/ALK3), PD-0325901 (MEK1/2), radicicol (HSP90), WYE-125132 (mTORC1/2), and fedratinib (JAK2). Pipeline code: https://github.com/glenritschel/calcinosis-crest