Drug Design in the Age of Network Medicine and Systems Biology: Transcriptomics Identifies Potential Drug Targets Shared by Sarcoidosis and Pulmonary Hypertension

Abstract

Network medicine considers the interconnectedness of human diseases and their underlying molecular substrates. In this context, sarcoidosis and pulmonary hypertension (PH) have long been thought of as distinct diseases, but there is growing evidence of shared molecular mechanisms. This study reports on common differentially expressed genes (DEGs), regulatory elements, and pathways between the two diseases. Publicly available transcriptomic datasets for sarcoidosis (GSE157671) and PH (GSE236251) were retrieved from the Gene Expression Omnibus database. DEGs were identified using GEO2R, followed by pathway enrichment and gene interaction analyses via GeneMANIA and STRING. Importantly, a total of 13 common DEGs were identified between sarcoidosis and PH, with 7 upregulated and 6 downregulated genes. The SMAD2/3 nuclear pathway was a shared enriched pathway, suggesting a role in fibrosis and immune regulation. There were also divergences between sarcoidosis and PH. For example, gene set enrichment analysis indicated significant associations of the IFN-gamma signaling pathway with sarcoidosis and the TNF-alpha signaling with PH. miRNA network analysis identified hsa-miR-34a-5p, hsa-let-7g-5p, and hsa-miR-19a-3p as key shared regulators linked to common genes in both sarcoidosis and PH. Finally, DGIdb analysis revealed potential therapeutic candidates targeting these genes in both diseases. This study contributes to the field of drug design and discovery from a network medicine standpoint. The shared molecular links uncovered between sarcoidosis and PH in this study point to several potential biomarkers and therapeutic targets. Further experimental validation and translational medical research are called for diagnostics and drugs, which can effectively and safely help the clinical management of both diseases.