scRNA-Seq-based drug repurposing targeting idiopathic pulmonary fibrosis (IPF)

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease, which affects around three million people worldwide and is characterized by impaired regeneration from recurrent injury to the alveolar epithelium resulting in progressive lung scarring. In this work, we target a cell transition in the differentiation of AT2 cells into mature AT1 cells which is inhibited in IPF and contributes to the regeneration of the alveolar epithelium. We hypothesize that inducing this transition promotes lung regeneration and can ameliorate the disease. To this end, we characterized the intermediate population to AT1 cell transition signature using multiple recently generated single-cell RNA-Seq datasets on murine bleomycin injury and IPF patients. We then matched this signature to drug perturbation signatures retrieved from the LINCS database to identify the most suitable candidates for drug repurposing. Compound classes identified in this analysis include glucocorticoids, HSP90 inhibitors, HDAC inhibitors and a range of kinase inhibitors. Furthermore, we are able to interpret our findings by identifying multiple potential direct targets and downstream effectors, such as NFKB1 and HIF1A. Overall, we show how scRNA-Seq data can potentially be leveraged for drug repurposing by enabling better characterization of cell transitions which can subsequently be used for signature matching.