Abstract Currently, there is no pharmacological treatment targeting defective tissue repair in chronic disease. Here we utilized a transcriptomics-guided drug target discovery strategy using gene signatures of smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke, identifying druggable targets expressed in alveolar epithelial progenitors of which we screened the function in lung organoids. We found several drug targets with regenerative potential of which EP and IP prostanoid receptor ligands had the most significant therapeutic potential in restoring cigarette smoke-induced defects in alveolar epithelial progenitors in vitro and in vivo . Mechanistically, we discovered by using scRNA-sequencing analysis that circadian clock and cell cycle/apoptosis signaling pathways were enriched in alveolar epithelial progenitor cells in COPD patients and in a relevant model of COPD, which was prevented by PGE2 or PGI2 mimetics. Conclusively, specific targeting of EP and IP receptors offers therapeutic potential for injury to repair in COPD.

A transcriptomics-guided drug target discovery strategy identifies novel receptor ligands for lung regeneration

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