Novel Molecular Subtyping Revealed Molecular Pathways That Contribute to the Pathogenesis of Rosacea

The latest progress in rosacea research over the past two decades has revealed important limitations of the current clinical subtyping approach. A new framework of rosacea molecular subtyping is urgently needed to gain insight into the pathogenesis of rosacea. Here, we propose a novel molecular subtype of rosacea based on pathogenetic progression using gene set enrichment analysis (GSEA) and consensus clustering analysis. We identified molecular pathways that contribute to the severity of rosacea. Specifically, the renin angiotensin system (RAS) pathway contributes to erythema and flushing in the mild stage, and the gradual activation of inflammatory pathways and decreased metabolism and biosynthesis were found to be correlated with the severity of rosacea. In addition, angiogenesis and neutrophil activation may contribute to persistent erythema and a large number of papules and pustules in the severe stage of rosacea. Finally, the transcription factor (TF) regulatory network revealed that the key TFs (ETV4, ETS1, USF1, IFR1, NFKB1, and STAT1) and their targets regulated the RAS, inflammatory, and angiogenesis pathways, contributing to the pathogenesis of rosacea. This work correlated molecular subtyping of rosacea with its pathogenetic progression, which provided insight into the pathogenesis and therapeutic strategies for rosacea patients of different severity.