Integrated Multi‐Omics and Experimental Validation Unveil the GZMK/NF‐κB Axis Driving Inflammation and Fibroblast Proliferation in Rosacea: A Novel Drug Target Selection Strategy

The prevalence of rosacea is high, while the drug options remain limited. Mendelian randomization (MR) is an effective way to prioritize plasma proteins as novel drug targets based on their causal effects on rosacea. The plasma proteins were categorized into different levels of drug targets by the MR and Bayesian colocalization analysis. Their genetic and protein expression was investigated using an RNA sequencing dataset and experiments in vitro and in vivo. MR and colocalization identified Granzyme K (GZMK) as a drug target, whose expression increased in the affected samples. A novel mouse model of rosacea was established by GZMK, mimicking rosacea-like symptoms both in vitro and in vivo. GZMK also promoted cell proliferation and inflammatory factors (including IL-1β, IL-6, and TNFα) production in fibroblasts through activating the NF-κB pathway in vitro. Our research identified a novel protein involved in rosacea pathogenesis, elucidated the underlying mechanisms, and advanced the development of potential rosacea treatments.