Abstract

BACKGROUND: Rosacea represents a chronic inflammatory dermatosis with potential systemic manifestations. While neuroimmune dysregulation and systemic inflammation are implicated in its pathogenesis, comprehensive proteomic profiling remains unexplored. OBJECTIVE: To characterize serum proteomic signatures and identify molecular endotypes in rosacea. METHODS: Using a prospectively characterized clinical cohort, we conducted quantitative proteomic profiling of serum samples from 27 rosacea patients and 25 healthy controls matched for age and sex. Bioinformatic analyses then correlated differentially expressed serum proteins with clinical symptom measures. RESULTS: Analysis identified 490 differentially expressed proteins (431 upregulated, 59 downregulated; log2FC > 1, P < .05). Downregulated proteins were enriched in complement pathways, while upregulated proteins implicated inflammatory (PI3K-Akt, IL-17), metabolic (cholesterol), and neuroregulatory pathways. Cluster analysis revealed 2 distinct endotypes: an inflammatory-predominant subtype (n = 22) and a neurogenic-metabolic subtype (n = 5). Integrative biomarker analysis revealed distinct molecular signatures for rosacea symptoms. Flushing was linked to neutrophil-driven inflammation and lipid metabolism (46 proteins), while burning was associated with neuronal repair and complement activation (120 proteins). LIMITATIONS: Cross-sectional design and female-predominant cohort. CONCLUSION: This pioneering proteomic study establishes rosacea as a systemic inflammatory disorder with distinct molecular endotypes, supporting tailored therapeutic approaches targeting neuroimmune-metabolic dysregulation.