Supplemental Material: Proteomic profiling reveals distinct inflammatory and neurogenic endotypes in rosacea

Rosacea is a chronic inflammatory skin disorder with possible systemic involvement. To investigate its underlying molecular mechanisms, we conducted quantitative serum proteomic profiling on plasma samples from 27 rosacea patients and 25 age- and sex-matched healthy controls. A total of 490 differentially expressed proteins were identified, including 431 upregulated and 59 downregulated proteins. Upregulated proteins were enriched in inflammatory (PI3K-Akt, IL-17), metabolic (cholesterol), and neuroregulatory pathways, while downregulated proteins were mainly involved in complement pathways. Cluster analysis revealed two distinct molecular endotypes: an inflammatory-predominant subtype and a neurogenic-metabolic subtype. Symptom-specific biomarker patterns were also observed, with flushing linked to neutrophil-driven inflammation and lipid metabolism, and burning sensations associated with neuronal repair and complement activation. This study provides the first comprehensive proteomic evidence that rosacea is a systemic inflammatory disease with heterogeneous molecular profiles. These findings support the development of tailored therapeutic strategies targeting neuroimmune and metabolic dysregulation.