Systemic Proteomic Alterations and Predictive Biomarkers of Paroxetine Response in Refractory Rosacea

Importance: Rosacea is a chronic inflammatory cutaneous disorder characterized by persistent erythema and vascular dysregulation. While paroxetine has shown clinical efficacy in reducing these symptoms, the systemic molecular mechanisms underlying its therapeutic response remain poorly characterized. Objective: To investigate systemic proteomic alterations and identify potential predictive biomarkers in patients with refractory erythematous rosacea following paroxetine treatment. Design, Setting, and Participants: This prospective plasma proteomic analysis was nested within a multicenter, randomized, double-blind, placebo-controlled clinical trial (Prospective Rosacea Refractory Erythema Randomized Clinical Trial [PRRERCT]). Participants included patients aged 18 to 65 years with refractory rosacea (Clinician's Erythema Assessment [CEA] score ≥3). Plasma samples were collected at baseline and after 12 weeks of treatment. The data for this study were analyzed between September 2025 and November 2025. Interventions: Participants received oral paroxetine, 25 mg per day, for a 12-week treatment period. Main Outcomes and Measures: Systemic protein expression profiles were analyzed using data-independent acquisition liquid chromatography-tandem mass spectrometry. Clinical response was evaluated using CEA and the Flushing Assessment Tool. Correlations between proteomic changes and clinical improvements were assessed, and predictive biomarkers were identified using receiver operating characteristic curve analysis. Results: Among 24 participants (mean [SD] age, 35 [11] years; 24 [100%] female), paroxetine treatment significantly reduced mean (SD) CEA scores from 3.1 (0.3) to 2.3 (0.7) and Flushing Assessment Tool scores from 3.1 (0.6) to 2.0 (0.9) (P < .001). Exploratory proteomic analysis revealed 497 candidate differentially expressed proteins after treatment. Downregulated proteins showed preliminary enrichment in pathways related to immune response activation, insulin receptor signaling, and neuronal remodeling. A subset of 98 reversed-response proteins was observed, primarily linked to synaptic vesicle cycles and vascular smooth muscle contraction. Proteomic alterations were associated with clinical improvement (65 proteins for erythema; 73 for flushing). Candidate biomarkers, notably OLFML3 (area under the receiver operating characteristic curve [AUC], 0.87 [95% CI, 0.70-1.00]) and IGFBP2 (AUC, 0.80 [95% CI 0.55-1.00]), demonstrated high predictive value for clinical response. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, paroxetine treatment was associated with modulation of systemic neuro-vascular-immune networks in patients with rosacea. These exploratory findings provide preliminary mechanistic clues regarding the possible disease-modifying potential of paroxetine and point to circulating protein signatures that may facilitate personalized therapeutic strategies for rosacea management. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000031479.