Neurohormonal-Immune Dysregulation in Rosacea: Emerging Perspectives from the Skin-Gut-Brain Axis

Rosacea is a chronic inflammatory skin disease with a global prevalence of approximately 5.1%. Existing evidence suggests that its pathogenesis may be associated with dysregulation of the neuro-hormone-immune network within the skin-gut-brain axis framework. This review summarizes the potential roles of stress hormones, sex hormones, and insulin-like growth factor-1 in the four major subtypes. In erythematotelangiectatic rosacea, glucocorticoid resistance within keratinocytes may induce CCL20-driven Th17 inflammation, while catecholamines released by sympathetic nerves are associated with neurovascular flushing. In papulopustular rosacea, androgen excess, relative estrogen deficiency, LL-37-mediated innate immune activation, and gut microbiota dysbiosis may collectively contribute to the formation of inflammatory skin lesions.In the phymatous type, insulin-like growth factor-1 and androgens may interact through the PI3K/Akt/mTOR and FoxO1 pathways, promoting sebaceous gland hyperplasia and fibrosis. Ocular rosacea is associated with gut-derived low-grade systemic inflammation and neurogenic inflammation. For treatment, β-receptor blockers such as carvedilol and selective serotonin reuptake inhibitors such as paroxetine can be used for erythematotelangiectatic rosacea; anti-androgen drugs like spironolactone and metformin may be explored for papulopustular rosacea; metformin for the phymatous type; and for ocular rosacea, topical corticosteroids can be used cautiously for a short term under ophthalmological supervision. Adjunctive interventions such as eradication of small intestinal bacterial overgrowth, a low glycemic index diet, and mindfulness-based stress reduction therapy also demonstrate potential.Taken together, existing evidence supports viewing rosacea as a systemic disease potentially mediated by the skin-gut-brain axis and characterized by dysregulation of the neuro-hormone-immune network. However, more high-quality randomized controlled trials and stratified studies guided by hormone-related biomarkers are currently needed to further validate its mechanisms and advance precision treatment.