Rosacea Pathogenesis Linked to Neurohormonal-Immune Dysregulation Across Skin-Gut-Brain Axis

Rosacea is a chronic inflammatory skin disease with a global prevalence of approximately 5.1%, primarily affecting the centrofacial region. Traditionally viewed as a localized skin condition, its underlying mechanisms remain complex and not fully understood. Current treatments often target symptoms rather than root causes, leading to variable efficacy and recurrence. Emerging evidence suggests a critical role for dysregulation within the neuro-hormone-immune network, operating across the skin-gut-brain axis, as a key driver of rosacea's diverse manifestations.

This review article synthesizes existing evidence on the potential roles of various systemic factors in rosacea pathogenesis. Researchers explored the influence of stress hormones, sex hormones, and insulin-like growth factor-1 (IGF-1) across the four major rosacea subtypes. The review systematically summarized findings related to neurovascular flushing, inflammatory lesion formation, sebaceous gland hyperplasia, fibrosis, and ocular manifestations, linking them to specific hormonal and immune pathways and gut microbiota interactions.

The review highlights distinct neurohormonal-immune dysregulations across rosacea subtypes. In erythematotelangiectatic rosacea, glucocorticoid resistance in keratinocytes may drive CCL20-mediated Th17 inflammation, while catecholamines from sympathetic nerves are implicated in neurovascular flushing. For papulopustular rosacea, a combination of androgen excess, relative estrogen deficiency, LL-37-mediated innate immune activation, and gut microbiota dysbiosis collectively contributes to inflammatory skin lesions. > In the phymatous type, insulin-like growth factor-1 and androgens 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. The review also identified potential therapeutic avenues, including β-receptor blockers (e.g., carvedilol), selective serotonin reuptake inhibitors (e.g., paroxetine), anti-androgen drugs (e.g., spironolactone), and metformin, depending on the subtype.