Beyond the classic players: Mas‐related G protein‐coupled receptor member X2 role in pruritus and skin diseases

Abstract Chronic spontaneous urticaria (CSU), atopic dermatitis (AD), psoriasis and rosacea are highly prevalent inflammatory skin conditions which impose a significant burden on patients' quality of life. Their pathophysiology is likely multifactorial, involving genetic, immune and environmental factors. Recent advancements in the field have demonstrated the key role of mast cells (MC) in the pathophysiology of these conditions. The Mas‐related G protein‐coupled receptor X2 (MRGPRX2) has emerged as a promising non‐IgE‐mediated MC activation receptor. MRGPRX2 is predominately expressed on MC and activated by endogenous and exogenous ligands, leading to MC degranulation and release of various pro‐inflammatory mediators. Mounting evidence on the presence of endogenous MRGPRX2 agonists (substance P, cortistatin‐14, LL37, PAMP‐12 and VIP) and its high expression among patients with CSU, AD, rosacea, psoriasis and chronic pruritus emphasizes the pathogenic role of MRGPRX2 in these conditions. Despite the currently available treatments, there remains a pressing need for novel drug targets and treatment options for these chronic inflammatory skin conditions. Here, we reviewed the pathogenic role of MRGPRX2 and its potential as a novel therapeutic target and provided an update on future research directions.