The MRGPRX2 paradigm shift: Redefining mast cell activation pathways in chronic urticaria

Chronic urticaria (CU) is a skin disease characterized by recurrent episodes of vascular dilation and increased permeability of the cutaneous and mucosal microvasculature. Although antihistamines and omalizumab remain first-line and second-line therapies, respectively, a significant proportion of patients develop recalcitrant disease phenotypes, highlighting critical unmet needs for innovative therapeutic paradigms. In recent years, emerging insights into Mas-related G protein-coupled receptor X2 (MRGPRX2) have revealed transformative perspectives for elucidating the pathobiology of refractory CU. As a class A G protein-coupled receptor (GPCR) that is predominantly localized to mast cells, MRGPRX2 orchestrates non-IgE-mediated mast cell degranulation through its pluripotent ligand recognition capacity, engaging diverse exogenous cationic compounds, neuropeptides, and certain pharmacological agents. This comprehensive review evaluates recent advancements in deciphering the mechanistic contributions of MRGPRX2 to CU pathogenesis, with the ultimate aim of informing the development of precision diagnostic and therapeutic frameworks for CU management.