Mas-related G protein-coupled receptor X2 in non-IgE-mediated mast cell activation and anaphylaxis: a paradigm shift

Purpose of review – The understanding of anaphylaxis has evolved over time beyond the classical IgE-mediated paradigm. This review examines the role of Mas-related G protein-coupled receptor X2 (MRGPRX2) in non-IgE-mediated mast cell activation, a mechanism increasingly recognized in mast cell activation, anaphylaxis, and other mast cell-driven conditions. Recent findings – Recent studies have identified MRGPRX2 as a key receptor in rapid mast cell degranulation in response to a broad range of cationic ligands such as drugs, neuropeptides, and host defence-related peptides. Structural and signalling insights have clarified its dual coupling to Gi and Gq pathways. Clinically, MRGPRX2 has been implicated in immediate reactions to antibiotics, neuromuscular blocking agents and other compounds, often occurring upon first exposure. Additionally, emerging evidence suggests roles in chronic urticaria, neurogenic inflammation, and host defence, as well as growing interest in MRGPRX2 as a therapeutic target. Summary – MRGPRX2 represents a paradigm shift in mast cell biology, providing a solid base for non-IgE-mediated hypersensitivity. Improved understanding of this pathway may enhance diagnostic accuracy and enable the development of targeted therapies, although significant challenges remain in distinguishing activation mechanisms in clinical practice.