The MRGPRX2 gene, a member of the G protein-coupled receptor (GPCR) family, encodes a unique receptor protein with a pivotal role in immunological and neurological signaling ^[1]. Primarily expressed on mast cells and sensory neurons, the MRGPRX2 protein functions as a non-canonical receptor that circumvents traditional IgE-mediated pathways. Its ligand repertoire is remarkably broad, encompassing a diverse array of stimuli, including endogenous neuropeptides (e.g., substance P) and exogenous cationic drugs (e.g., fluoroquinolones, neuromuscular blocking agents) ^[2]. Ligand binding to MRGPRX2 initiates mast cell degranulation, a process that releases potent pro-inflammatory mediators such as histamine and tryptase. This activation mechanism is a central driver of pseudo-allergic reactions, a class of drug hypersensitivities that mimic true allergic responses without involving IgE ^[3]. Emerging evidence further implicates MRGPRX2 in the pathophysiology of various inflammatory and pruritic diseases, including chronic spontaneous urticaria and atopic dermatitis, underscoring its therapeutic potential as a target for modulating mast cell activity ^[4]. The B6-hMRGPRX2 mouse is a humanized model, constructed by replacing the sequences from exon 1 to partial intron 1 of mouse Mrgprx2 with the Kozak-human MRGPRX2 CDS-3'UTR of mouse Mrgprx2-WPRE-BGH pA cassette. B6-hMRGPRX2 mice can be used for research into the pathogenesis of various inflammatory and pruritic diseases, including chronic spontaneous urticaria and atopic dermatitis. They are also useful for the development of MRGPRX2-targeted drugs.