EGR1 regulates degranulation and mediator release in C48/80-induced pseudo-allergic reactions

Allergic diseases significantly impair human health and quality of life, and IgE-independent pseudo-allergic reactions represent a common yet incompletely understood subtype with limited diagnostic and therapeutic options. Cationic secretagogues such as compound 48/80 (C48/80) can trigger mast-cell degranulation in IgE-independent pseudo-allergic responses, but the downstream transcriptional mechanisms remain largely unclear. In this study, we employed a C48/80-induced IgE-independent pseudo-allergic reaction model, combined with transcriptome sequencing, cellular functional assays, and pharmacological interventions, to investigate the role of the transcription factor early growth response 1 (EGR1). Transcriptomic analysis revealed significant upregulation of EGR1 during pseudo-allergic reactions. Functional assays showed that C48/80 stimulation induced characteristic degranulation morphology in RBL-2H3 cells, accompanied by increased beta-hexosaminidase and histamine release. Genetic knockdown of EGR1 or pharmacological inhibition with ML264 markedly suppressed degranulation, was associated with reduced phosphorylation of Lyn, Syk, ERK1/2, and AKT in C48/80-stimulated RBL-2H3 cells, and alleviated tissue edema and inflammatory cell infiltration in a C48/80-induced murine cutaneous vascular permeability/swelling model. Collectively, these findings identify EGR1 as an important regulator of C48/80-responsive pseudo-allergic phenotypes in the RBL-2H3 cell model and mouse models and provide a basis for further mechanistic and translational validation.