Glycerophospholipid metabolism licenses IgE-mediated mast cell degranulation

Immunoglobulin E (IgE) antibodies and mast cells have been extensively recognized to dictate the pathophysiology of anaphylaxis and allergic reactions; nevertheless, the pivotal cues driving IgE-mediated mast cell degranulation remain enigmatic. Here, we demonstrate that FcεRI aggregation-initiated p38α signaling stimulates Ets-1 transcription by recruitment of the SWI-SNF chromatin-remodeling complex, contributing to Pcyt1a expression and glycerophospholipid metabolism in IgE-stimulated mast cells. Most importantly, Pcyt1a-mediated glycerophospholipid metabolism facilitates mast cell degranulation through the limited macropinocytosis of FcεRI via altering H3K9me3 deposition at the promoter of Prkcd. Moreover, the metabolic cue functions as an instigator of allergic diseases (e.g., atopic dermatitis [AD]) according to preclinical findings of murine models, in silico analysis of human disease studies, and examination of clinical samples. In summary, our study establishes that lipid metabolism and signaling orchestrate mast cell activation and provides promising therapeutic targets for clinically tackling allergic diseases.