Saffron-derived crocin and its active metabolite crocetin ameliorate pseudo-allergic reactions and allergic asthma via MRGPRX2

Saffron ( Crocus sativus L. ) is a medicinal and edible plant, widely regarded as a superfood due to its diverse bioactive constituents. However, its potential application in allergic diseases remains largely underexplored. In this study, we found that saffron extract and its major active component, crocin, effectively target MRGPRX2 on mast cells and alleviate pseudo-allergic reaction as well as allergic asthma by inhibiting the oxidative stress pathway. After oral administration, crocin is almost fully deglycosylated into crocetin in the gastrointestinal tract. Crocin and crocetin share identical MRGPRX2 binding pockets and exhibit comparable receptor antagonistic potency. The study applied MRGPRX2-based cell membrane chromatography (CMC) for active compound screening, along with in vitro MRGPRX2-mediated mast cell activation assays, and i n vivo models including passive local and systemic pseudo-allergic reactions as well as allergic asthma for pharmacological evaluation. Results demonstrated that saffron extract inhibited MRGPRX2-mediated mast cell activation; crocin exhibited specific chromatographic retention on MRGPRX2/CMC columns, and molecular docking together with Ca²⁺ influx assays further confirmed its antagonistic activity against MRGPRX2. In mast cell activation assays, crocin significantly suppressed MRGPRX2-mediated Ca²⁺ influx, degranulation, and pro-inflammatory cytokine release. In vivo , crocin effectively inhibited both passive local and systemic pseudo-allergic reactions, and alleviated airway hyperresponsiveness (AHR), Th2 cytokine levels in bronchoalveolar lavage fluid, lung tissue injury, as well as mast cell degranulation in allergic asthma mice. Mechanistic studies revealed that crocin reduced the production of oxidative mediators in mast cells both in vitro and in vivo , and suppressed the activation of the PLC/PKC/OX-CaMKII signaling pathway. Collectively, these findings demonstrate that saffron extract and its active component crocin exert anti-allergic effects by targeting the MRGPRX2/ROS/OX-CaMKII pathway, and the in vivo anti-allergic efficacy of oral crocin is mainly mediated by its bioactive metabolite crocetin. Given the favorable safety profile and the medicinal-and-edible nature of saffron, its extract and crocin hold promise as functional food or nutraceutical additives for the prevention or adjuvant management of MRGPRX2-related allergic diseases; nanocarrier encapsulation strategies could be further explored to enhance intact crocin tissue delivery, offering broad prospects for further application.