Activated mast cells (MCs) are crucial effectors in the initiation and progression of psoriasis by secreting inflammatory mediators. The MC activation mediated by Mas-related G-protein-coupled receptor X2 (MrgprX2) has been implicated in psoriasis progression. However, the therapeutic strategies targeting MrgprX2 for psoriasis treatment remain less explored. Alkannin (Alk) is the main active component of the plant Arnebia euchroma and exhibits significant anti-inflammatory activities. However, in psoriasis, the effect of Alk on MCs and MrgprX2 remains elusive. In psoriatic mouse models, Alk alleviated epidermal hyperplasia, vascular dilation, and splenomegaly, regulated the Th17 to Treg cells ratio, and reduced the proinflammatory cytokine levels. In vitro analyses indicated that Alk inhibited β-hexosaminidase release, downregulated the expression of inflammation-related cytokines, and reduced intracellular Ca2+ levels in a MrgprX2-dependent manner. Moreover, SPR, CETSA, DARTS, and molecular docking assays revealed a direct interaction between Alk and MrgprX2, suggesting that Alk targets MrgprX2 to inhibit MC activation. Furthermore, Alk inhibited the downstream PLCγ-IP3R-PKC-ERK signaling pathways via targeting MrgprX2. Consistently, in vivo functional assays confirmed that Alk inhibits MrgprB2-related MC activation, a critical process driving psoriatic symptom progression. Collectively, these results demonstrate that Alk directly binds to MrgprX2 and modulates MC activation by inhibiting downstream PLCγ-IP3R-PKC-ERK signaling pathways, thus mitigating psoriasis symptoms. These findings provide a novel target and theoretical basis for the treatment of psoriasis.
