Senkyunolide I alleviates allergic rhinitis by inhibiting JAK1/3-STAT3/6 and JNK signalings.

Background: Allergic rhinitis (AR) is a common allergic disease with a high incidence rate. Senkyunolide I (SEI), a bioactive ingredient isolated from Ligusticum sinense 'Chuanxiong', exhibits known analgesic and anti-inflammatory effects, yet its anti-AR potential remains unexplored. Here, we aim to investigate the therapeutic efficacy and molecular mechanisms of SEI against AR.

Methods: In IL-4-stimulated human nasal epithelial cells (HNEpCs), the levels of allergic mediators were quantified by RT-qPCR. The anti-AR efficacy of SEI was then validated in ovalbumin (OVA)/Al(OH)-induced mice. Mechanistic studies combining western blotting, CETSA, and molecular docking identified the molecular mechanisms and targets of SEI.

Results: In vitro, SEI effectively reduced IL-4-induced mRNA expression of CCL11, CCL26, IL-33, periostin, VCAM-1, and MUC5AC in HNEpCs. Furthermore, oral administration of SEI significantly alleviated OVA/Al(OH)-induced AR in mice, which mainly manifested as: (1) reduced serum levels of IL-4, IL-13, OVA-IgE, and IgE; (2) decreased nasal lavage fluid (NALF) levels of IL-4, IL-13, and OVA-IgE; (3) down-regulated mRNA expression of CCL11, CCL26, IL-5, IL-33, periostin, and MUC5AC; and (4) inhibited infiltration of eosinophils and mast cells in the nasal mucosa. Mechanistically, SEI was able to directly interact with JAK1/3 kinases, resulting in the inactivation of JAK1/3-STAT3/6 signaling cascades in IL-4-stimulated HNEpCs and OVA/Al(OH)-challenged mice. Additionally, SEI was found to inhibit IL-4-induced JNK phosphorylation in vitro and in vivo.

Conclusion: We confirmed that SEI alleviated AR via inhibiting JAK1/3-STAT3/6 and JNK pathways, raising the possibility that SEI could function as a promising candidate for the therapy of AR or other allergic diseases.