Polypharmacological effects of honokiol on allergic rhinitis: Modulation of TMEM16A, TRPV1, and calcium signaling

Background: Allergic rhinitis (AR) affects approximately 400 million people globally and causes rhinorrhea, nasal congestion, and sneezing. Nonetheless, current treatments often provide incomplete relief and have side effects. Recent studies have indicated that various ion channels contribute to AR symptoms, suggesting that multichannel targeting may offer a more effective treatment. Methods: We first demonstrated that the inhibition of either ANO1 or ORAI1 channels individually alleviated symptoms in an ovalbumin-induced AR mouse model, with enhanced effects when both channels were targeted simultaneously. We then investigated whether honokiol, from magnolia bark, exhibited anti-AR effects by inhibiting multiple ion channels (ANO1, TRPV1, ORAI1). These effects were assessed using patch-clamp electrophysiology, calcium imaging, immune cell function assays (in T and mast cells), and in vivo studies. Results: Honokiol inhibited all three ion channels with comparable potency (IC₅₀ values: ANO1, 7.50 µM; TRPV1, 4.58 µM; ORAI1, 7.35 µM). This multi-channel inhibition suppressed key allergic responses, functionally attenuating mast cell degranulation while reducing T cell proliferation (45.6 % at 10 µM) and IL-2 secretion (52.8 %). In AR mice, honokiol significantly reduced allergic symptoms (by 37.4 %), serum IgE levels (by 18.3 %), and eosinophil infiltration (by 64.3 %), demonstrating an efficacy comparable to corticosteroid therapy. Conclusions: Our findings revealed that the therapeutic effect of honokiol stems from its novel polypharmacological action on multiple ion channels and critical immune cells. By suppressing both early- (mast cell-driven) and late-phase (T cell-driven) allergic responses, this multitarget approach represents a new strategy for AR treatment that could overcome the limitations of current single-target therapies.