Pedunculoside alleviates cheilitis-like inflammation by suppressing the TLR3/TRIF/NF-κB signaling

Pedunculoside as a TLR3-targeting immunomodulator for cheilitis-like inflammation treatment. • Pedunculoside has anti-skin inflammation and barrier repaire effects. • Pedunculoside inhibits the TLR3/TRIF/NF-κB signaling. • Pedunculoside provides a novel plant-assisted strategy for the treatment of cheilitis. Background Cheilitis is a lip-specific inflammatory disorder lacking safe long-term therapies. Topical glucocorticoids are limited by adverse effects, highlighting the need for plant-derived immunomodulators with dual anti-inflammatory and barrier-repairing effects. Objective To evaluate the therapeutic potential, mechanism and human efficacy of pedunculoside in cheilitis. Methods Pedunculoside was evaluated in vitro using CCK-8, scratch, ELISA, immunofluorescence, RT-qPCR, western blot, molecular docking and SPR. In human efficacy evaluation, pedunculoside formulation were assessed by VISIA-CR imaging, skin hydration and transepidermal water loss on the lips. Results Pedunculoside (≤120 μM) showed no cytotoxicity and increased scratch wound closure 4.5-fold ( N  = 4). It upregulated barrier genes (AQP3: 1.7-fold, FLG: 2.3-fold, SPINK5: 11.16-fold, IVL: 7.96-fold, ZO-1: 2.26-fold, OCLN: 2.22-fold and KRT1: 4.41-fold) ( N  = 4) and suppressed inflammatory cytokines (IL-6: 0.68-fold, IL-8: 0.53-fold, IL-1β: 0.65-fold, TSLP: 0.69-fold, CCL5: 0.55-fold and CCL17: 0.58-fold) ( N  = 3). Mechanistically, pedunculoside directly bound with TLR3 and suppressed TLR3/TRIF/NF-κB signaling. In human efficacy, the pedunculoside formulation reduced lip redness by 0.3-fold (4 h, N  = 32) and 0.23-fold (at 28 days, N  = 20), decreased TEWL value by 0.22-fold (at 4 h) and 0.27-fold (at 28 days) and improved hydration by 0.22-fold (at 4 h) and 0.27-fold (at 28 days) versus baseline. Conclusion Pedunculoside is a novel TLR3-targeting immunomodulator that enhances barrier repair and suppresses inflammation in vitro, while its formulation improves cheilitis symptoms. The absence of animal studies before human testing represents a limitation; larger trials are warranted to confirm long-term safety and efficacy. Download: Download high-res image (372KB) Download: Download full-size image