超短环肽Cy<sub>RL-QN15</sub>作为TLR4拮抗剂加速口腔溃疡愈合

Oral ulcers (OUs) are prevalent oral mucosal lesions characterized by pain and burning sensations, and remain clinically challenging due to limited therapies, necessitating innovative treatment approaches. CyRL-QN15, a novel ultra-short cyclic heptapeptide, has recently shown efficacy in skin repair, diabetic foot ulcer healing, and hair regeneration. This study evaluated the mucosal regenerative efficacy of CyRL-QN15 using a rat OU model and a primary oral epithelial cell inflammation model. Results revealed that CyRL-QN15 accelerated OU healing by orchestrating immune-epithelial crosstalk mechanisms, including suppression of inflammatory cytokine release from macrophages and neutrophils, reduction of pro-inflammatory factor secretion by oral epithelial cells, and enhancement of their proliferative and migratory capacities. Mechanistically, through alanine scanning mutagenesis and microscale thermophoresis validation, CyRL-QN15 directly bound to Toll-like receptor 4 (TLR4) via a methionine residue (Kd = 2.64 µM), inhibiting the MyD88/NF-κB pathway. As the first reported ultra-short cyclic heptapeptide TLR4 antagonist, CyRL-QN15 uniquely modulates the inflammation-repair balance, offering both a novel therapeutic candidate and mechanistic insights for TLR4-based OU intervention.