Ultra-short cyclic peptide CyRL-QN15 acts as a TLR4 antagonist to expedite oral ulcer healing

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.