Rosacea is a chronic inflammatory skin condition marked by persistent redness, visible blood vessels, and facial lesions, affecting approximately 5.5% of the global population. Triggers include UV exposure, heat, spicy food, and genetic factors. At the molecular level, excess activation of TLR2 and overexpression of LL-37 leads to inflammation, angiogenesis, and skin barrier breakdown via the NF-κB pathway. Current treatments—like antibiotics and laser therapy—target limited aspects of the disease and carry side effects. Peptide-based therapeutics like AdhPep3, derived from mussel adhesive protein, offer a promising multi-targeted approach with fewer adverse effects.
Methods
The study evaluated AdhPep3’s therapeutic potential using LL-37-stimulated HaCaT keratinocytes and HUVECs. Researchers assessed inflammation, angiogenesis, and skin barrier markers through ELISA, RT-qPCR, and Western blotting. Angiogenesis was examined using scratch and tube formation assays, and immunocytochemistry was used to detect endothelial marker expression. Comparative analysis with doxycycline and metronidazole provided context for therapeutic efficacy.
Key Findings
- Lead Candidate Selection: AdhPep3 was chosen among three peptides for its superior anti-inflammatory effect in keratinocytes, with no cytotoxicity at therapeutic doses.
- Anti-Inflammatory Activity: AdhPep3 significantly suppressed secretion and mRNA expression of key cytokines including VEGF, TNF-α, IL-1β, IL-6, and IL-8 in LL-37-induced keratinocytes, confirming its strong immunomodulatory potential.
- Pathway Regulation: It inhibited LL-37-induced TLR2, KLK5, and MMP9 protein expression. It also blocked the phosphorylation of NF-κB (p65, p50, IκB-α) and MAPK pathway components (AKT, ERK1/2, JNK), indicating broad anti-inflammatory signaling suppression.
- Anti-Angiogenic Effect: AdhPep3 reduced angiogenesis-related cytokines and proteins such as VEGF-A, IL-6, TGF-β, and CD31. It also decreased endothelial cell migration and disrupted blood vessel-like structure formation in HUVEC models.
- Barrier Function Restoration: It upregulated skin structural proteins including Filaggrin, Involucrin, Claudin-1, Claudin-4, and Occludin, pointing to improved skin integrity and barrier resilience—critical in rosacea care.
- Comparable to Standard Drugs: At just 300 nM, AdhPep3 matched or surpassed doxycycline and metronidazole in reducing inflammation and angiogenesis—at a fraction of their concentration (20 µg/mL).
Conclusion
AdhPep3 is a promising therapeutic peptide that offers a three-pronged strategy for managing rosacea: calming inflammation, suppressing abnormal angiogenesis, and repairing the compromised skin barrier. Its mechanism centers on modulating LL-37-induced pathways, with efficacy comparable to current drugs but at significantly lower doses. As a peptide-based agent, it holds excellent potential for optimization, stability, and topical delivery. Further preclinical and clinical studies will be crucial to confirm its safety, pharmacokinetics, and therapeutic benefits, potentially positioning AdhPep3 as a next-generation treatment in both medical and cosmetic dermatology.
Link to the study: https://www.mdpi.com/2079-9284/12/4/143
