Development of a Novel VDR-Activating Peptide as a Functional Cosmetic Ingredient for Skin Barrier Health and Photoprotection

The vitamin D receptor (VDR) plays a pivotal role in maintaining epidermal barrier homeostasis and regulating cutaneous inflammatory responses. However, the cosmetic application of vitamin D and its active metabolites is limited by photoinstability, formulation challenges, and regulatory considerations. In this study, we evaluated a synthetic VDR-activating peptide (VDR-Pep) as a potential functional cosmetic ingredient capable of modulating VDR-associated signaling pathways in human keratinocytes. In situ proximity ligation assays (PLAs) demonstrated that VDR-Pep enhanced the heterodimerization of VDR and retinoid X receptor (RXR), indicating activation of canonical VDR signaling. Treatment with VDR-Pep significantly increased the expression of S100A3 and key terminal differentiation markers, including filaggrin, involucrin, and loricrin, in a dose-dependent manner. In addition, VDR-Pep stimulated intracellular calcium mobilization at levels comparable to or exceeding those induced by 1,25-dihydroxyvitamin D3. Under UVB-induced stress conditions, the peptide attenuated the expression of the pro-inflammatory cytokine interleukin-6 (IL-6) and enhanced NRF2-associated transcriptional engagement, as evidenced by increased interaction between NRF2 and RNA polymerase II. Collectively, these findings suggest that VDR-Pep supports epidermal homeostasis through coordinated modulation of VDR/RXR signaling, calcium-mediated differentiation, barrier-related protein expression, inflammatory responses, and antioxidant-associated pathways. The results indicate that VDR-targeting peptides may represent a promising non-hormonal strategy for cosmetic formulations aimed at reinforcing skin barrier function and improving resilience to environmental stress. Future studies should focus on validating these effects in in vivo human skin models, assessing long-term safety and efficacy, and optimizing formulation stability for practical cosmetic applications.