Multi-Pathway Fibroblast Modulation by PDRN Restores Dermal Structure and Improves Periocular Aging

Background: Polydeoxyribonucleotide (PDRN), a DNA-derived macromolecule, has demonstrated regenerative potential in dermatology, yet its molecular mechanisms in skin anti-aging remain underexplored. This study investigated the cellular and transcriptomic mechanisms of PDRN and validated its clinical efficacy in periocular rejuvenation. Methods: Human dermal fibroblasts (HDFs) were subjected to UVB-induced damage and treated with PDRN. Cell viability was evaluated by MTT assay, while immunohistochemistry (IHC) assessed type I/III collagen and elastin expression. Transcriptomic changes were profiled by RNA sequencing with pathway annotation through GO and KEGG analyses. Ex vivo Raman spectroscopy was used to characterize PDRN skin penetration. Finally, a randomized, double-blind, split-face clinical trial in 33 women compared the efficacy of a PDRN-containing eye cream with placebo after 28 days of use. Results: PDRN significantly restored collagen I/III and elastin expression in UVB-damaged fibroblasts. RNA-seq revealed a multi-pathway modulatory mechanism whereby PDRN: 1) activated PI3K-Akt and TGF-β signaling to promote ECM regeneration, 2) enhanced autophagy-lysosome and spliceosome activity to restore proteostasis, and 3) suppressed chemokine signaling to rebalance fibroblast-immune interactions. Ex vivo Raman spectroscopy confirmed that PDRN penetrates into the dermis. Clinically, a PDRN-containing eye cream significantly improved periocular elasticity and firmness, increased dermal density (+8.67%), reduced wrinkle number and volume, decreased under-eye bag volume (–18.42%), and enhanced skin brightness (+4.88%) compared with placebo (all p Conclusion: PDRN exerts anti-aging effects through multi-pathway modulation of fibroblast activity—integrating ECM repair, proteostasis, and immune modulation—establishing it as a clinically effective macromolecular active for periocular skin rejuvenation.