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 < 0.05). Morphometric analysis further demonstrated improvements in periocular contour geometry. 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.
References
[1]
Hussein, R.S., Bin Dayel, S., Abahussein, O. and El-Sherbiny, A.A. (2025) Influences on Skin and Intrinsic Aging: Biological, Environmental, and Therapeutic Insights. Journal of Cosmetic Dermatology, 24, e16688. https://doi.org/10.1111/jocd.16688
[2]
Shin, S.H., Lee, Y.H., Rho, N. and Park, K.Y. (2023) Skin Aging from Mechanisms to Interventions: Focusing on Dermal Aging. Frontiers in Physiology, 14, Article 1195272. https://doi.org/10.3389/fphys.2023.1195272
[3]
Flament, F., Bazin, R., Rubert, L.S., et al. (2013) Effect of the Sun on Visible Clinical Signs of Aging in Caucasian Skin. Clinical, Cosmetic and Investigational Dermatology, 6, 221-232. https://doi.org/10.2147/ccid.s44686
[4]
Panich, U., Sittithumcharee, G., Rathviboon, N. and Jirawatnotai, S. (2016) Ultraviolet Radiation-Induced Skin Aging: The Role of DNA Damage and Oxidative Stress in Epidermal Stem Cell Damage Mediated Skin Aging. Stem Cells International, 2016, Article 7370642. https://doi.org/10.1155/2016/7370642
[5]
Watson, R.E.B., Gibbs, N.K., Griffiths, C.E.M. and Sherratt, M.J. (2014) Damage to Skin Extracellular Matrix Induced by UV Exposure. Antioxidants & Redox Signaling, 21, 1063-1077. https://doi.org/10.1089/ars.2013.5653
[6]
Kim, D.J., Iwasaki, A., Chien, A.L. and Kang, S. (2022) UVB-Mediated DNA Damage Induces Matrix Metalloproteinases to Promote Photoaging in an AhR and SP1-Dependent Manner. JCI Insight, 7, e156344. https://doi.org/10.1172/jci.insight.156344
[7]
Shin, J., Kwon, S., Choi, J., Na, J., Huh, C., Choi, H., et al. (2019) Molecular Mechanisms of Dermal Aging and Antiaging Approaches. International Journal of Molecular Sciences, 20, Article 2126. https://doi.org/10.3390/ijms20092126
[8]
Wang, Q., Hu, F., Hu, X., Xie, Y., Du, L. and Ye, R. (2023) The Synergistic Effect of Retinyl Propionate and Hydroxypinacolone Retinoate on Skin Aging. Journal of Cosmetic Dermatology, 22, 2040-2049. https://doi.org/10.1111/jocd.15662
[9]
Al-Niaimi, F. and Chiang, N.Y.Z. (2017) Topical Vitamin C and the Skin: Mechanisms of Action and Clinical Applications. Journal of Clinical and Aesthetic Dermatology, 10, 14-17.
[10]
Maia Campos, P.M.B.G., Melo, M.O. and Siqueira César, F.C. (2019) Topical Application and Oral Supplementation of Peptides in the Improvement of Skin Viscoelasticity and Density. Journal of Cosmetic Dermatology, 18, 1693-1699. https://doi.org/10.1111/jocd.12893
[11]
Wang, Q., Zhong, Y., Li, N., Du, L., Ye, R., Xie, Y., et al. (2023) Combination of Dimethylmethoxy Chromanol and Turmeric Root Extract Synergically Attenuates Ultraviolet-Induced Oxidative Damage by Increasing Endogenous Antioxidants in Hacat Cells. Skin Research and Technology, 29, e13539. https://doi.org/10.1111/srt.13539
[12]
Leok Goh, C., Tang, M.B.Y., Briantais, P., Kaoukhov, A. and Soto, P. (2009) Adapalene Gel 0.1% Is Better Tolerated than Tretinoin Gel 0.025% among Healthy Volunteers of Various Ethnic Origins. Journal of Dermatological Treatment, 20, 282-288. https://doi.org/10.1080/09546630902763164
[13]
Bai, D., Hu, F., Xu, H., Huang, J., Wu, C., Zhang, J., et al. (2023) High Stability and Low Irritation of Retinol Propionate and Hydroxypinacolone Retinoate Supramolecular Nanoparticles with Effective Anti-Wrinkle Efficacy. Pharmaceutics, 15, Article 731. https://doi.org/10.3390/pharmaceutics15030731
[14]
Veronesi, F., Dallari, D., Sabbioni, G., Carubbi, C., Martini, L. and Fini, M. (2017) Polydeoxyribonucleotides (PDRNs) from Skin to Musculoskeletal Tissue Regeneration via Adenosine A2A Receptor Involvement. Journal of Cellular Physiology, 232, 2299-2307. https://doi.org/10.1002/jcp.25663
[15]
Squadrito, F., Bitto, A., Irrera, N., Pizzino, G., Pallio, G., Minutoli, L., et al. (2017) Pharmacological Activity and Clinical Use of PDRN. Frontiers in Pharmacology, 8, Article 224. https://doi.org/10.3389/fphar.2017.00224
[16]
Marques, C., Porcello, A., Cerrano, M., Hadjab, F., Chemali, M., Lourenço, K., et al. (2025) From Polydeoxyribonucleotides (PDRNs) to Polynucleotides (PNs): Bridging the Gap between Scientific Definitions, Molecular Insights, and Clinical Applications of Multifunctional Biomolecules. Biomolecules, 15, Article 148 https://doi.org/10.3390/biom15010148
[17]
Hwang, K.H., Kim, J.H., Park, E.Y. and Cha, S.K. (2018) An Effective Range of Polydeoxyribonucleotides Is Critical for Wound Healing Quality. MolecularMedicineReports, 18, 5166-5172. https://doi.org/10.3892/mmr.2018.9539
[18]
Alkilani, A.Z., McCrudden, M.T. and Donnelly, R.F. (2015) Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the Stratum Corneum. Pharmaceutics, 7, 438-470. https://doi.org/10.3390/pharmaceutics7040438
[19]
Pal, I. and Mandal, M. (2012) PI3K and Akt as Molecular Targets for Cancer Therapy: Current Clinical Outcomes. Acta Pharmacologica Sinica, 33, 1441-1458. https://doi.org/10.1038/aps.2012.72
[20]
Ke, Y. and Wang, X. (2021) TGFβ Signaling in Photoaging and UV-Induced Skin Cancer. Journal of Investigative Dermatology, 141, 1104-1110. https://doi.org/10.1016/j.jid.2020.11.007
[21]
Shi, L., Wu, Z., Miao, J., Du, S., Ai, S., Xu, E., et al. (2019) Adenosine Interaction with Adenosine Receptor A2A Promotes Gastric Cancer Metastasis by Enhancing PI3K-Akt-mTOR Signaling. Molecular Biology of the Cell, 30, 2527-2534. https://doi.org/10.1091/mbc.e19-03-0136
López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M. and Kroemer, G. (2023) Hallmarks of Aging: An Expanding Universe. Cell, 186, 243-278. https://doi.org/10.1016/j.cell.2022.11.001
[24]
Xie, Y., Yang, A., Li, N., Zheng, H., Zhong, Y., Jin, Y., et al. (2024) Lapagyl Mitigates UV-Induced Inflammation and Immunosuppression via Foxp3+ Tregs and CCL Pathway: A Single-Cell Transcriptomics Study. Phytomedicine, 129, Article 155679. https://doi.org/10.1016/j.phymed.2024.155679
[25]
Solá, P., Mereu, E., Bonjoch, J., Casado-Peláez, M., Prats, N., Aguilera, M., et al. (2023) Targeting Lymphoid-Derived IL-17 Signaling to Delay Skin Aging. Nature Aging, 3, 688-704. https://doi.org/10.1038/s43587-023-00431-z
[26]
Lee, W.J., Jo, S.Y., Lee, M.H., Won, C.H., et al. (2016) The Effect of MCP-1/CCR2 on the Proliferation and Senescence of Epidermal Constituent Cells in Solar Lentigo. InternationalJournalofMolecularSciences, 17, Article 948. https://doi.org/10.3390/ijms17060948
[27]
Reichert, O., Kolbe, L., Terstegen, L., Staeb, F., Wenck, H., Schmelz, M., et al. (2015) UV Radiation Induces CXCL5 Expression in Human Skin. ExperimentalDermatology, 24, 309-312. https://doi.org/10.1111/exd.12652
