{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T15:59:42Z","timestamp":1784563182820,"version":"3.55.0"},"reference-count":43,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Skin aging stems from intrinsic decline and external stressors that induce oxidative stress and mitochondrial damage, ultimately lowering cellular energy production and slowing epidermal turnover to cause wrinkles, dryness, and pigment imbalances. While disodium adenosine monophosphate (AMP2Na) is hypothesized to enhance cellular adenosine triphosphate production and restore epidermal metabolism, its broader anti-aging effects have remained underexplored. To address this, a multi-tiered study integrating in vitro, ex vivo, and clinical investigations was conducted. Specifically, a 12-week exploratory clinical trial involving female participants with facial hyperpigmentation (n = 23), alongside a short-term forearm study (n = 22), suggested that the AMP2Na-containing product could reduce wrinkles and hyperpigmentation while safely improving hydration, barrier function, skin lifting, and epidermal turnover with high participant satisfaction. Mechanistically, in vitro assays on human dermal fibroblasts showed that the formulation restored antioxidant enzyme activity and mitigated senescence. Ex vivo UVB-irradiated skin explant models corroborated these findings by revealing reduced melanin levels, preserved collagen and elastin networks, and an upregulation of key structural and barrier-related proteins. Ultimately, by potentially supporting epidermal turnover and restoring barrier function through this biomimetic mechanism, the AMP2Na-containing product might offer a promising option for alleviating wrinkles, dryness, and hyperpigmentation. Future randomized, vehicle-controlled clinical trials and comprehensive laboratory studies are warranted to validate its true potential in skin rejuvenation.<\/jats:p>","DOI":"10.3390\/ijms27114840","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T14:36:56Z","timestamp":1779892616000},"page":"4840","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Translational Evaluation of a Disodium Adenosine Monophosphate (AMP2Na)-Based Topical Formulation for Physiology-Aligned Skin Rejuvenation: Integrated In Vitro, Ex Vivo, and Clinical Evidence"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4466-9550","authenticated-orcid":false,"given":"Ngoc Ha","family":"Nguyen","sequence":"first","affiliation":[{"name":"Department of Dermatology & Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Department of Dermatology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6831-7379","authenticated-orcid":false,"given":"Young In","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Dermatology & Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Scar Laser and Plastic Surgery Center, Yonsei Cancer Hospital, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoo Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Global Medical Research Center, Seoul 06526, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwiyeong","family":"Lee","sequence":"additional","affiliation":[{"name":"Global Medical Research Center, Seoul 06526, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0047-5941","authenticated-orcid":false,"given":"Jihee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin-si 16995, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1739-5956","authenticated-orcid":false,"given":"Ju Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Dermatology & Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"},{"name":"Scar Laser and Plastic Surgery Center, Yonsei Cancer Hospital, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111525","DOI":"10.1016\/j.mad.2021.111525","article-title":"Faces of cellular senescence in skin aging","volume":"198","author":"Ho","year":"2021","journal-title":"Mech. Ageing Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1089\/wound.2011.0356","article-title":"Characteristics of the Aging Skin","volume":"2","author":"Farage","year":"2013","journal-title":"Adv. Wound Care"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1111\/exd.14778","article-title":"Ageing is associated with a reduction in markers of mitochondrial energy metabolism in the human epidermis","volume":"32","author":"Vidali","year":"2023","journal-title":"Exp. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Chin, T., Lee, X.E., Ng, P.Y., Lee, Y., and Dreesen, O. (2023). The role of cellular senescence in skin aging and age-related skin pathologies. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1297637"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"115574","DOI":"10.1016\/j.bcp.2023.115574","article-title":"Targeting tyrosinase in hyperpigmentation: Current status, limitations and future promises","volume":"212","author":"Zolghadri","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Boo, Y.C. (2021). Arbutin as a Skin Depigmenting Agent with Antimelanogenic and Antioxidant Properties. Antioxidants, 10.","DOI":"10.3390\/antiox10071129"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Phasha, V., Senabe, J., Ndzotoyi, P., Okole, B., Fouche, G., and Chuturgoon, A. (2022). Review on the Use of Kojic Acid-A Skin-Lightening Ingredient. Cosmetics, 9.","DOI":"10.3390\/cosmetics9030064"},{"key":"ref_8","first-page":"e48840","article-title":"Topical Hydroquinone for Hyperpigmentation: A Narrative Review","volume":"15","author":"Fabian","year":"2023","journal-title":"Cureus"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e16562","DOI":"10.1111\/jocd.16562","article-title":"The Efficacy of Topical Cosmetic Containing Alpha-Arbutin 5% and Kojic Acid 2% Compared with Triple Combination Cream for the Treatment of Melasma: A Split-Face, Evaluator-Blinded Randomized Pilot Study","volume":"24","author":"Tantanasrigul","year":"2025","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1042\/EBC20180038","article-title":"Understanding biochemistry: Structure and function of nucleic acids","volume":"63","author":"Minchin","year":"2019","journal-title":"Essays Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/cbf.3089","article-title":"AMP promotes oxygen consumption and ATP synthesis in heart mitochondria through the adenylate kinase reaction: An NMR spectroscopy and polarography study","volume":"33","author":"Doliba","year":"2015","journal-title":"Cell Biochem. Funct."},{"key":"ref_12","unstructured":"Patra, C., Foster, K., Corley, J.E., Dimri, M., and Brady, M.F. (2025). Biochemistry, cAMP. StatPearls, StatPearls Publishing."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1104\/pp.54.4.560","article-title":"Adenosine Phosphates in Germinating Radish (Raphanus sativus L.) Seeds","volume":"54","author":"Moreland","year":"1974","journal-title":"Plant Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Dufoo-Hurtado, M.D., Huerta-Ocampo, J.A., Barrera-Pacheco, A., Barba de la Rosa, A.P., and Mercado-Silva, E.M. (2015). Low temperature conditioning of garlic (Allium sativum L.) \u201cseed\u201d cloves induces alterations in sprouts proteome. Front. Plant Sci., 6.","DOI":"10.3389\/fpls.2015.00332"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Caba-Flores, M.D., Ramos-Ligonio, A., Camacho-Morales, A., Martinez-Valenzuela, C., Viveros-Contreras, R., and Caba, M. (2022). Breast Milk and the Importance of Chrononutrition. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.867507"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1093\/geronj\/38.2.137","article-title":"Age-associated changes in human epidermal cell renewal","volume":"38","author":"Grove","year":"1983","journal-title":"J. Gerontol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1196\/annals.1354.044","article-title":"Prevention and treatment of skin aging","volume":"1067","author":"McCullough","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s00403-008-0882-x","article-title":"Effects of adenosine 5\u2032-monophosphate on epidermal turnover","volume":"300","author":"Furukawa","year":"2008","journal-title":"Arch. Dermatol. Res."},{"key":"ref_19","first-page":"250","article-title":"Improvement of hyperpigmentation based on accelerated epidermal turnover: Clinical effects of disodium adenosine monophosphate in patients with melasma","volume":"62","author":"Kawashima","year":"2008","journal-title":"Jpn. J. Clin. Dermatol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Maeda, K. (2022). Timeline of the Development of Skin-Lightening Active Ingredients in Japan. Molecules, 27.","DOI":"10.3390\/molecules27154774"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Martic, I., Papaccio, F., Bellei, B., and Cavinato, M. (2023). Mitochondrial dynamics and metabolism across skin cells: Implications for skin homeostasis and aging. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1284410"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.3390\/ijms10094066","article-title":"Mechanisms regulating skin pigmentation: The rise and fall of complexion coloration","volume":"10","author":"Ebanks","year":"2009","journal-title":"Int. J. Mol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.2147\/CCID.S372456","article-title":"Melasma: A Step-by-Step Approach Towards a Multimodal Combination Therapy","volume":"17","year":"2024","journal-title":"Clin. Cosmet. Investig. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s00412-018-0659-8","article-title":"Ki-67: More than a proliferation marker","volume":"127","author":"Sun","year":"2018","journal-title":"Chromosoma"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0378-5122(96)01066-3","article-title":"Changes of the basement membrane and type IV collagen in human skin during aging","volume":"25","author":"Vazquez","year":"1996","journal-title":"Maturitas"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.exger.2014.09.015","article-title":"Skin aging, gene expression and calcium","volume":"68","author":"Rinnerthaler","year":"2015","journal-title":"Exp. Gerontol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1111\/ics.12673","article-title":"Facial radiance influences facial attractiveness and affective impressions of faces","volume":"43","author":"Ikeda","year":"2021","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1111\/srt.13161","article-title":"Analysis of correlation and construction of a predictive model of skin transparency using parameters from digital images of the face","volume":"28","author":"Marin","year":"2022","journal-title":"Skin Res. Technol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/s41746-024-01176-8","article-title":"A survey of skin tone assessment in prospective research","volume":"7","author":"Weir","year":"2024","journal-title":"npj Digit. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Dorf, N., and Maciejczyk, M. (2024). Skin senescence-from basic research to clinical practice. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1484345"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1002\/path.6159","article-title":"Skin fibroblast functional heterogeneity in health and disease","volume":"260","author":"Bensa","year":"2023","journal-title":"J. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S1016-8478(23)17053-1","article-title":"Modulation of catalase in human skin by acute and chronic UV radiation","volume":"11","author":"Rhie","year":"2001","journal-title":"Mol. Cells"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/j.1396-0296.2004.04S1005.x","article-title":"Moisturization and skin barrier function","volume":"17","author":"Rawlings","year":"2004","journal-title":"Dermatol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Iaconisi, G.N., Lunetti, P., Gallo, N., Cappello, A.R., Fiermonte, G., Dolce, V., and Capobianco, L. (2023). Hyaluronic Acid: A Powerful Biomolecule with Wide-Ranging Applications\u2014A Comprehensive Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210296"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Evrard, C., Lambert de Rouvroit, C., and Poumay, Y. (2021). Epidermal Hyaluronan in Barrier Alteration-Related Disease. Cells, 10.","DOI":"10.3390\/cells10113096"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/jidsymp.2009.5","article-title":"Possible involvement of basement membrane damage in skin photoaging","volume":"14","author":"Amano","year":"2009","journal-title":"J. Investig. Dermatol. Symp. Proc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.clindermatol.2019.04.009","article-title":"Aging of the skin barrier","volume":"37","author":"Choi","year":"2019","journal-title":"Clin. Dermatol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Chylinska, N., and Maciejczyk, M. (2025). Hyaluronic Acid and Skin: Its Role in Aging and Wound-Healing Processes. Gels, 11.","DOI":"10.3390\/gels11040281"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Khalid, K.A., Nawi, A.F.M., Zulkifli, N., Barkat, M.A., and Hadi, H. (2022). Aging and Wound Healing of the Skin: A Review of Clinical and Pathophysiological Hallmarks. Life, 12.","DOI":"10.3390\/life12122142"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1046\/j.1523-1747.1998.00204.x","article-title":"Regulatory effects of heat on normal human melanocyte growth and melanogenesis: Comparative study with UVB","volume":"110","author":"Nakazawa","year":"1998","journal-title":"J. Investig. Dermatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1111\/php.12628","article-title":"Protective Effect of Curcumin Against Acute Ultraviolet B Irradiation-induced Photo-damage","volume":"92","author":"Li","year":"2016","journal-title":"Photochem. Photobiol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Baek, Y., Nguyen, N.H., Ham, S., Kim, W., Lee, J.H., and Lee, Y.I. (2026). Monopolar Radiofrequency for Facial Hyperpigmentation Treatment: An Integrated Retrospective Clinical Trial and Ex Vivo Study. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27020761"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Roh, H., Nguyen, N.H., Jung, J., Hwang, J.K., Lee, Y.I., Baek, Y., Jung, I., Kim, J., and Lee, J.H. (2026). Therapeutic Anti-Fibrotic Effects of a Dual Hyaluronic Acid Hybrid Complex in Bleomycin-Induced Dermal Fibrosis and UVB-Irradiated Human Skin. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27073038"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4840\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T14:38:31Z","timestamp":1779892711000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/4840"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,27]]},"references-count":43,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27114840"],"URL":"https:\/\/doi.org\/10.3390\/ijms27114840","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,27]]}}}