First Direct In Vitro Comparison Between Cordycepin (MDRN) and PDRN: Skin-Repair-Related Cellular Responses at Lower Tested Mass Concentrations

This study introduces the concept of MDRN, referring to monomeric deoxyribonucleoside, and evaluates cordycepin (251.24 Da) as a low-molecular-weight alternative to polydeoxyribonucleotide (PDRN). Cordycepin (1–20 μM) was compared with PDRN (100 μg/mL) in human keratinocytes and dermal fibroblasts. Molecular simulations and cellular thermal-shift assays supported a potential interaction with the adenosine A2A receptor, while 3,7-dimethyl-1-propargylxanthine (DMPX), an adenosine receptor antagonist, attenuated selected signaling responses. Cordycepin reduced UVA-induced oxidative and inflammatory responses in keratinocytes, altered autophagy-related reporter signals in HEK293T cells, and selectively modulated barrier- and tight-junction-related gene expression. In fibroblasts, it decreased MMP-1 expression and increased COL1A1 expression. Cordycepin also increased scratch-wound closure in both cell types at selected concentrations. Selected cordycepin treatments significantly increased fibroblast scratch-wound closure and the expression of specific keratinocyte barrier-associated genes compared with PDRN. These comparative responses depended on the endpoint and concentration. Notably, 20 μM cordycepin corresponds to approximately 5.02 μg/mL, one-twentieth of the tested PDRN mass concentration. These findings support cordycepin as an MDRN candidate that elicits skin-repair-related cellular responses at substantially lower mass concentrations than PDRN. Further studies are required to establish relative potency and topical applicability.