Polydeoxyribonucleotide (PDRN) Signaling Pathways - From A2A Receptor Activation to Reactive Oxygen Species Regulation -

Polydeoxyribonucleotide (PDRN) has emerged as a biologically active nucleic-acid therapeutic with broad applications in dermatology, regenerative medicine, and tissue repair. Although its clinical utility has been recognized across diverse ROS-driven pathological conditions, the underlying molecular signaling mechanisms have remained fragmented. This review integrates and systematizes current findings to reconstruct PDRN’s signaling network within a hierarchical, multilayered framework. Evidence from existing studies indicates that PDRN-mediated activation of the A2A adenosine receptor initiates a coordinated cascade involving cAMP-PKA signaling, MAPK modulation, PI3K-Akt activation, NF-κB suppression, MITF inhibition, and HIF-1α regulation. These pathways collectively converge on the upstream suppression of ROS generated through mitochondrial dysfunction, NOX activation, UV-induced MAPK signaling, and melanogenesis-associated oxidative reactions. Beyond its anti-inflammatory and pro-regenerative properties, PDRN reprograms multiple transcriptional regulators―including CREB, NF-κB, MITF, and HIF-1α—thereby influencing ECM homeostasis, cytokine balance, apoptosis resistance, angiogenesis, and pigmentation. Taken together, current evidence positions PDRN not as a classical antioxidant but as an upstream network regulator that mitigates ROS-driven cellular damage and restores tissue homeostasis. This mechanistic framework provides a rationale for its therapeutic potential in photoaging, wound healing, pigmentary disorders, and ischemic injury, while highlighting future research opportunities involving Nrf2 signaling, NOX isoform specificity, and mitochondrial dynamics.