Synergistic protective and regenerative effects of hyaluronic acid and polynucleotides against UVA-induced oxidative stress in dermal fibroblasts

Abstract Ultraviolet A (UVA) radiation, a principal driver of skin photoaging, generates excessive reactive oxygen species (ROS) in dermal fibroblasts, causing oxidative stress, loss of viability, inflammatory signaling, and extracellular matrix (ECM) degradation. Hyaluronic acid (HA) and polynucleotides (PN) are clinically used dermal biomaterials; however, their protection against UVA injury remains insufficiently defined. We evaluated HA, PN, and their combination in human dermal fibroblasts (HDFs) subjected to photodamage. HDFs were pretreated with HA, PN, or both, irradiated with 20 J/cm 2 UVA, and then maintained in treated media to mimic therapeutic recovery. UVA reduced viability and proliferation, downregulated ECM genes ( COL1A1 , FN1 ), and increased intracellular and mitochondrial ROS and proinflammatory cytokine gene ( TNF-α ). Monotherapy partially alleviated these changes. In contrast, combined HA + PN synergistically improved survival and proliferation, lowered ROS to near baseline, restored ECM transcription, and upregulated antioxidant enzymes ( GPX1 , S OD2 ). HA + PN also increased fibroblast invasion, indicating regenerative activity beyond cytoprotective effects. Under basal conditions, neither HA nor PN showed cytotoxicity or prooxidant effects, while modestly enhancing ECM transcription. These findings demonstrate that HA and PN act synergistically to counter UVA-induced oxidative stress and support dermal regeneration, highlighting a combinatorial bioactive strategy for photoaged skin.