Polydeoxyribonucleotide Attenuates Human Dermal Fibroblast Senescence and Preserves Extracellular Matrix‐Related Protein Expression

ABSTRACT Dermal fibroblasts maintain skin structural integrity through extracellular matrix (ECM) synthesis and remodelling. Fibroblast senescence, driven by intrinsic aging and environmental stress, disrupts ECM homeostasis, sustains the senescence‐associated secretory phenotype (SASP), and may alter interactions with macrophages. Polydeoxyribonucleotide (PDRN) is a purified mixture of DNA polymers with reported activity in skin‐related contexts, but its role in fibroblast senescence, macrophage‐fibroblast interactions, and stress‐related metabolic dysfunction remains insufficiently defined. Here, PDRN was evaluated using in vitro models of replicative fibroblast senescence and UVA stress, together with ex vivo human skin explants exposed to combined UVA/UVB irradiation. PDRN attenuated multiple features of fibroblast senescence, including senescence‐associated beta‐galactosidase (SA‐β‐gal) activity, p16/p21 expression, selected SASP factors, and markers of ECM remodelling. In macrophage–fibroblast co‐cultures, PDRN treatment was associated with an increased proportion of CFDA‐SE‐positive events and higher fluorescence intensity. Reduced CD47 expression in fibroblasts and increased STAB1 expression in macrophages were also observed. Under UVA stress, PDRN increased intracellular ATP levels, the NAD + /NADH ratio and cell viability. Collagen I expression and LOX‐associated staining also increased. In ex vivo skin explants, PDRN attenuated UVR‐induced epidermal alterations, reduced CPD intensity, increased Ki67‐positive basal cells, and increased the ECM and dermal–epidermal junction (DEJ) protein expression. Together, these findings suggest that PDRN may attenuate fibroblast senescence‐associated changes and support cellular and tissue responses to UV stress.