BACKGROUND: Platelet-released-growth factors (PRGF) and platelet-rich plasma (PRP) are blood-derived products used in regenerative treatments and in overall aesthetic rejuvenation. Keratinocytes possess distinctive characteristics responsible for protection against environmental stressors and oxidant clearance. One such mechanism is the transcription factor NRF2, which plays a critical role in regulating cytoprotective genes, inflammation, and oxidative stress response. Data on the activation of the NRF2-ARE and NF-κB axes by PRGF are very limited. AIM: This study aims to investigate whether PRGF activates NRF2 and, if so, is responsible for the described anti-inflammatory effect of PRGF/PRP in an in vitro primary human keratinocyte model. METHODS: NRF2 activation is analyzed by NQO1 and HO-1 western blotting, gene expression analysis, and by an ARE-promoter study using luciferase-based reporter gene assays in patient-derived keratinocytes. Besides direct determination of the PRGF-NRF2 interaction, we investigated the NF-κB response by treating cells with PRGF and the inflammatory stimuli TNF-α. Inflammatory parameters were analyzed using ELISAs for IL-1β, IL-4, Il-10, TNF-α and IL-6 in the supernatant, NF-κB luciferase reporter gene assays as well a-NF-κB western blotting. NRF2 involvement was tested by treating the cell-culture model with the NRF2-inhibitor ML-385. RESULTS: We were able to show that ARE activity was significantly upregulated in PRGF-treated keratinocytes, leading subsequently to increased NQO1 and HO-1 protein expression. Inflammatory IL-secretion showed an association with NRF2 availability. CONCLUSIONS: In summary, PRGFs activate NRF2 target proteins and downregulate NF-κB-associated inflammation in an NRF2-dependent manner. Therefore, we further suggest PRGF as an anti-inflammatory treatment after medical aesthetic procedures.