Potential Value of a Combination of Polypodium leucotomos and Aspalathus linearis Extracts in Protecting Vitamin D Receptor Levels During Skin Oxidative Stress

<b>Background/Objectives:</b> Vitamin D (VD), through the interaction with its receptor (VDR), plays essential roles in the skin. VDR-mediated signaling prevents cancer development and improves prognosis, making it an appealing target for therapy. However, VD cutaneous synthesis begins with solar exposure, which is the first etiological factor for cutaneous cancer and increases oxidative stress (OS). This complicates the dermatologist's perspective when advising photoprotective strategies while aiming to consider the benefits of VD signaling. In this context, and in the absence of cutaneous data to date, this research aims to address VDR dynamics in skin cells and tissue subjected to OS. It also explores the potential of a natural photoprotectant with antioxidant properties (a specific combination of <i>Polypodium leucotomos</i> and <i>Aspalathus linearis</i> extracts) in preventing VDR depletion. <b>Methods:</b> HaCaT cell cultures and skin explants were used as experimental models. OS was induced by treatments with hydrogen peroxide (H₂O₂). The proteins of interest (VDR and Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)) were analyzed by immunostaining. Cell viability, nuclear counterstaining, and Haematoxylin/Eosin staining were used as cyto/histochemical controls. <b>Results:</b> In both experimental models, we observed the reduction of VDR under OS. Pre-treatments with the botanical ingredient preserved VDR levels from that decline, probably through a mechanism involving NRF2. <b>Conclusions:</b> Cutaneous VDR levels are altered under oxidative stress, and certain photoprotectants could preserve them. This opens the door to preserving the benefits of VDR signaling while preventing solar radiation damage, bringing a new viewpoint for designing future strategies in skin cancer prevention and treatment.