Quercetin Emulsion Ameliorates UVA-Induced Skin via Modulation of NRF2/NF-κB Signaling Pathways

Background: UVA-induced photoaging is driven by a self-reinforcing cycle of persistent oxidative stress, inflammation, and extracellular matrix (ECM) degradation. Quercetin (Que) offers potent photoprotective potential, yet its clinical utility is hindered by poor aqueous solubility and low skin permeability. Objective: To develop a stable quercetin delivery system and evaluate its protective efficacy against UVA-induced photoaging via the NRF2/NF-κB signaling axis. Methods: Network pharmacology and molecular docking identified potential targets. An oil-in-water (O/W) nano-emulsion was formulated and characterized. Its effects were evaluated in UVA-irradiated human skin fibroblasts (HSFs; 1.2 J/cm2/day for 5 days) and a BALB/c mouse model (20 J/cm2/day for 8 weeks). Results: Network pharmacology identified 85 shared targets between Quercetin and photoaging. Molecular docking confirmed high affinities (binding energies < −7.0 kcal/mol) for NRF2, NF-κB p65, SOD2, and MMP-1. The optimized O/W nano-emulsion (144–154 nm, Zeta potential −38 to −43 mV) enhanced Quercetin solubility by 175-fold and followed Higuchi release kinetics. In HSFs, 30 μm Quercetin reduced SA-β-Gal positivity from 45.8% to 12.5% (73% inhibition), decreased ROS by 66%, and restored Type I collagen intensity to 82 ± 3 a.u. In vivo, topical 0.3% Que emulsion significantly attenuated skin-fold thickening (reducing thickness from 3135 μm to 2170 μm; 30.6% reduction) and achieved a 91% collagen retention rate. Mechanistically, Quercetin treatment significantly upregulated NRF2 and SOD2 expression while suppressing the NF-κB p65/MMP-1/3 inflammatory axis at both mRNA and protein levels (p < 0.01). Conclusions: Topical Quercetin emulsion effectively facilitates dermal delivery and alleviates UVA-induced photoaging by rebalancing the NRF2/NF-κB axis, thereby enhancing antioxidant defenses and preserving ECM integrity. This formulation represents a robust strategy for skin photoprotection and functional cosmetic intervention.