Novel Bioactive Peptides Targeting Keap1-Nrf2 Interaction for Combating UVA-Induced Skin Aging: Computational Discovery and Experimental Validation

Ultraviolet A (UVA)-induced skin aging poses a significant threat to skin health and aesthetics, yet effective and biosafe therapeutic interventions remain scarce. This study focused on identifying bioactive peptide inhibitors targeting the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) protein-protein interaction (PPI) to counteract UVA-induced skin aging. Using computational virtual screening, we identified two high-affinity, low-toxicity peptides, Seq1 and Seq3, which effectively activated the Nrf2-antioxidant response element (ARE) pathway. This activation led to the upregulation of antioxidant genes and significantly reduced oxidative stress. Additionally, these peptides inhibited the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways, thereby reducing inflammation and suppressing the expression of matrix metalloproteinases (MMPs), key contributors to skin aging. In vivo studies demonstrated that Seq1 and Seq3 effectively prevented UVA-induced epidermal thickening, collagen degradation, and the upregulation of pro-inflammatory cytokines in mouse models. Our results underscore the therapeutic potential of Seq1 and Seq3, particularly Seq3, as novel bioactive peptides targeting the Keap1-Nrf2 PPI for combating UVA-induced skin aging, offering promising avenues for skincare and healthcare applications. • Novel Peptides Identified: Seq1 and Seq3, targeting Keap1-Nrf2 PPI, discovered via computational virtual screening. • Innovative CADD Approach: Combines computational design with experimental validation for peptide-based drug discovery. • Dual-Action Mechanism: Activates Nrf2-ARE pathway to reduce oxidative stress and inhibits MAPK/NF-κB pathways to suppress inflammation. • In Vivo Protection: Prevent UVA-induced skin damage, including epidermal thickening, collagen degradation, and pro-inflammatory cytokine upregulation. • Therapeutic Potential: High biosafety and peptide-based strategy for skincare applications.