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Haiqiong Guo, Yueting Sun, Wenyu Shi, Rui Huang, Xiaobei Zhi, Qingsong Liu, Ping Zhao, Qingyou Xia. Novel Bioactive Peptides Targeting Keap1-Nrf2 Interaction for Combating UVA-Induced Skin Aging: Computational Discovery and Experimental Validation[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101446
Citation: Haiqiong Guo, Yueting Sun, Wenyu Shi, Rui Huang, Xiaobei Zhi, Qingsong Liu, Ping Zhao, Qingyou Xia. Novel Bioactive Peptides Targeting Keap1-Nrf2 Interaction for Combating UVA-Induced Skin Aging: Computational Discovery and Experimental Validation[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101446

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

doi: 10.1016/j.jpha.2025.101446
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This work was supported by the National Key Research and Development Program of China (Grant No.: 2022YFD1201600) and the National Natural Science Foundation, China (Grant Nos.: 32030103 and 32172798). Thanks for the support of the Academy for Advanced Interdisciplinary Studies Device Sharing Service Platform (Equipment No.: 14A00784), Southwest University, China.

  • Received Date: Mar. 16, 2025
  • Accepted Date: Sep. 08, 2025
  • Rev Recd Date: Jul. 28, 2025
  • Available Online: Sep. 10, 2025
  • 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.
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