A Subcellular Keap1-Nrf2 Disruption Strategy for Atopic Dermatitis Therapy.

Authors

Zixi Zhang, Jia Wu, Jingqi Liu, Daniel Shiu-Hin Chan, Chun-Yuen Wong, Jing Wang, Chung-Hang Leung, Wanhe Wang

Published in

Journal of medicinal chemistry. Volume 69. Issue 17. Pages 20326-20337. Sep 10, 2026.

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a promising target for atopic dermatitis due to its role in skin barrier repair, yet effective modulators of Nrf2 are lacking. Here, we report an itaconate-iridium(III) complex conjugation strategy for the disruption of the Keap1-Nrf2 protein-protein interaction (PPI) for treating atopic dermatitis. The conjugate (1) specifically engages cytoplasmic Keap1 to restore Nrf2 activity, thus upregulating anti-inflammatory genes HO-1 and NQO1 while suppressing reactive oxygen species (ROS) in keratinocytes. It also reduces IL-13 production and boosts skin barrier proteins filaggrin and involucrin in a reconstructed human epidermis (RHE) model. In vivo studies revealed that compound 1 ameliorated DNFB-induced atopic dermatitis-like lesions and hypersensitivity. Its optical characteristics further enabled the flow cytometric discrimination of HaCaT cells based on Keap1 levels. This work provides a promising strategy for developing bioactive molecules to efficiently disrupt subcellular PPIs, laying the basis to progress theranostic candidates for atopic dermatitis.

PMID:
42720490
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

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