A Subcellular Keap1-Nrf2 Disruption Strategy for Atopic Dermatitis Therapy

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.