Year: 2024
Type: article
Abstract: The Cap'n'collar transcription factor BACH1 represses the transcription of gene products involved in oxidative stress protection. Accordingly, agents capable of inhibiting the activity of BACH1 would be of keen interest in treating several autoimmune and age‐related diseases. Here, we report that a previously annotated BACH1 inhibitor, HPPE, does not inhibit BACH1 but instead activates a NRF2 driven transcription program that is dependent on the canonical cysteine sensors of NRF2 inhibitory protein KEAP1. Mechanistically, HPPE acts as an ionophore, liberating cellular Zn2+ stores and inducing non‐lethal levels of reactive oxygen species, resulting in KEAP1 inactivation. These data provide a surprising mechanism by which HPPE acts in cells and suggest that inducing small amounts of cellular stress may be a viable mechanism for activating NRF2 therapeutically.
Source: ChemBioChem
Authors: Rebecca Freeman, Michael J. Bollong
Institution: Scripps Research Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G4795575403, G9000153987
OpenAlex ID: W4402309525