HPPE Activates NRF2 Signaling by Liberating Heavy Metal Stores

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 repo...

Full description

Saved in:
Bibliographic Details
Published in:Chembiochem : a European journal of chemical biology 2024-10, p.e202400529
Main Authors: Freeman, Rebecca, Bollong, Michael
Format: Article
Language:English
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1439-4227
1439-7633
1439-7633
DOI:10.1002/cbic.202400529