Targeting NRF2 to promote epithelial repair

Abstract

The transcription factor NRF2 is well known as a master regulator of the cellular stress response. As such, activation of NRF2 has gained widespread attention for its potential to prevent tissue injury, but also as a possible therapeutic approach to promote repair processes. While NRF2 activation affects most or even all cell types, its effect on epithelial cells during repair processes has been particularly well studied. In response to tissue injury, these cells proliferate, migrate and/or spread to effectively repair the damage. In this review, we discuss how NRF2 governs repair of epithelial tissues, and we highlight the increasing number of NRF2 targets with diverse roles in regulating epithelial repair.

Keywords: Keap1; NRF2; cell proliferation; cytoprotection; tissue repair; wound healing.

Figure 1.. Mechanisms of NRF2 activation.

NRF2 binds to KEAP1 during cellular homeostasis, resulting in its rapid proteasomal degradation. Left: The classical (canonical) mechanism for NRF2 activation relies on the accumulation of intracellular electrophilic or oxidative compounds, which are common by-products during cellular stress. These compounds react with cysteine residues in KEAP1, which weakens the KEAP1–NRF2 interaction, allowing NRF2 to accumulate in the nucleus and facilitate transcription of its target genes by binding to AREs. Right: Non-canonical mechanisms of NRF2 activation involve p62-dependent degradation of KEAP1 during autophagy. Alternatively, phosphorylated p62 and several other proteins can compete with NRF2 for binding to KEAP1, allowing NRF2 to accumulate in the nucleus.

Figure 2.. Cellular processes regulated by NRF2 with implications for epithelial repair.

NRF2 activation can promote proliferation of epithelial cells in multiple tissues and organs. In contrast, constitutive NRF2 activation promotes fibroblast senescence, which leads to increased proliferation of neighboring epithelium via the senescence-associated secretome. NRF2 activation can also encourage epithelial cell differentiation and migration, while at the same time limit complications that contribute to impaired healing by reducing epithelial to mesenchymal transition (EMT) and subsequent fibrosis, and protecting cells from apoptosis.