NRF2-targeted therapeutics: New targets and modes of NRF2 regulation

Abstract

Pharmacological activation of the transcription factor nuclear factor-erythroid derived 2-like 2 (NRF2), the key regulator of the cellular antioxidant response, has been recognized as a feasible strategy to reduce oxidative/electrophilic stress and prevent carcinogenesis or other chronic illnesses, such as diabetes and chronic kidney disease. In contrast, due to the discovery of the "dark side" of NRF2, where prolonged activation of NRF2 causes tissue damage, cancer progression, or chemoresistance, efforts have been devoted to identify inhibitors. Currently, only one NRF2 activator has been approved for use in the clinic, while no specific NRF2 inhibitors have been discovered. Future development of NRF2-targeted therapeutics should be based on our current understanding of the regulatory mechanisms of this protein. In addition to the KEAP1-dependent mechanisms, the recent discovery of other pathways involved in the degradation of NRF2 have opened up new possibilities for the development of safe and specific therapeutics. Here, we review available and putative NRF2-targeted therapeutics and discuss their modes of action as well as their potential for disease prevention and treatment.

Keywords: NRF2; autophagy; cancer; chemoprevention; diabetes; electrophiles.

Figure 1. NRF2-targeted therapeutics

NRF2 can be activated by targeting the proteins that promote its degradation, such as KEAP1-CUL3-RBX1, GSK3-SCF-β-TrCP, and HRD1, or by targeting p62, which sequesters KEAP1 into autophagosomes. The different classes of NRF2 activators available to date are represented. Conversely, NRF2 could possibly be inhibited by targeting the NRF2-sMAF protein complex. No specific NRF2 inhibitor classes have been identified yet.

Figure 2. Post-translational modification of key p62 domains affects NRF2 activation

p62/SQSTM1 consists of an N-terminal Phox and Bem1 (PB1) domain, a ZZ-type zinc finger domain, a Traf6 binding (TB) domain, two nuclear localization sequences (NLS), a nuclear export signal (NES), an LC3-interacting region (LIR), a KEAP1-interacting region (KIR), and a C-terminal ubiquitin association domain (UBA). The PB1 domain can be phosphorylated at S24 by PKA and ubiquitylated at K7 by tripartite TRIM21 to prevent p62 oligomerization and sequestration of target proteins, including KEAP1, which results in NRF2 being degraded by the proteasome. Phosphorylation of S349 in the KIR by mTOR and S403 in the UBA domain by ULK1, CK2 or TBK1, enhances p62-KEAP1 binding, resulting in upregulation of NRF2. Therefore, the enzymes that modify p62 could be potential targets for p62-based NRF2 therapeutics.