Nrf2 Pathway

The KEAP1-NRF2 pathway is the principal protective response to oxidative and electrophilic stresses, in which the transcription factor NRF2 promotes an antioxidant transcription program. ^[1] NRF2 is a master transcriptional regulator of a battery of genes involved in the adaptive response to oxidative stress, and the KEAP1-NRF2 system forms the major node of cellular and organismal defense against oxidative and electrophilic stresses of both exogenous and endogenous origins. ^{[2] [3]}

Under homeostatic conditions, KEAP1 forms part of an E3 ubiquitin ligase that tightly regulates NRF2 by targeting it for ubiquitination and proteasome-dependent degradation. ^[1] In response to stress, an intricate mechanism facilitated by sensor cysteines within KEAP1 allows NRF2 to escape ubiquitination, accumulate within the cell, and translocate to the nucleus where it can promote its antioxidant transcription program. ^[1] KEAP1 acts as a cysteine thiol-rich sensor of redox insults while NRF2 robustly transduces chemical signals to regulate cytoprotective genes, and this rapid inducibility based on a derepression mechanism is an important feature of the system. ^[3] Keap1-Nrf2 signaling is also modulated by a more complex regulatory network, including phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), protein kinase C, and mitogen-activated protein kinase. ^[4]

The Keap1-Nrf2 system is closely associated with aging and controls the transcription of multiple antioxidant enzymes, and increased oxidative stress from diverse sources has been implicated in most senescence-related diseases and in aging itself. ^[4] There is convincing evidence that Nrf2 not only declines with age but that Nrf2 and heme oxygenase-1 can reduce cellular senescence and the senescence-associated secretory phenotype, which is considered an underlying driver of age-related inflammatory disease. ^[2] Controlled harnessing of the KEAP1-NRF2 system is proposed as a key to healthy aging and well-being in humans, and the system is an important prophylactic and therapeutic target for aging-related disorders. ^[3]

Activation of NRF2 is emerging as an attractive therapeutic approach to counteract oxidative stress, inflammation, and metabolic imbalances that underpin many chronic pathologies including neurodegenerative and metabolic diseases. ^[5] NRF2 exhibits a Janus-faced duality, safeguarding normal cells against environmental insults to prevent disease onset, whereas in certain cancers constitutively elevated NRF2 levels provide a tumour survival advantage promoting progression, therapy resistance and metastasis. ^[6]