NRF2, a Transcription Factor for Stress Response and Beyond

Abstract

<jats:p>Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the cellular defense against toxic and oxidative insults through the expression of genes involved in oxidative stress response and drug detoxification. NRF2 activation renders cells resistant to chemical carcinogens and inflammatory challenges. In addition to antioxidant responses, NRF2 is involved in many other cellular processes, including metabolism and inflammation, and its functions are beyond the originally envisioned. NRF2 activity is tightly regulated through a complex transcriptional and post-translational network that enables it to orchestrate the cell’s response and adaptation to various pathological stressors for the homeostasis maintenance. Elevated or decreased NRF2 activity by pharmacological and genetic manipulations of NRF2 activation is associated with many metabolism- or inflammation-related diseases. Emerging evidence shows that NRF2 lies at the center of a complex regulatory network and establishes NRF2 as a truly pleiotropic transcription factor. Here we summarize the complex regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity.</jats:p>

Intranasal Administration of Mesenchymal Stem Cell Secretome Reduces Hippocampal Oxidative Stress, Neuroinflammation and Cell Death, Improving the Behavioral Outcome Following Perinatal Asphyxia

“…NRF2 activation is an important endogenous antioxidant mechanism protecting against oxidative stress [ 22 , 24 , 81 , 82 ]. It has been shown that under hypoxia-ischemia conditions, the expression of NRF2 is enhanced, released from Keap1, and translocated to the nucleus, binding to the ARE sequences.…”

Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects

“…In subjects with MAFLD, Nrf2 activation occurs in response to disease development, but the expression of antioxidant enzymes seems to decrease as MAFLD progresses [ 39 ]. Nrf2-knockout (Nrf2-KO) cells have lower levels of glutathione, whereas Keap1 deficiency promotes glutathione upregulation [ 24 , 40 ]. The induction of the Keap1/Nrf2 signaling pathway may provide protection to hepatic cells from oxidative stress and avoid the progression of MAFLD [ 41 ].…”

“…The induction of the Keap1/Nrf2 signaling pathway may provide protection to hepatic cells from oxidative stress and avoid the progression of MAFLD [ 41 ]. A microarray study revealed that both genetic and pharmacologic activation of Nrf2 resulted in induction of pathways beyond detoxification and cytoprotection, including genes of lipid metabolism [ 9 , 40 ]. Nrf2 activation also inhibits the transcription of IL-6 and IL-1β [ 40 ] and reduces hepatic glucose production in humans [ 32 ].…”

“…A microarray study revealed that both genetic and pharmacologic activation of Nrf2 resulted in induction of pathways beyond detoxification and cytoprotection, including genes of lipid metabolism [ 9 , 40 ]. Nrf2 activation also inhibits the transcription of IL-6 and IL-1β [ 40 ] and reduces hepatic glucose production in humans [ 32 ]. Osteocalcin, scutellarin, apigenin, and berberine were found to improve MAFLD by activating the Keap1/Nrf2 antioxidant system [ 4 , 42 ].…”

“…Nrf2 activation ameliorates methionine- and choline-deficient (MCD) diet-induced hepatic steatosis, inhibiting Cluster of differentiation 36 (CD36), Fibroblast growth factor 21 (Fgf21), and PPARα expression in the liver of mice [ 45 ], whereas Nrf2 deletion increases PPARα expression [ 3 , 40 , 46 ]. Mouse embryonic fibroblasts extracted from Keap1-knockdown (Keap1-KD) mice exhibit impaired adipogenesis, which identifies Nrf2 as a negative regulator of lipid metabolism [ 47 ].…”