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Cucullo, L. Protective Role of NRF2. Encyclopedia. Available online: https://encyclopedia.pub/entry/18216 (accessed on 15 December 2025).
Cucullo L. Protective Role of NRF2. Encyclopedia. Available at: https://encyclopedia.pub/entry/18216. Accessed December 15, 2025.
Cucullo, Luca. "Protective Role of NRF2" Encyclopedia, https://encyclopedia.pub/entry/18216 (accessed December 15, 2025).
Cucullo, L. (2022, January 13). Protective Role of NRF2. In Encyclopedia. https://encyclopedia.pub/entry/18216
Cucullo, Luca. "Protective Role of NRF2." Encyclopedia. Web. 13 January, 2022.
Protective Role of NRF2
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This entry is adapted from the peer-reviewed paper 10.3390/ijms20143433

Nuclear factor erythroid 2-related factor (NRF2) is the major modulator of the xenobiotic-activated receptor (XAR) and is accountable for activating the antioxidative response elements (ARE)-pathway modulating the detoxification and antioxidative responses of the cells.

NRF2 cerebrovascular neurodegenerative

1. NRF2 Regulation and Response to Oxidative Stress

Domain analysis by high-resolution crystal structure and nuclear magnetic resonance spectroscopy has shown that the molecular structure of NRF2 includes seven functional domains (Neh1–Neh7) that regulate its transcriptional activity and stability [1]. The first conserved domain, Neh1, containing basic bZIP motif binds, to the ARE sequence exposing a nuclear localization signal required for translocation of released NRF2 from Kelch-like ECH-associated protein 1 (KEAP1) into the nucleus [2][3][4]. Neh1 and Neh2 play differing roles with respect to NRF2 regulation. While Neh1 modulates NRF2 protein stability through interaction with the E2 ubiquitin-conjugating enzyme, Neh2, a negative regulatory domain located in the N-terminal region, promotes NRF2 ubiquitination followed by proteasomal degradation, which is a result of increased KEAP1–NRF2 binding [5]. While Neh3 (which is located in the carboxyl-terminal region of the protein) modulates the transcriptional activation of the ARE genes [1][6], the Neh4 and Neh5 domains play a cooperative role in facilitating NRF2 transcription by binding to a transcriptional co-activator [7] and also increases NRF2–ARE gene expression by interfacing with the nuclear cofactor RAC3/AIB1/SRC-3 [7][8]. The Neh6 and Neh7 domains control KEAP1-independent degradation of NRF2 and regulate the activity of NRF2 so that KEAP1-alternative pathway of NRF2 degradation arises based on the recognition of phosphorylated Neh6 by the E3 ligase adapter beta-TrCP [9][10][11] and Neh7 inhibits NRF2 via interaction with retinoid X receptor α [12]. The main step in detoxification is the nuclear and cytoplasmic disposition of NRF2 so that under basal conditions, NRF2 is rapidly polyubiquitinated while cellular redox homeostasis is sustained by the accumulation of the NRF2 in the nucleus to mediate the normal expression of ARE-dependent genes [13][14].
KEAP1, the main intracellular regulator of NRF2, is composed of three main domains (totaling 624 amino acids) including the Broad-complex (1), Tramtrack (2), and the Bric-a-Brac (BTB) domain (3) which includes a cysteine-rich region and a double glycine repeat -DGR- binding site between KEAP1 and NRF2. Several cysteine residues within the BTB domain act as OS sensors and/or inducer ligands within the cell’s environment [1]. The activity of the NRF2–ARE signaling pathway is controlled by degradation and sequestration of NRF2 in the cytoplasm through binding with KEAP1 [15][13]. Other factors including post-transcription changes, gene polymorphisms in the promoter region, and protein–protein interactions are also influenced by NRF2 basal activity [14][16]. It is noteworthy that in response to mitochondrial oxidative stressors NRF2 provides direct interaction with the mitochondrial membrane [17].
Under basal conditions, KEAP1 binds to NRF2 in the cytoplasm and enhances the ubiquitination and proteasomal degradation of NRF2, whereas in response to oxidative stress condition, the NRF2 DLG motif is released from the DGR domain in KEAP1, which then undergoes conformational changes and dissociate NRF2 from itself to shift into the nucleus freely [14]. Independently from KEAP1 activity, not only phosphorylation of NRF2’s serine enhance separation of NRF2 from KEAP1 [13], but also glycogen synthase kinase-3β (GSK-3β), synthesis of specific microRNAs, methylation of CpG islands, histone phosphorylation, and acetylation modulate the expression and activation of NRF2 [18][19][20][21]. This cytoprotective pathway encompasses detoxification systems such as oxidation/reduction factors (Phase I), conjugation enzymes (Phase II), and drug efflux transporters (Phase III) [14][21].  NRF2 also controls/enhances the expression of active efflux transporters that remove or keep out potentially detrimental endogenous or xenobiotics of the cell [14] as well as tight junction (TJ) expression and BBB integrity at the neurovascular unit [22]. NRF2 nuclear accumulation can also have harmful effects [3] which accounts for the necessity of autoregulating the cellular levels of NRF2 [6][23]. For this end, the cullin3/ring box 1 (Cul3/Rbx1) E3 ubiquitin ligase complex promotes polyubiquitination of NRF2 coupled with KEAP 1 followed by NRF2 proteasomal degradation. This mechanism controls the “switching off” of NRF2-activated gene expression in the nucleus [6].

2. Role of NRF2 in Aging and Traumatic Brain Injury

Non-effective antioxidative responses to excessive ROS production and changes in redox signaling playing are one of the major reasons for advanced aging, whereas the inability to properly counteract OS leads to the progressive accumulation of OS-induced cellular damage [24][25]. Recent studies have, in fact, shown that age-related OS damages are dependent upon decreased antioxidant responses, as well as proteasome reduction, and reduced efficiency of mitochondrial proteases. The resulting effect of this impaired antioxidative response and inability to effectively maintain the redox balance is an accumulation of intracellular and intramitochondrial aggregates of oxidized proteins [26]. Similarly, the decreased level NADPH and GSH with aging could likely be due to a decreased cellular antioxidative capacity, as well as reduced intake of dietary antioxidants. Although there is a lot of dispute over the effect of age on the basal expression levels of antioxidative response factors, it seems that the primary underlying cause is a reduced NRF2 activity [27][28][29].
In respect to traumatic brain injury (TBI), disruption in the normal brain function following TBI is one of the foremost causes of death as well as severe emotional, physical, and cognitive impairments [30][31][32]. In spite of the pathogenic role of the primary brain injury immediate to TBI, the post-traumatic secondary injury derived from OS, inflammation, excitotoxicity, enhanced vascular permeability, and BBB impairment can significantly worsen post-traumatic brain damage as well as clinical outcomes [33][34]. Excessive ROS generation following cell damage, neuronal cell death, and brain dysfunction are the results of several secondary biochemical and metabolic changes in the cells [35]. According to recent studies, NRF2 plays a neuroprotective role in TBI so that NRF2 activation counteracts TBI-induced OS, loss of BBB integrity, etc. Unsurprisingly, impairments of the NRF2–ARE pathway leading to reduced activity of this protective system can result in more extensive post-TBI tissue damage, thus aggravating the secondary injury and worsening outcome. Accordingly, promoting upregulation of NRF2 activity could be exploited to reduce post-traumatic brain injuries, improve clinical outcomes, and reduce the risk of additional neurological disorders [36][37].

3. Ischemic Stroke and Protective Role of NRF2

Stroke, the fifth leading cause of death in the United States and a major cause of permanent disability, is defined by a bursting or blockage of blood vessels resulting in the sudden interruption of the local blood supply and the initiation of an anoxic and hypoglycemic state in the affected brain tissue [38]. Moreover, neuronal cell membrane depolarization causes the release of the neurotransmitter glutamate, which is the activator of the ionotropic glutamate receptor N-methyl-d-aspartate (NMDA) [15]. The resulting opening of these non-selective cation channels leads to calcium overload and neuronal cell death [39]. These events are associated with excessive ROS production by the mitochondria which overwhelm the antioxidant defenses, leading to post-ischemic inflammation and enhanced brain tissue damage [40][41][42][43]. Furthermore, degradation of the structural proteins of the vascular wall and loss of BBB integrity also occur as a result of blood flow restoration, which suddenly enhances tissue oxygenation further exacerbating ROS production, inflammatory responses, and OS damage [15]. Adhesion of leukocytes across the blood vessels and transmigration into the brain parenchyma is facilitated by the concurrent expression of vascular adhesion molecules on the luminal surface of the vascular walls. Based on these premises, it is evident that control of ROS levels and OS prevention could be a potential therapeutic strategy to address post-ischemic secondary brain injury and improve stroke outcome [15][44][45][46]. Recent studies demonstrated that the protective effect of interactions between p62 and the NRF2–EpRE signaling pathway inhibited OS damage during cerebral ischemia/ reperfusion in rat undergoing transient middle artery occlusion (tMCAO) and also promoted NRF2 activity to lower the infarct volume and post-ischemic neurocognitive impairments [47][48]. NRF2 activity is also crucial to protect the brain against injury. In fact, NRF2 activation through the use of pharmacological enhancers improved neuronal cell viability, decreased BBB permeability, and promoted the transcription of cytoprotective genes [49][50]. Furthermore, enhanced infarct size, inflammatory damages, and neurological deficits were reported in NRF2 KO mice when compared to controls (wild-type mice). By contrast to controls, the use of NRF2 enhancer in knock out mice did not elicit any beneficial effect [51]. Most recently, other studies have shown that NRF2 downregulated the activity of the NOD-like receptor protein 3 (NLRP3) inflammasome by acting on thioredoxin-1 (Trx1)/thioredoxin interacting protein (TXNIP) complex [44]. The NLRP3 inflammasome plays a key role in inflammation damage in cerebral ischemia-reperfusion injury by promoting the activity of interleukin-23/interleukin-17 axis which contributes to the ischemic reperfusion damage at the CNS [52]. The activation of NLRP3 is dependent upon the interaction with TXNIP, which dissociates from the Trx1/TXNIP complex under OS. Thus, it is clear how targeting NRF2 represent a viable target for the treatment of ischemia and reperfusion injury.

4. Role of NRF2 in Neurodegenerative Diseases

Recent discoveries have mentioned OS as a major pathogenesis of neurodegenerative disorders (NDDs) due to the accumulation of ROS [38][53]. In fact, a failure in maintaining the proper balance between ROS generation and their neutralization causes a disruption of brain homeostasis leading to neurodegenerative disorders [54][55] (see Figure 1).
Ijms 20 03433 g002 550
Figure 1. Schematic representation of the Cerebrovascular and neurodegenerative diseases associated with impaired redox metabolism and oxidative stress.
Alzheimer’s disease: A neuropathological hallmark of AD is the formation of intracellular neurofibrillary tangles (NFTs) and extracellular senile plaques (SPs) composed of small Aβ peptides [56]. Several studies propose that OS is an early prodromal event for progressive neurodegenerative disorders [57]. According to several studies on AD, NRF2 was able to provide a neuroprotective effect by decreasing ROS generation and ROS-induced toxicity mediated by Aβ [58][59]. Supporting data have shown that NRF2 activators, such as sulforaphane (SFN) lower toxin-induced Aβ1-42 secretion, while enhancing cell viability and improving cognitive function [60][61]. These beneficial effects may be due to the formation of Aβ aggregates or the inhibition of the release of monomer/oligomeric Aβ from dead cells [62]. A recent study also outlined the role of NRF2 in facilitating autophagy as well as altering β-Amyloid precursor proteins (APP) and Aβ processing whereas NRF2 knockout APP/PS1 mice showed increased accumulation of insoluble APP fragments and Aβ as well as mammalian targets of rapamycin (mTOR) activity [15][63]. The investigators also found that overexpression of mitochondria catalase in APP transgenic mice (Tg2576), decreases the formation of full-length APPs and lowers soluble and insoluble Aβ levels. From a clinical perspective, this may translate into extending the lifespan of the patient while improving working memory [15]. In a recent study, Rojo et al. demonstrated the protective effect of NRF2 against exacerbation of astrogliosis and microgliosis using transgenic mouse models [62]. Specifically, the investigators have shown a reduction in homeostatic responses with aging along with NRF2 activity resulting in reduced protection against proteotoxic, inflammatory and oxidative stress stimuli [15][64].
Parkinson’s disease: PD is a progressive neurodegenerative disorder characterized by lowered dopamine levels in the striatum due to the loss of dopaminergic neurons located in the substantia nigra affecting movement [65]. The initial symptoms in PD patients sometimes are tremors affecting one hand or slowing of movement. With the progression of the disease controls over movement is completely compromised and the effects are extended to neurocognitive functions dementia [15]. The certain diagnosis of PD in both familial and sporadic PD patients is the presence of Lewy bodies (LBs) as abnormal protein aggregates developing inside nerve cells. The main constituent of LBs is Alpha-synuclein (αSyn) which is a small protein with 140 amino acids. αSyn is abundant in presynaptic nerve terminals playing a role in synaptic transmission and dopamine levels adjustment [15]. Recent studies strongly postulate the association between PD with abnormal ROS production promoted by the dopamine metabolism, excitatory amino acids and iron content [57]. Moreover, it is emphasized that this increased OS plays a pivotal role in αSyn proteostasis, whereas NRF2 activity can counteract αSyn production and the associated cellular damage [58][66][67][68][69]. Recently, NRF2 overexpression has not only confirmed the reduction of the generation of αSyn aggregates in the CNS [70], but also the activation of NRF2 has appeared to prevent the loss of dopaminergic neurons mediated by αSyn and the consequent impairment of motor functions [15][71]. NRF2 deficiency and promoted expression of αSyn experienced enhanced loss of dopaminergic neuron and increased neuroinflammation and protein aggregation, whereas the enhanced expression level of NRF2 in a mutant αSyn transgenic mouse model, provided neuroprotective effects [15][72][69].
Huntington’s disease: HD as an inherited neurodegenerative disease is characterized by the loss of GABAergic inhibitory spiny projection neurons in the striatum [65] due to abnormally elongated poly-glutamine (polyQ) stretch encoded by the atypical expansion of adenine, cytosine, and guanine (CAG) trinucleotide repeats at the huntingtin protein (Htt). According to several in vitro studies, NRF2 activation can play a protective role in the reduction of mHtt-induced toxicity, while in HD patients the initiation of the NRF2–ARE system in striatal cells in response to OS failed because of the concurrent activation of the autophagy pathway [73][74]. Moreover, additional data have confirmed that Htt aggregation directly enhanced ROS generation promoting cell toxicity [75]. Furthermore, co-transfection of NRF2 with mHtt in primary striatal neurons, reduction of the mean lifetime of mHtt N-terminal fragments, and, subsequently, improvement of cell viability suggest that NRF2 is more likely to decrease mHtt -toxicity by negatively affecting its aggregation [76].
Amyotrophic lateral sclerosis: ALS is a progressive neurodegenerative disease characterized by the loss of motor neurons in the ventral horn of the spinal cord and in the motor cortex. The disease leads to progressive motor weakness and loss of controls of voluntary movements [15][65]. Although, for more than two decades, the mutation of Cu–Zn superoxide dismutase 1 (SOD1) was the only genetic aberration relevant to the initiation of familial ALS, recent studies have found more abnormalities associated with the onset of sporadic and non-SOD1 familial ALS, including a host of RNA/DNA-binding proteins such as the 43-kDa transactive response (TAR) DNA-binding protein (TDP-43) and the fused in sarcoma/translocated in liposarcoma (FUS/TLS) [15]. Several recent studies support that NRF2 activation plays a protective role against OS and cell death promoted by the SOD1 mutant protein so that glial NRF2 overexpression improves the survival of the spinal cord’s motor neurons and extends their viable lifespan [77][78]. Additional studies will be required to evaluate the impact of NRF2 on cellular proteostasis as well as other ALS-associated gene mutations and the effect of NRF2 stimulation on late-stage microglia activation to prevent OS.

7. Role of NRF2 in Blood-Brain Barrier (BBB) Integrity and Function

In the central nervous system, the vascular endothelium acquires a set of specific characteristics and functions that differ from other vascular beds [79]. This specialized endothelium, which forms the BBB, becomes a dynamic functional interface between the blood and the brain that strictly regulates the passage of substances, maintains the brain homeostasis, and protects the brain from pathogens as well as endogenous and xenobiotic substances [30]. According to numerous studies, there is a relationship between NRF2 and BBB relevant to cerebrovascular disorders, so that NRF2 signaling plays a neurovascular protective role in the conservation of the BBB and CNS [80][81][82][83]. With regard to BBB endothelium, it has been emphasized that NRF2 upregulates the expression of tight junctional proteins (TJ), promotes redox metabolic functions, and produces ATP with mitochondrial biogenesis [84][81][83][85]. In fact, recently published data from side by side experiments investigating the impact of electronic cigarettes (e-Cig) versus TS on mouse primary brain microvascular endothelial cells (BMVEC) clearly showed that NRF2 was strongly activated by the resulting OS and promoted upregulation of its downstream signaling molecule NQO-1 [83], whereas NQO-1 exerts acute detoxification and cytoprotective functions. However, chronic exposure to these pro-oxidative stimuli ended up compromising NRF2 activity and that of its downstream effector NQO-1. These resulted in an overall impairment of BBB integrity associated with increased permeability to paracellular markers and decreased trans-endothelial electrical resistance (TEER) [45][83]. In addition to the loss of BBB integrity, in vivo data also showed upregulation of inflammatory markers including vascular adhesion molecules and pro-inflammatory cytokines as well as blood hemostasis changes favoring blood coagulation and, therefore, risk of stroke. Recent preliminary data and work by others have also clearly demonstrated that NRF2 modulates mitochondrial biogenesis, redox metabolism, and antioxidant/detoxification functions, thus, strongly suggesting that impairment of NRF2 activity can negatively affect mitochondrial biogenesis and function [84]. Altogether, these studies have shown that NRF2 plays a major role in critical BBB cellular functions ranging from modulation of barrier integrity, inflammatory responses, redox metabolism, and antioxidative responses [38][15][18][21][27][50][62][82][83][86][87]. In fact, cerebrovascular and neurodegenerative disorders such as subarachnoid brain hemorrhage, MS, ALS, AD, PD, stroke, and type-2 diabetes mellitus (TD2M) have been tied to dysfunctions of NRF2 activity [18][81][88][82][89][90][91][92][93]. Unsurprisingly, the activation of the NRF2–ARE system can potentially prevent/reduce the BBB impairments and, consequently, decrease some types of brain injury [94]. Since vascular endothelial dysfunction and consequent CNS damages have been relevant to ROS [95][96][97] and OS-driven inflammation [98], NRF2 activation is likely to preserve the BBB by maintaining ROS homeostasis that ultimately leads to a decrease in the risk of cerebrovascular, neurodegenerative, and CNS disorders [47][94][99][100][101]. For instance, the well-known NRF2 promoter/activator Sulforaphane (SFN) has been shown to have neuroprotective characteristics that counteract oxidative stress by enhancing NRF2 activation [88][94][102][103][104][105][106][107][108][109] and regulating antioxidant reactions [110].

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