Nuclear factor E2-related factor 2 (NRF2) plays an important role in redox metabolism and antioxidant defense. Under normal conditions, NRF2 proteins are maintained at very low levels because of their ubiquitination and proteasomal degradation via binding to the kelch-like ECH associated protein 1 (KEAP1)-E3 ubiquitin ligase complex. However, oxidative and/or electrophilic stresses disrupt the KEAP1-NRF2 interaction, which leads to the accumulation and transactivation of NRF2. During recent decades, a growing body of evidence suggests that NRF2 is frequently activated in many types of cancer by multiple mechanisms, including the genetic mutations in the KEAP1-NRF2 pathway. This suggested that NRF2 inhibition is a promising strategy for cancer therapy. Recently, several NRF2 inhibitors have been reported with anti-tumor efficacy. Here, we review the mechanisms whereby NRF2 is dysregulated in cancer and its contribution to the tumor development and radiochemoresistance. In addition, among the NRF2 inhibitors reported so far, we summarize and discuss repurposed NRF2 inhibitors with their potential mechanisms and provide new insights to develop selective NRF2 inhibitors.
Metabolism ; NF-E2-Related Factor 2 ; Oxidation-Reduction ; Transcriptional Activation ; Ubiquitin ; Ubiquitination

Wound healing is one of the common pathophysiological processes in the body. How to improve the condition of wound healing to promote rapid wound healing has always been a hotspot in research. Oxidative stress is one of the important factors affecting wound healing. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a classic antioxidant stress factor as well as a factor with great potential in facilitating wound healing. The activation of Nrf2 can regulate the downstream antioxidant stress elements and play roles of anti-apoptosis and cell homeostasis maintaining, which improves wound healing environment and promotes wound repair. This paper summarized the common agonists and inhibitors of Nrf2 and reviewed the roles of Nrf2 in promoting skin wound healing including diabetic ulcers, radiation injury, and ischemia-reperfusion injury, etc.
Antioxidants/pharmacology* ; NF-E2-Related Factor 2/metabolism* ; Oxidative Stress ; Wound Healing/physiology*

In the development of oxidative stress-relevant diseases, reactive oxygen species (ROS) removal obstacle or excess production results in the damage of the body tissues and organs. Recent studies have demonstrated that nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) axis played a significant role in anti-oxidative stress. The Nrf2/HO-1 axis counteracts oxidative stress injury by its resistance to inflammation, oxidation, mitochondrial damage and calcium influx, apoptosis, pyroptosis, ferroptosis and autophagy, which provides a theoretical basis for its therapeutic effect on various oxidative stress-relevant diseases in multiple organs (respiratory, cardiovascular, nervous, digestive, urinary and blood systems). Therefore, effective regulation of the Nrf2/HO-1 signal axis can be an important strategy for treatment of oxidative stress-relevant diseases.
Heme Oxygenase-1 ; NF-E2-Related Factor 2 ; Oxidative Stress ; Reactive Oxygen Species ; Signal Transduction

This study aims to investigate the detoxification effects of different processing methods on the cardiotoxicity induced by radix Tripterygium wilfordii, and preliminarily explore the detoxification mechanism via the nuclear factor E2-related factor 2(Nrf2)/heme oxygenase 1(HO-1) pathway. The raw and processed products [stir-fried product, product stir-fried with Lysimachiae Herba(JQC), product stir-fried with Phaseoli Radiati Semen(LD), product stir-fried with Paeoniae Radix Alba(BS), product stir-fried with Glycyrrhizae Radix et Rhizoma(GC), and product stir-fried with vinegar(CZ)] of radix T. wilfordii were administrated to mice by gavage at a dose of 2 g·kg~(-1)(based on crude drugs) for 28 days. Twenty-four hours after the last administration, we measured the serum biochemical indexes of mice to evaluate the detoxification effect. Furthermore, we determined the expression of key proteins of Nrf2/HO-1 pathway in mouse heart tissue by Western blot and some oxidation/antioxidation-related indexes by corresponding kits to explore the detoxification mechanism. The administration of the raw product elevated the levels of serum creatine kinase, lactate dehydrogenase, and malondialdehyde, a product of cardiac lipid peroxidation(P<0.01), down-regulated the protein levels of Nrf2 and HO-1(P<0.01), and reduced the levels of total superoxide dismutase, glutathione, glutathione peroxidase, and glutathione S-transferase(P<0.01). However, after the administration of the products stir-fried with JQC, LD, BS, GC, and CZ, the abnormalities of the above indexes induced by the raw product were recovered(P<0.05 or P<0.01). In particular, the product stir-fried with JQC showed the best performance. Taken all together, the cardiotoxicity induced by radix T. wilfordii could be attenuated by stir-frying with JQC, LD, BS, GC, and CZ, and the stir-frying with JQC showed the best detoxification effect. The mechanism might be associated with the cardiac antioxidant defense and oxidative damage mitigation mediated by the up-regulated Nrf2.
Animals ; Antioxidants/pharmacology* ; Cardiotoxicity ; Mice ; NF-E2-Related Factor 2/metabolism* ; Oxidative Stress ; Tripterygium

Objective To observe the expression changes of nuclear factor-erythroid derived 2-related factors （Nrf2） in different cells at different time points after human cerebral cortex contusion, and to discuss its application in brain wound age estimation. Methods Thirty-six human brain tissues were selected, of which 6 were for control and 30 were cortical contusion at different time points post-injury, which were divided into 0-1 h, 3-6 h, 1-3 d, 5-7 d, and 10-14 d post-injury groups, with 6 cases in each group. Based on paraffin embedded sections, HE staining was used to observe the morphological changes post-injury, and double immunofluorescence staining was used to detect the expression of Nrf2 in neurons, astrocytes, and microglia. The number of positive cells was counted and statistical analysis was made. Results The number of neurons decreased 1-3 d post-injury. The expression of Nrf2 cells in neurons increased after injury, and the rate of positive cells peaked at 1-3 d post-injury. Glial cells were activated 1-3 d post-injury, and the activation peaked at 5-7 d post-injury. The cerebromalacia began to form at 10-14 d post-injury. Glial fibrillary acidic protein （GFAP） positive cells in mice increased gradually after injury and peaked at 5-7 d post-injury, while the proportion of Nrf2 in GFAP positive cells was relatively stable. After injury, ionized calcium-binding adapter molecule 1 （IBA1） positive cells increased and activated gradually. The expression proportion of Nrf2 in IBA1 positive cells increased gradually, reached its peak at 5-7 d post-injury, and then decreased. Conclusion The expression of Nrf2 in different cells involves in the biological function of different cells post-injury, and the dynamic expression of single cells has a time-dependent pattern. This may provide a new reference index for the wound age estimation of brain contusion in human.
Animals ; Brain Contusion ; Cerebral Cortex ; Glial Fibrillary Acidic Protein ; Humans ; Mice ; NF-E2-Related Factor 2

This study aims to explore the effects of Shenqi Dihuang Decoction on high-glucose induced ferroptosis and the nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)/glutathione peroxidase 4(GPX4) axis in human renal tubular epithelial cells(HK-2) and to clarify the underlying mechanism. The cell injury model was established by exposing HK-2 to high glucose, and the Shenqi Dihuang Decoction-medicated serum was prepared. The optimal concentration and intervention time of Shenqi Dihuang Decoction were determined. HK-2 were divided into normal, high glucose, and low-, medium-, and high-dose Shenqi Dihuang Decoction groups. After interventions, the cell proliferation rate in each group was determined and the cell morphology and mitochondrial ultrastructure were observed. Then, the levels of intracellular reactive oxygen species(ROS), ferrous ion(Fe~(2+)), glutathione(GSH), and malondialdehyde(MDA) and the protein levels of Nrf2, HO-1, GPX4, and xCT were measured. The optimal concentration and intervention time of Shenqi Dihuang Decoction-medicated serum were determined to be 10% and 24 h, respectively. Compared with the high glucose group, high-dose Shenqi Dihuang Decoction promoted the proliferation of HK-2. The cells in the low-, medium-, and high-dose Shenqi Dihuang Decoction groups presented tight arrangement, an increased cell count, improved morphology from a spindle-fiber shape to a cobblestone shape, and improved morphology and structure of mitochondrial membrane and cristae, compared with those in the high glucose group. Meanwhile, all the doses of Shenqi Dihuang Decoction inhibited ROS elevation to mitigate the peroxidation damage, lowered the Fe~(2+) and MDA levels and elevated the GSH level to inhibit lipid peroxidation, and activated the antioxidant pathway to upregulate the protein levels of Nrf2, HO-1, xCT, and GPX4. In conclusion, Shenqi Dihuang Decoction-medicated serum can inhibit high-glucose induced ferroptosis of HK-2 in vitro, which involves the antioxidant effect and the activation of the Nrf2/HO-1/GPX4 pathway.
Humans ; Ferroptosis ; NF-E2-Related Factor 2/genetics* ; Reactive Oxygen Species ; Epithelial Cells ; Antioxidants ; Glutathione ; Glucose

Lung cancer is one of the most common cancers in the world, and its treatment strategy is mainly surgery combined with radiotherapy and chemotherapy. However, long-term chemotherapy will result in drug resistance, which is also one of the difficulties in the treatment of lung cancer. Ferroptosis is an iron-dependent and lipid peroxidation-driven non-apoptotic cell death cascade, occurring when there is an imbalance of redox homeostasis in the cell. Nuclear factor erythroid 2-related factor 2 (Nrf2) is key for cellular antioxidant responses. Numerous studies suggest that Nrf2 assumes an extremely important role in regulation of ferroptosis, for its various functions in iron, lipid, and amino acid metabolism, and so on. In this review, a brief overview of the research progress of ferroptosis over the past decade will be presented. In particular, the mechanism of ferroptosis and the regulation of ferroptosis by Nrf2 will be discussed, as well as the role of the Nrf2 pathway and ferroptosis in tumor drug resistance, which will provide new research directions for the treatment of drug-resistant lung cancer patients.
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Humans ; Ferroptosis ; NF-E2-Related Factor 2/genetics* ; Lung Neoplasms/genetics* ; Drug Resistance, Neoplasm ; Iron

The imbalance of redox homeostasis is a major characteristic of aging and contributes to the pathogenesis of various aging-related diseases. As a regulatory hub of redox homeostasis, nuclear factor erythroid 2-related factor 2 (NRF2) can attenuate oxidative stress by activating the transcription of many antioxidant enzymes. China is the birthplace of traditional Chinese medicine (TCM) which has been wildly used as medicine for thousands of years. Recently, TCM as anti-aging medicine has attracted enormous attention. Focusing on the NRF2 signaling pathway, this paper summarizes the correlation between various anti-aging TCM and the NRF2 signaling, and discusses the common key mechanisms by which TCM slows the aging process by targeting the NRF2 signaling network.
Medicine, Chinese Traditional ; NF-E2-Related Factor 2/metabolism* ; Oxidative Stress ; Signal Transduction

The nuclear factor erythroid 2 related factor 2 (Nrf2) is a key protein of endogenous antioxidant defense systems in the body. In response to oxidative stress, Nrf2 translocates to nucleus and binds to antioxidant response elements (ARE), regulating the expression of a large amounts of antioxidant genes and maintaining a proper redox balance. The pathological processes of neurodegenerative diseases are associated with generation of reactive oxygen species, which cause oxidative stress. Oxidative stress plays a cardinal role in the onset and progression of neurodegenerative diseases. Nrf2-inducer compounds can reduce oxidant stress and have shown therapeutic efficacy in many neurodegenerative disease models. How to activate the Nrf2 signaling pathway effectively has been received much attention. Here we provided an overview of specific mechanism of Nrf2-ARE pathway and the protective effects of Nrf2 in different neurodegenerative diseases, and summarized the Nrf2 activators recently in preclinical study.
Antioxidants ; physiology ; Humans ; NF-E2-Related Factor 2 ; physiology ; Neurodegenerative Diseases ; metabolism ; Oxidative Stress ; Reactive Oxygen Species ; metabolism ; Signal Transduction

The transcription factor Nrf2, nuclear factor erythroid-2-related factor 2, activates the transcription of over 500 genes in the human genome, most of which have cytoprotective functions. Nrf2 produces cytoprotection by detoxification mechanisms leading to increased detoxification and excretion of both organic xenobiotics and toxic metals; its action via over two dozen genes increases highly coordinated antioxidant activities; it produces major anti-inflammatory changes; it stimulates mitochondrial biogenesis and otherwise improves mitochondrial function; and it stimulates autophagy, removing toxic protein aggregates and dysfunctional organelles. Health-promoting nutrients and other factors act, at least in part by raising Nrf2 including: many phenolic antioxidants; gamma- and delta-tocopherols and tocotrienols; long chain omega-3 fatty acids DHA and EPA; many carotenoids of which lycopene may be the most active; isothiocyanates from cruciferous vegetables; sulfur compounds from allium vegetables; terpenoids. Other health promoting, Nrf2 raising factors include low level oxidative stress (hormesis), exercise and caloric restriction. Raising Nrf2 has been found to prevent and/or treat a large number of chronic inflammatory diseases in animal models and/or humans including various cardiovascular diseases, kidney diseases, lung diseases, diseases of toxic liver damage, cancer (prevention), diabetes/metabolic syndrome/obesity, sepsis, autoimmune diseases, inflammatory bowel disease, HIV/AIDS and epilepsy. Lesser evidence suggests that raising Nrf2 may lower 16 other diseases. Many of these diseases are probable NO/ONOO(-) cycle diseases and Nrf2 lowers effects of NO/ONOO(-) cycle elements. The most healthful diets known, traditional Mediterranean and Okinawan, are rich in Nrf2 raising nutrients as apparently was the Paleolithic diet that our ancestors ate. Modern diets are deficient in such nutrients. Nrf2 is argued to be both lifespan and healthspan extending. Possible downsides to too much Nrf2 are also discussed. Nrf2 is not a magic bullet but is likely to be of great importance in health promotion, particularly in those regularly exposed to toxic chemicals.
Animals ; Antioxidants ; physiology ; Cytoprotection ; Diet ; Humans ; Inflammation ; prevention & control ; NF-E2-Related Factor 2 ; physiology ; Oxidation-Reduction ; Oxidative Stress