Table 1.

Examples of genes regulated by Nrf2 and their biological functions.

Primary role	Gene	Protein	Function	Cellular processes	References
Redox homeostasis	GCLC	Glutamate–cysteine ligase catalytic subunit	Catalytic subunit of the enzyme responsible for the rate-limiting step in synthesis of the cellular antioxidant glutathione	Maintenance of cellular redox homeostasis	[36, 37, 40, 41]
Redox homeostasis	GLCM	Glutamate–cysteine ligase modifier subunit	Modifier subunit of the enzyme responsible for the rate-limiting step in synthesis of the cellular antioxidant glutathione	Maintenance of cellular redox homeostasis	[36–38, 40, 123]
Redox homeostasis	GPX2	Glutathione peroxidase 2	Detoxification of H2O2 and an important cellular antioxidant	Maintenance of cellular redox homeostasis	[126, 127]
Redox homeostasis	PRDX1	Peroxiredoxin 1	Reduces peroxides, regulates cellular concentrations of H2O2	Maintenance of cellular redox homeostasis	[36–38, 41, 117]
Redox homeostasis	SRXN1	Sulfiredoxin	Contributes to the thioredoxin-based antioxidant system that reduces oxidized protein thiols; reduces sulfinic acid in proteins	Thiol maintenance, maintenance of cellular redox homeostasis	[36, 37, 40, 41]
Redox homeostasis	TXN1	Thioredoxin 1	Reversible oxidation of active center allows participation in dithiol–disulfide exchange reactions; reduces sulfenic acid in proteins	Thiol maintenance, maintenance of cellular redox homeostasis	[36, 37, 39–41, 117]
Detoxification	ABCB6	ATP-binding cassette B6 (MDR/TAP)	Mitochondrial transporter; transports heme and porphyrin in an ATP-dependent manner, crucial for heme metabolism	Phase III drug metabolism, heme metabolism	[37, 41]
Detoxification	ABCC2	ATP-binding cassette C2 (MRP2)	Biliary transport/hepatic excretion; involved in the extrusion of certain anti-cancer drugs and implicated in multidrug resistance	Phase III drug metabolism	[36, 38, 39, 41, 120]
Detoxification	AKR1B10	Aldo-keto reductase 1B10	Converts retinal to retinol; reduces aromatic and aliphatic aldehydes	Phase I drug metabolism and retinal metabolism	[36, 38–40]
Detoxification	AKR1C1	Aldo-keto reductase 1C1	Converts 4-hydroxy-2-nonenal to 1,2-dihydroxy nonene; inactivates progesterone	Phase I drug metabolism	[36, 39, 40, 128]
Detoxification	AKR1C3	Aldo-keto reductase 1C3	Type 5 17β-hydroxysteroid dehydrogenase and prostaglandin F2α synthase	Phase I drug metabolism	[129–131]
Detoxification	CES1G	Carboxyl esterase 1G	Catalyzes the trans-esterification of xenobiotics, hydrolysis of long-chain fatty acid esters	Phase I drug metabolism, fatty acid oxidation, fatty acid degradation	[123]
Detoxification	CES1H	Carboxyl esterase 1H	Catalyzes the trans-esterification of xenobiotics, hydrolysis of long-chain fatty acid esters	Phase I drug metabolism, fatty acid oxidation, fatty acid degradation	[123]
Detoxification	GSTA1	Glutathione S-transferase A1	Detoxification and metabolism of electrophilic compounds; metabolism of bilirubin and certain anti-cancer drugs; also displays glutathione peroxidase activity	Phase II drug metabolism, cytoprotection	[38, 41, 58]
Detoxification	GSTM1	Glutathione S-transferase M1	Detoxification and metabolism of electrophilic compounds	Phase II drug metabolism	[38, 41, 58]
Detoxification	NQO1	NAD(P)H quinone oxidoreductase 1	Reduces quinones to hydroquinones and prevents the one-electron reduction of quinones that would otherwise produce free radicals	Phase I drug metabolism	[36, 37, 40]
Heme metabolism	FECH	Ferrochelatase	Catalyzes the insertion of Fe2+ into protoporphyrin IX during heme synthesis; localized in mitochondria	Heme metabolism	[37, 40]
Heme metabolism	HMOX1	Heme oxygenase 1	Cleaves heme to produce biliverdin during heme catabolism	Heme metabolism	[36–41]
Lipid metabolism	AWAT1	Acyl-CoA wax alcohol acyltransferase 1	Catalyzes the production of wax esters from long-chain alcohols and acyl-CoA-derived fatty acids; enriched in skin	Lipid metabolism	[123]
Lipid metabolism	FABP1 ↓	Fatty acid binding protein 1	Binds long-chain fatty acids, their CoA derivatives, and bile acids in the cytoplasm for intracellular transport	Lipid uptake and intracellular transport	[116]
Lipid metabolism	LIPH	Lipase H	Membrane-bound triglyceride lipase that hydrolyzes phosphatidic acid to produce 2-acyl lysophosphatidic acid, which is a potent bioactive lipid mediator	Platelet aggregation, smooth muscle contraction, cell proliferation and motility	[123]
Lipid metabolism	PPARγ	Peroxisome proliferator-activated receptor γ	Transcription factor that orchestrates lipid metabolism; key regulator of adipocyte differentiation and glucose homeostasis	Lipid mobilization, β-oxidation of fatty acids, adipocyte differentiation, glucose metabolism	[37, 116]
Lipolysis	ACOT7	Acyl-CoA thioesterase 7	Catalyzes the hydrolysis of palmitoyl-CoA and other long-chain fatty acids to form free fatty acid and CoA	Fatty acid oxidation, fatty acid degradation	[115]
Lipolysis	ACOX2	Acyl-CoA oxidase 2	Catalyzes peroxisomal degradation of long branched-chain fatty acids and bile acid intermediates	Fatty acid oxidation, fatty acid degradation	[123]
Lipogenesis	ACLY ↓	ATP citrate lyase	Catalyzes the production of acetyl-CoA and oxaloacetate from CoA and citrate using ATP	Lipogenesis, cholesterol synthesis, gluconeogenesis	[115, 116, 118]
Lipogenesis	FASN ↓	Fatty acid synthase	Generation of long-chain fatty acids such as palmitate from malonyl-CoA and acetyl-CoA using NADPH	Lipogenesis	[115, 116, 118]
Lipogenesis	SCD1 ↓	Stearoyl-CoA desaturase 1	Catalyzes the introduction of a double bond into stearoyl-CoA to create the mono-unsaturated fatty acid oleic acid	Lipogenesis	[115, 122]
Lipogenesis	SREBF1 ↓	Sterol-regulatory element binding transcription factor 1	Transcription factor that controls expression of the LDL receptor, and genes involved in glucose metabolism and lipid synthesis	Lipogenesis, glucose metabolism	[116]
Glucose metabolism	FGF21 ↓	Fibroblast growth factor 21	Stimulates glucose uptake in adipocytes, involved in regulation of insulin	Glucose uptake and clearance, insulin signaling	[132]
Cholesterol synthesis	HMGCS1 ↓	3-Hydroxy-3-methylglutaryl-CoA synthase 1	Catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA to produce HMG-CoA, the substrate for HMG-CoA reductase	Cholesterol synthesis	[115, 116]
NADPH generation	G6PD	Glucose-6-phosphate dehydrogenase	Generates NADPH in the pentose phosphate pathway; maintains cellular glutathione redox status	Pentose phosphate pathway, NADPH generation, maintenance of cellular redox homeostasis	[36, 38–41, 115]
NADPH generation	IDH1	Isocitrate dehydrogenase 1	Catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, using NADP+ as a cofactor, outside the context of the citric acid cycle in the cytoplasm or in peroxisomes	NADPH generation	[38, 41, 115]
Pentose synthesis	TALDO1	Transaldolase 1	Involved in production of ribose 5′-phosphate required for nucleic acid synthesis	Pentose phosphate pathway	[36, 37, 39, 115]
Pentose synthesis	TKT	Transketolase	Channels excess sugars from the pentose phosphate pathway to glycolysis by the creation of glyceraldehyde 3-phosphate	Pentose phosphate pathway, glycolysis	[36]
Scavenger receptor	CD36	CD36 molecule/fatty acid translocase	Major platelet glycoprotein that binds long-chain fatty acids and functions in the transport and regulation of transport of fatty acids	Fatty acid transport, adhesion	[133]
Autophagy	p62/SQSTM1	Sequestosome 1	Required for formation and autophagic degradation of polyubiquitin-containing bodies; used as a scaffold protein	Autophagy, inflammation	[134]
Tissue regeneration	NOTCH1	Notch 1	Transmembrane protein containing multiple epidermal growth factor-like repeats that is involved in signaling processes during development and tissue regeneration	Cell fate determination, developmental signaling	[135]
Regulation of xenobiotic response	AHR	Aryl hydrocarbon receptor	Transcription factor that binds planar aromatic compounds and upregulates genes involved in xenobiotic metabolism, including CYP family members	Xenobiotic metabolism	[124]
E3 ligase substrate adaptor	Keap1	Kelch-like ECH associated protein 1	E3 ubiquitin ligase substrate adaptor that targets proteins for degradation by the 26S proteasome; known negative regulator of Nrf2	Targeting for ubiquitination, Nrf2 repression, regulation of antioxidant response	[37]
Heterodimeric binding partner	MAFG	Musculoaponeurotic fibrosarcoma G	Transcriptional regulator; forms heterodimers with a number of transcription factors, including Nrf2, allowing their activation; also forms homodimers restricting the activation of obligate heterodimeric partner molecules	Transcriptional activation, regulation of anti-oxidant response	[37, 40, 41, 123]
Regulation of antioxidant response	NFE2L2	NF-E2 p45-like 2	Transcription factor that regulates genes involved in the oxidative stress response; maintains cellular redox homeostasis and detoxification and contributes to lipid and carbohydrate metabolism	Drug metabolism, xenobiotic metabolism, maintenance of cellular redox homeostasis	[119]
Regulation of lipid metabolism	PPARα ↓	Peroxisome proliferator-activated receptor α	Transcription factor, key regulator of lipid metabolism; activator of Nrf2	Lipid mobilization, fatty acid oxidation, lipogenesis, gluconeogenesis, ketogenesis	[116, 125]
Transcriptional regulator	RXRα	Retinoid X receptor α	Transcriptional regulator; mediates the biological effect of retinoids by forming homo- or heterodimers and binds to target gene sequences; known negative regulator of Nrf2; known binding partner and activator of PPARα	Transcriptional activation, Nrf2 repression, regulation of antioxidant response, PPARα activation	[37, 41]

A selection of Nrf2-target genes taken from the literature is shown. Genes that are in bold (with an adjacent down arrow) are those that have been reported to be downregulated by Nrf2.