NRF2 Cancer Research Results

NRF2, nuclear factor erythroid 2-related factor 2: Click to Expand ⟱
Source: TCGA
Type: Antiapoptotic
Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress. Thought of as "Master Regulator" of antioxidant response.
-One way to estimate Nrf2 induction is through the expression of NQO1.
NQO1, the most potent inducer:
SFN 0.2 μM,
quercetin (2.5 μM),
curcumin (2.7 μM),
Silymarin (3.6 μM),
tamoxifen (5.9 μM),
genistein (6.2 μM ),
beta-carotene (7.2μM),
lutein (17 μM),
resveratrol (21 μM),
indol-3-carbinol (50 μM),
chlorophyll (250 μM),
alpha-cryptoxanthin (1.8 mM),
and zeaxanthin (2.2 mM)

1. Raising Nrf2 enhances the cell's antioxidant defenses and ↓ROS. This strategy is used to decrease chemo-radio side effects.
2. Downregulating Nrf2 lowers antioxidant defenses and ↑ROS. In cancer cells this leads to DNA damage, and cell death.
3. However there are some cases where increasing Nrf2 paradoxically causes an increase in ROS (cancer cells). Such as cases of Mitochondial overload, signal crosstalk, reductive stress

-In some cases, Nrf2 is overexpressed in cancer cells, which can lead to the activation of genes involved in cell proliferation, angiogenesis, and metastasis. This can contribute to the development of resistance to chemotherapy and targeted therapies.
-Increased Nrf2 expression: Lung, Breast, Colorectal, Prostrate.
Decreased Nrf2 expression: Skine, Liver, Pancreatic.
-Nrf2 is a cytoprotective transcription factor which demonstrated both a negative effect as well as a positive effect on cancer
- "promotes Nrf2 translocation from the cytoplasm to the nucleus," means facilitates the movement of Nrf2 into the nucleus, thereby enhancing the cell's antioxidant and cytoprotective responses. -Major regulator of Nrf2 activity in cells is the cytosolic inhibitor Keap1.

Nrf2 Inhibitors and Activators
Nrf2 Inhibitors: Brusatol, Luteolin, Trigonelline, VitC, Retinoic acid, Chrysin
Nrf2 Activators: SFN, OPZ EGCG, Resveratrol, DATS, CUR, CDDO, Api
- potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany

Nrf2 plays dual roles in that it can protect normal tissues against oxidative damage and can act as an oncogenic protein in tumor tissue.
– In healthy tissues, NRF2 activation helps protect cells from oxidative damage and maintains cellular homeostasis.
– In many cancers, constitutive activation of NRF2 (often through mutations in NRF2 itself or loss-of-function mutations in KEAP1) leads to an enhanced antioxidant capacity.
– This upregulation can promote tumor cell survival by enabling cancer cells to thrive under oxidative stress, resist chemotherapeutic agents, and sustain metabolic reprogramming.
– Elevated NRF2 levels have been implicated in promoting tumor growth, metastasis, and resistance to therapy in various malignancies.
– High or sustained NRF2 activity is frequently associated with aggressive tumor phenotypes, poorer prognosis, and decreased overall survival in several cancer types.
– While its activation is essential for protecting normal cells from oxidative stress, aberrant or sustained NRF2 activation in tumor cells can lead to enhanced survival, therapeutic resistance, and tumor progression.

NRF2 inhibitors: (to decrease antioxidant defenses and increase cell death from ROS).
-Brusatol: most cited natural inhibitors of Nrf2.
-Luteolin: luteolin can reduce Nrf2 activity in specific cancer models and may enhance cell sensitivity to chemotherapy. However, luteolin is also known as an antioxidant, and its influence on Nrf2 can sometimes be context dependent.
-Apigenin: certain studies to down‑regulate Nrf2 in cancer cells: Dose and context dependent .
-Oridonin:
-Wogonin: although its effects might be cell‑ and dose‑specific.
- Withaferin A

Scientific Papers found: Click to Expand⟱
5237- AgNPs,    Nrf2 Activation Mitigates Silver Nanoparticle-Induced Ferroptosis in Hepatocytes
- in-vitro, Liver, HepG2
Ferroptosis↑, we provide evidence that AgNPs trigger ferroptosis in both mouse hepatocytes and HepG2 cells
p62↑, AgNPs increased p62 expression, which in turn stabilized Nrf2 by suppressing its interaction with Keap1.
NRF2↝,
eff↓, Upon activation, Nrf2 enhances the transcription of key antioxidant enzymes, including NQO1 and HO-1, thereby alleviating ferroptosis.

5239- AgNPs,    NOX4- and Nrf2-mediated oxidative stress induced by silver nanoparticles in vascular endothelial cells
- in-vitro, Nor, HUVECs
*ROS↑, AgNP exposure significantly and dose-dependently decreased the cell viability, induced reactive oxygen species (ROS) generation and led to early apoptosis in HUVECs.
*Apoptosis↑,
*NRF2↝, AgNPs could disrupt the inactivation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response, which is considered another important element for oxidative stress caused by AgNPs in HUVECs.

5501- Ba,    Therapeutic effects and mechanisms of action of Baicalein on stomach cancer: a comprehensive systematic literature review
- Review, GC, NA
AntiCan↑, The review demonstrated that BC exerts therapeutic effects on GC through multiple biochemical mechanisms.
Apoptosis↑, BC plays an important role in inducing apoptosis, inhibiting cell proliferation, and suppressing metastasis in GC cells.
TumCP↓,
TumMeta↓,
BAX↑, graphical abstract
TumAuto↑,
ROS↑,
NRF2↝, BC induced apoptosis and autophagy in MGC-803, SGC-7901, and HGC-27 cells, enhancing cisplatin sensitivity via suppression of the AKT/mTOR pathway and modulation of the Nrf2/Keap1 axis.
PI3K↓,
Akt↓,
NF-kB↓,
TGF-β↓,
SMAD4↓,
GPx4↓, It induces autophagy and ferroptosis, partly through p53 activation and suppression of SLC7A11/GPX4, and disrupts mitochondrial membrane potential via reactive oxygen species (ROS) generation [31, 37]
MMP↓,
*HO-1↑, BC stabilizes Nrf2, leading to the induction of antioxidant enzymes such as HO-1, GST, and NQO1, which mitigate oxidative stress and contribute to its antitumor effects [38].
*GSTs↑,
*antiOx↑,
*AntiTum↑,
*NRF2↑,
ChemoSen↑, BC induced apoptosis and autophagy in MGC-803, SGC-7901, and HGC-27 cells, enhancing cisplatin sensitivity via suppression of the AKT/mTOR pathway and modulation of the Nrf2/Keap1 axis.
Akt↓,
mTOR↓,
FAK↓, reducing FAK expression
Ki-67↓, Immunohistochemical analysis also revealed lower Ki-67 levels, indicating reduced cellular proliferation.

15- CUR,  UA,    Effects of curcumin and ursolic acid in prostate cancer: A systematic review
- Review, Pca, NA
NF-kB↝, involve NF-κB, Akt, androgen receptors, and apoptosis pathways.
Akt↝, see figure 5
AR↝,
Apoptosis↝,
Bcl-2↝,
Casp3↝,
BAX↝,
P21↝,
ROS↝,
Bcl-xL↝,
JNK↝,
MMP2↝,
P53↝,
PSA↝,
VEGF↝,
COX2↝,
cycD1/CCND1↝,
EGFR↝,
IL6↝,
β-catenin/ZEB1↝,
mTOR↝,
NRF2↝,
AP-1↝,
Cyt‑c↝,
PI3K↝,
PTEN↝,
Cyc↝,
TNF-α↝,

4800- Lyco,    Recent insights on pharmacological potential of lycopene and its nanoformulations: an emerging paradigm towards improvement of human health
- Review, Var, NA
*antiOx↑, It is a potent antioxidant and free radical scavenger owing to the presence of 13 carbon–carbon double bonds, out of which 11 are conjugated and the remaining 2 are non-conjugated.
Keap1↝, many biological effects on different types of cancers like prostate, breast, skin, and oral cancer by targeting the Keap1-NF-kB, Keap1-Nrf 2 and PI3K/AKT/m-TOR signalling pathway.
NF-kB↝,
NRF2↝,
PI3K↝,
Akt↝,
mTOR↝,
*GutMicro↑, lycopene also has the ability to modify the gut microbiome

4795- Lyco,    Updates on the Anticancer Profile of Lycopene and its Probable Mechanism against Breast and Gynecological Cancer
- Review, BC, NA
TumCG↓, Experimental studies suggest that lycopene can inhibit tumor growth by regulating various signaling pathways for cell growth, arresting the cell cycle, and inducing cell apoptosis.
TumCCA↑,
Apoptosis↑,
P53↝, Lycopene is reported to combat breast cancer specifically via mechanisms, such as regulation of expression of p53 and Bax, suppression of cyclin D
BAX↝,
cycD1/CCND1↓,
ERK↓, inhibiting the activation of ERK and Akt signaling pathway,
Akt↓,
STAT3↓, and gynecological cancer via various signaling pathways such as STAT3, Nrf2, and NF-κB, down-regulation of ITGB1, ITGA5, FAK, MMP9, and EMT markers, etc.
NRF2↝,
NF-kB↓,
ITGB1↓,
ITGA5↓,
FAK↓,
MMP9↓,
EMT↓,

4726- Se,  Oxy,    Oxygen therapy accelerates apoptosis induced by selenium compounds via regulating Nrf2/MAPK signaling pathway in hepatocellular carcinoma
- in-vivo, HCC, NA
eff↝, Selenium has good antitumor effects in vitro, but the hypoxic microenvironment in solid tumors makes its clinical efficacy unsatisfactory.
NRF2↓, We found that, in contrast to hypoxia, the hyperoxic environment facilitated the H2Se, produced by the selenium metabolism in cells, to be rapidly oxidized to generate H2O2, leading to inhibit the expression level of Nrf2
p‑p38↑, and to increase that of phosphorylation of p38 and MKK4, resulting in inhibiting autophagy and accelerating apoptosis
Apoptosis↑,
eff↑, These findings highlight oxygen can significantly enhance the anti-HCC effect of selenium compounds through regulating the Nrf2 and MAPK signaling pathways
TumVol↓, The results showed that hyperoxia could improve the efficacy of Na2SeO3 and CysSeSeCys in the treatment of HCC, enhance the death rate of HepG2 cells, and further reduce the tumor volume in mice
other↝, These results also suggest that the anticancer mechanism of selenium compounds may be different in different oxygen environments.
toxicity↓, staining results of the liver and kidney of mice showed that the selenium compound combined with oxygen therapy did not show toxicity or side effects on normal organs
Dose↝, therapeutic effect reached the level of the 5 mg/kg selenium compound treatment group
NRF2↝, The results showed that in the 1 % O2 environment, the two selenium compounds promoted the expression of Nrf2, and the Nrf2 level gradually decreased with increasing oxygen concentration.
HO-1↓, The expression of HO-1, CAT and SOD also showed a decreasing trend with increasing oxygen concentration
Catalase↓,
SOD↓,
e-pH↓, The results showed that the extracellular pH value decreased after treatment with selenium compounds for 48 h
pH∅, However, there was no significant change in extracellular pH value in the selenium compound treatment group compared with the oxygen alone group
MAPK↑, Selenium combined with oxygen therapy accelerates cell apoptosis by activating the MAPK signaling pathway
eff↑, In summary, oxygen can significantly enhance the antihepatocellular carcinoma effect of selenium compounds

4722- Se,    The Yin and Yang of Nrf2-Regulated Selenoproteins in Carcinogenesis
- Review, Var, NA
Risk↓, Selenium deficiency is associated with a higher cancer risk making also this essential trace element a promising candidate for cancer prevention.
*NRF2↓, Selenium deficiency activates Nrf2 as does a TrxR1 knockout making a synergism between both systems plausible. Although this might hold true for healthy cells, the interplay may turn into the opposite in cancer cells
NRF2↑, The induction of the detoxifying and antioxidant enzymes by Nrf2 will make cancer cells chemoresistant and will protect them against oxidative damage.
*NRF2↓, Selenium exerts its effects mainly as part of selenoproteins with redox functions, and Nrf2 upregulates enzymes of the adaptive response.
OS↑, selenium, vitamin E, and β-carotene, called factor D, significantly reduced total mortality, total cancer mortality, and most significantly mortality from gastric cancer. selenium ... according to subsequent studies it appeared to have the most effic
eff↝, Considering age, the effect of factor D was much stronger in individuals younger than 55 but almost absent in subjects older than 55 years.
eff↝, selenium appears to prevent initiation of cancer in healthy cells at young age, in the elderly it may be harmful and rather support tumor growth of already initiated cells
NRF2↝, “dark” side of Nrf2. Its upregulation in cancer cells provides an advantage for these cells to grow and, in addition, makes them resistant against chemotherapy


Showing Research Papers: 1 to 8 of 8

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 8

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Catalase↓, 1,   Ferroptosis↑, 1,   GPx4↓, 1,   HO-1↓, 1,   Keap1↝, 1,   NRF2↓, 1,   NRF2↑, 1,   NRF2↝, 7,   ROS↑, 1,   ROS↝, 1,   SOD↓, 1,  

Mitochondria & Bioenergetics ⓘ

MMP↓, 1,  

Cell Death ⓘ

Akt↓, 3,   Akt↝, 2,   Apoptosis↑, 3,   Apoptosis↝, 1,   BAX↑, 1,   BAX↝, 2,   Bcl-2↝, 1,   Bcl-xL↝, 1,   Casp3↝, 1,   Cyt‑c↝, 1,   Ferroptosis↑, 1,   JNK↝, 1,   MAPK↑, 1,   p‑p38↑, 1,  

Transcription & Epigenetics ⓘ

other↝, 1,  

Autophagy & Lysosomes ⓘ

p62↑, 1,   TumAuto↑, 1,  

DNA Damage & Repair ⓘ

P53↝, 2,  

Cell Cycle & Senescence ⓘ

Cyc↝, 1,   cycD1/CCND1↓, 1,   cycD1/CCND1↝, 1,   P21↝, 1,   TumCCA↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

EMT↓, 1,   ERK↓, 1,   mTOR↓, 1,   mTOR↝, 2,   PI3K↓, 1,   PI3K↝, 2,   PTEN↝, 1,   STAT3↓, 1,   TumCG↓, 1,  

Migration ⓘ

AP-1↝, 1,   FAK↓, 2,   ITGA5↓, 1,   ITGB1↓, 1,   Ki-67↓, 1,   MMP2↝, 1,   MMP9↓, 1,   SMAD4↓, 1,   TGF-β↓, 1,   TumCP↓, 1,   TumMeta↓, 1,   β-catenin/ZEB1↝, 1,  

Angiogenesis & Vasculature ⓘ

EGFR↝, 1,   VEGF↝, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↝, 1,   IL6↝, 1,   NF-kB↓, 2,   NF-kB↝, 2,   PSA↝, 1,   TNF-α↝, 1,  

Cellular Microenvironment ⓘ

pH∅, 1,   e-pH↓, 1,  

Hormonal & Nuclear Receptors ⓘ

AR↝, 1,  

Drug Metabolism & Resistance ⓘ

ChemoSen↑, 1,   Dose↝, 1,   eff↓, 1,   eff↑, 2,   eff↝, 3,  

Clinical Biomarkers ⓘ

AR↝, 1,   EGFR↝, 1,   IL6↝, 1,   Ki-67↓, 1,   PSA↝, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,   OS↑, 1,   Risk↓, 1,   toxicity↓, 1,   TumVol↓, 1,  
Total Targets: 82

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 2,   GSTs↑, 1,   HO-1↑, 1,   NRF2↓, 2,   NRF2↑, 1,   NRF2↝, 1,   ROS↑, 1,  

Cell Death ⓘ

Apoptosis↑, 1,  

Clinical Biomarkers ⓘ

GutMicro↑, 1,  

Functional Outcomes ⓘ

AntiTum↑, 1,  
Total Targets: 10

Scientific Paper Hit Count for: NRF2, nuclear factor erythroid 2-related factor 2
2 Silver-NanoParticles
2 Lycopene
2 Selenium
1 Baicalein
1 Curcumin
1 Ursolic acid
1 Oxygen, Hyperbaric
Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

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