Exploration of Medicine

Table 1. Nrf2 activators and inhibitors.

S. NO.	Compound	Source	Type	Mechanism of action	Cancer type	References
Nrf2 activators	Sulforaphane (SFN) [1-isothiocyanato-4-(methylsulfonyl)-butane]	Broccoli, Brussels sprouts	Isothiocyanate	Electrophilic modification of Keap1-Cys-151	Bladder cancer	[128]
	Oltipraz (4-methyl-5-[2-pyrazinyl]-1,2-dithiole-3-thione) (OPZ)	Cruciferous vegetables	Organosulfur compound	Electrophilic modification of Keap1-Cys-151	Various cancers in animal models	[129]
	Epigallocatechin gallate (EGCG)	Green tea	Catechin	Oxidizing the cysteine thiols of Keap1	Prostate cancer, head and neck, and lung cancer cell lines	[130]
	Dimethyl fumarate (tecfidera or DMF)	Synthetic drug	Fumaric acid ester	Electrophilic modification of Keap1-Cys-151	Breast, colon, melanoma, and pancreatic cancer	[131]
	Diallyl trisulfide (DATS)	Garlic	Isothiocyanate	Modification of Keap1-Cys-288	Colorectal, breast, and bladder cancer	[132]
	Curcumin (CUR)	Dried rhizome of Curcuma longa	Stilbene	Electrophilic modification of Keap1-Cys-151	Gastric cancer	[133]
	2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO)	Synthetic derivative of oleanolic acid, a naturally occurring plant compound	Synthetic triterpenoids	Electrophilic modification of Keap1-Cys-151	Pancreatic cancer (e.g., Panc1, Panc28 cells), colon cancer, ovarian cancer, and diffuse large B-cell lymphoma	[134]
	Apigenin (4,5,7-trihydroxyflavone (Api))	Celery, parsley	Plant flavone	Epigenetic modifications of Nrf2	Breast, colorectal, prostate, liver, lung, skin, and oral cancers	[135]
	Resveratrol (3,5,4’-trihydroxystilbene (RES))	Grapes, berries	(E)-Stilbene derivate	Electrophilic modification of Keap1-Cys-151	Breast, prostate, colon, ovarian, thyroid, and melanoma	[136]
	Carotenoids	Fruits and vegetables	Natural pigments	Potential for cancer prevention by activating the Nrf2 pathway	Initial stage of cancer	[137]
Nrf2 inhibitors	Brusatol (BRU)	Brucea javanica (an evergreen shrub)	Triterpene lactone compound	Stimulation of Nrf2 poly-ubiquitination	Colorectal, pancreatic, lung, liver, leukemia, and glioblastoma	[138]
	Luteolin (3’,4’,5,7-tetrahydroxyflavone (LUT))	Celery, parsley, green pepper	Plant flavone	Nrf2 mRNA degradation, reduction of Nrf2 binding to AREs	Lung, breast, prostate, liver, colon, and pancreatic cancers	[139]
	Trigonelline (TRG)	Coffee beans and many plants	Coffee-derived alkaloid	Prevention of nuclear translocation of Nrf2	Pancreatic cancer cell lines	[140]
	Ascorbic acid (vitamin C, L-ascorbic acid, AscA, AA)	Citrus fruits	Natural vitamin	Electrophilic modification of Keap1-Cys-151	Chronic myelogenous leukemia KCL22/SR cells	[141]
	Retinoic acid (RA)	Carrots, sweet potatoes, mangoes, papayas, and apricots	Metabolite of vitamin A	Prevention of nuclear translocation of Nrf2	Breast, prostate, and lung cancer	[142]
	Chrysin (5,7-dihydroxy-2-phenyl-4H-chromen-4-one (CHR))	Honey and propolis	Plant flavone	Prevention of nuclear translocation of Nrf2	Lung, breast, liver, colon, leukemia, prostate, and melanoma	[143]
	Quercetin	Apples, various fruits, and vegetables	Flavonoid	High concentrations can inhibit Nrf2 to increase oxidative stress and promoting cancer cell death	Malignant tumor formation	[144]
	Wogonin (5,7-dihydroxy-8-methoxyflavone)	Root of Scutellaria baicalensis	Flavonoids	Nrf2 inhibitor wogonin holds good potential as an efficient natural sensitizer for anti-neoplastic resistance in human myelogenous leukemia	Myelogenous leukemia	[145]
	Halofuginone	Root of Dichroa febrifuga Lour. (Blue Evergreen Hydrangea)	Naturally occurring alkaloid	Enhanced the chemosensitivity of cancer cells via suppressing Nrf2 activation	Cancer, fibrosis	[146]
	Berberine	Coptidis Rhizoma	Isoquinoline alkaloid	BBR could reverse the lapatinib resistance in HER2-positive breast cancer cells by upregulating the level of ROS through inhibiting the Nrf2 pathway	Breast cancer cells	[147]
	Brucein D	Seeds of Brucea javanica	Quassinoid compound	Inhibiting Nrf2 expression via promoting the ubiquitin-proteasome-dependent degradation and downregulating its downstream genes such as HO-1, NQO1, AKR1B10 and γGCSm	Pancreatic ductal adenocarcinoma	[148]
	Cryptotanshinone	Root of Salvia miltiorrhiza	Diterpene quinone	Induce cell death and apoptosis in human lung carcinoma A549 (A549/DDP) cells and enhance the sensitivity to cisplatin by down-regulating the Nrf2 pathway	Human lung carcinoma A549	[149]
	Ginsenoside Rd	Active constituents of ginsenosides, is a potent antitumor agent	Active ingredients of ginseng	Depletion of the expression of Nrf2 and its target genes, resulting in an enhanced sensitivity of A549 cells to cisplatin and amelioration of chemoresistance	NSCLC	[150]
	Triptolide	Tripterygium wilfordii	Diterpenoid	Reduced Nrf2 expression and transcriptional activity in NSCLC and liver cancer cells	Malignant tumors	[151]

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AA: arachidonic acid; HO-1: haem oxygenase 1; Keap1: Kelch-like ECH-associated protein 1; NQO1: NAD(P)H-quinone oxidoreductase 1; Nrf2: nuclear factor erythroid 2-related factor 2; NSCLC: non-small-cell lung cancer; ROS: reactive oxygen species; AREs: antioxidant response elements.

Declarations

Acknowledgments

Dr. Shrikant Kukreti acknowledges the Institute of Eminence, University of Delhi [IoE/2024-25/12/FRP].

Author contributions

AS: Investigation, Writing—original draft, Writing—review & editing. RK: Writing—review & editing. LS: Writing—review & editing. SK: Conceptualization, Investigation, Supervision, Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

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