Table 1.

List of phytochemicals reported to regulate NRF2 signaling epigenetically.

Sl No.	Phytochemical	Chemical Name	Epigenetic Mechanism of Nrf2 Regulation	Molecular Targets	Cell Type	Reference
1.	3,3′-diindolylmethane	3,3′-Methylenebis(1H-indole)	Decreased methylation of CpG sites in the promoter region of mouse Nfe2l2	Suppressed mRNA and protein expression of Dnmt1, Dnmt3a, and Dnmt3b; inhibited protein expression of Hdac2 and Hdac3	TRAMP-C1 prostate cells	[79]
2.	Apigenin	5,7-Dihydroxy-2-(4hydroxy-phenyl)-4H-chromen-4-one	Decreased Nfe2l2 hyper-methylation; induced expression of miR-101, targeting Nfe2l2 mRNA	Inhibited Dnmt1, Dnmt3a and Dnmt3b; inhibited Hdacs; induced miR101	Mouse epidermal JB6 P+ cells BEL-7402/ADM cells	[80,81]
3.	Corosolic acid	2α,3β-2,3-dihydroxyurs-12-en-28-oic acid	Decreased Nfe2l2 hypermethylation; increased histone H3 lysine 27 acetylation; decreased H3 lysine 27 trimethylation	Decreased levels of Dnmt1, Dnmt3a and Dnmt3b; reduced levels of Hdac1, Hdac2, Hdac3, Hdac4, Hdac7 and Hdac8	TRAMP-C1 prostate cells	[82]
4.	Curcumin	1, 7-bis (4-hydroxy-3-methoxy-phenyl)-1, 6 heptadiene-3, 5-dione	Decreased Nfe2l2 hypermethylation	Inhibited enzymatic activity of Dnmt enzymes	TRAMP-C1 prostate cells	[83]
5.	Delphinidin	3,5,7-Trihydroxy-2-(3,4,5-trihydroxyphenyl) chromenium	Demethylation of 15 CpG sites in the mouse Nfe2l2 promoter region	Decreased protein expression of Dnmt1, Dnmt3a, and class I/II Hdacs	Mouse epidermal JB6 P+ cells	[84]
6.	Fucoxanthin	3,5′-Dihydroxy-8-oxo-6′,7′-didehydro-5,5′,6,6′,7,8-hexahydro-5,6-epoxy-β,β-caroten-3′-yl acetate	Decreased Nfe2l2 hypermethylation	Reduced Dnmt activity	Mouse epidermal JB6 P+ cells	[85]
7.	Luteolin	2-(3,4dihydroxyphenyl)-5,7-dihydroxy-chromen-4-one	Decreased NFE2L2 hypermethylation	Decreased expression of DNMT1, DNMT3A and DNMT3B; decreased HDAC1, HDAC2, HDAC3, HDAC6, HDAC7; reduced activities of DNMTs and HDACs; increased ten-eleven translocation 1, 2 and 3 (TET1, TET2, and TET3)	Human colon cancer cells and SNU-407 cells	[86,87]
8.	Pelargonidin	3,5,7-Trihydroxy-2-(4hydroxyphenyl) chromenium	Decreased methylated CpGs in Nfe2l2 promoter	Decreased Dnmt1 and Dnmt3b expression; reduced levels of Hdacs 1–4 and Hdac7	JB6 P+ cells	[88]
9.	Polydatin	3-Hydroxy-5-[(E)-2-(4-hydroxyphenyl)vinyl] phenyl β-d-glucopyranoside	Enhanced miR-200a targeting KEAP1 to activate NRF2 signaling	Increased miR-200a expression under high fructose induction; downregulated KEAP1 mRNA and protein	Buffalo rat liver (BRL-3A) and human HepG2 cells	[89]
10.	Reserpine	Methyl 18β-hydroxy-11,17α-dimethoxy-3β,20α-yohimban-16βcarboxylate 3,4,5-trimethoxybenzoate	Decreased proportion of methylated CpG sites in the Nfe2l2 promoter	Concentration-dependent decreased mRNA and protein expression of Dnmt1, Dnmt3a, and Dnmt3b	JB6 P+ Cell	[90]
11.	Resveratrol	3,4′,5-trihydroxystilbene	Decreased methylation of the NFE2L2 promoter	Inhibited expression and activity of DNMT1, DNMT3a, and DNMT3b; miR93 implicated	HepG2 cells and estradiol-induced breast cancer	[91,92]
12.	Sulforaphane	1-Isothiocyanato-4-(methanesulfinyl)butane	CpG demethylation and histone acetylation at the Nfe2l2 promoter; lncRNA upregulation	Inhibition of Dnmt1, Dnmt3a, Dnmt3b, Hdacs 1–5, and Hdac7; upregulated functional pseudogene NMRAL2P	JB6 P+ cells; TRAMP C1 cells; human colon cancer cells	[93,94]
13.	Tanshinone IIA	1,6,6-trimethyl-8,9- dihydro-7H-naphtho [1,2-g] benzofuran-10,11-dione	Decreased methylated CpGs in Nfe2l2 promoter; increased recruitment of RNA polymerase complex II at the NFE2L2 transcription start site	Decreased mRNA and protein levels of HDAC1, HDAC3, and HDAC8, as well as DNMT1, DNMT3a, and DNMT3b; induced expression of TET2	JB6 P+ cells, human normal hepatocyte and Hepa RG cells; rifampicin-induced liver injury in mice	[95,96]
14.	Taxifolin	(2S,3S)-2-(3,4dihydroxy-phenyl)-3,5,7-trihydroxy-2,3dihydro-4H-chromen-4-one	Decreased proportion of methylated CpGs in the Nfe2l2 promoter	Reduced protein levels of Dnmt1, Dnmt3a and Dnmt3b as well as Hdacs 1, 3, 4, and 8	JB6 P+ cells	[97]
15.	Ursolic acid	(3β)-3-Hydroxyurs-12-en-28-oic acid	Nfe2l2 mouse promoter demethylation; increased acetylation and K4 monomethylation of histone H3 in human cells	Reduced DNMT1 and DNMT3a protein levels; inhibited expression of HDACs 1-3 and 8 (Class I) and HDAC 6 and 7 (Class II); induced Setd7	JB6 P+ cells PC3 and LnCaP cells	[98,99]
16.	γ Tocopherol–rich mixture of tocopherols (γ-TmT)	(2R)-2,5,7,8-tetramethyl-2-[ (4R,8R)-4,8,12-trimethyl-tridecyl]-6-chromanol	Reversed hyper-methylation in the Nfe2l2 promoter	Inhibited protein levels of Dnmt1, Dnmt3a, and Dnmt3b	Prostate tissues of C57BL/TGN TRAMP mice	[100]
17.	Z-Ligustilide	(3E)-3-butylidene-4,5-dihydro-2-benzofuran-1-one	Decreased methylation of the first five CpGs of the Nfe2l2 promoter	Inhibited Dnmt activity	TRAMP C1 cells	[101]