Table 1.

NRF2 cellular modulators.

Modulator	Model Studied	Results	Reference
DJ-1	BeWo cells	NRF2 and GPX4 expression was significantly reduced when DJ-1 was knocked down in BeWo cells. Cell death was significantly increased in DJ-1-deficient cells when these cells were treated with RSL3, a ferroptosis inducer.	[67]
VEGF	BeWo cells	VEGF activated NRF2, increasing thioredoxin (Trx), thioredoxin reductase (TXNRD1) and heme oxygenase-1 (HO-1). VEGF activated NRF2 in an ERK1/2-dependent manner, increasing HO-1 expression then augmenting the production of carbon monoxide, which increased VEGF expression.	[69]
oxLDL	JAR cells and placental explants	Treatment with oxLDL increased NRF2 and HO-1 expression while the blockade of LOX-1 with TS92 inhibited the increase in HO-1 expression induced by oxLDL treatment.	[74]
LXA4	HUVEC	LXA4 inhibited LPS-triggered ROS production, promoting the expression of NRF2 and improving vascular permeability under oxidant stimuli.	[79]
Hypoxia	HTR-8/SVneo cells	NRF2 overexpression in hypoxia-induced cells reduced the levels of MDA and ROS, and decreased ferroptosis.	[83]
Hypoxia	HTR-8/SVneo cells	Hypoxia reduced the activity of CAT, GSH-Px and SOD enzymes and increased NRF2 and HO-1 expression while decreasing KEAP1 expression. The activity of SOD, GSH-Px and CAT in placental tissues of patients with PE was lower compared to normal placental tissues. NRF2 and HO-1 expression in preeclamptic placentas was higher compared to normal pregnancies while KEAP1 expression was lower in PE placentas compared to the normal ones. Silencing NRF2 in HTR8/SVneo cells under hypoxic conditions reduced the activities of CAT, GSH-Px and SOD.	[84]
Hypoxia	PE placentas and HTR-8/SVneo cells	Lower CAT, GSH-Px and SOD activity in HTR8/SVneo cells under hypoxic conditions and in PE placentas. Increased NRF2 and HO-1 expression together with a reduced expression of KEAP1 under hypoxic conditions and in PE placentas.	[85]
AOPPs	HTR-8/SVneo cells	AOPPs increased apoptosis and inhibited the NRF2/ARE/HO-1 pathway. NRF2 silencing aggravated the AOPP-induced cell apoptosis, activating p53 and the caspase cascade while NRF2 overexpression showed cytoprotective effects by increasing HO-1 expression.	[93]
miR-133a-3p	HTR-8/SVneo cells exposed to H2O2	Transfecting cells with miR-133a-3p under an oxidative stress condition reduced ROS, MDA levels and apoptosis. MiR-133a-3p inhibited BACH1 (a NRF2 repressor), increasing NRF2 activation and HO-1 expression.	[106]
Syncytiotrophoblast differentiation	PE placentas and primary trophoblast cells	NRF2, CYP191A mRNAs and miR-1246 levels were upregulated during syncytiotrophoblast differentiation of trophoblast cells and significantly reduced by hypoxia and in PE placentas. JARID2, Axin-2 and GSK3β expression was significantly downregulated during syncytiotrophoblast differentiation. Silencing of NRF2 in cytotrophoblast cells inhibited miR-1246 and CYP19A1 due to the binding of NRF2 to the miR-1246 and CYP191A promoters.	[111]
CD151	PE placentas, HTR-8/SVneo cells and mice	PE placentas showed reduced expression of CD151, HO-1, NQO1, GCLC and SOD-1. Overexpression of CD151 in HTR-8/SVneo cells enhanced HO-1, NQO1, GCLC and SOD-1 expression. Tail intravenous injection of siCD151 in pregnant mice led to a PE-like phenotype, hypertension and proteinuria. The expression of NRF2, pERK1/2, HO-1, NQO1, GCLC and SOD-1 was decreased in mice and HTR8/SVneo cells when CD151 was silenced. The beneficial effect of CD151 in HTR8/SVneo cells was inhibited when ERK and NRF2 signaling was blocked with synthetic inhibitors.	[114]
BRD4	HTR8/SVneo exposed to H2O2	BRD4 inhibition attenuated oxidative stress injury by enhancing NRF2 activation via the downregulation of KEAP1.	[116]