Nuclear factor erythroid 2-related factor 2 (NRF2)

Overview

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in cellular defense against oxidative stress and inflammation. It regulates the expression of various antioxidant genes and enzymes, including heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), through its interaction with the antioxidant response element (ARE) in the promoter regions of target genes. Nrf2 is essential for maintaining cellular homeostasis and protecting against damage caused by reactive oxygen species (ROS). Dysregulation of Nrf2 signaling has been implicated in various diseases, including cancer, neurodegenerative disorders, and metabolic dysfunctions, making it a significant target for therapeutic interventions.

Recent Publications Summary

Recent studies continued to position NRF2 as a central regulator of cellular defense against oxidative stress, inflammation, and stress-related cell death across diverse disease models. In diabetic and metabolic settings, berberine was investigated for its neuroprotective effects in hyperglycemia-induced neurodegeneration with a focus on NRF2 modulation 42334690Jun. In acrylamide exposure, miR-128-1 was described as a posttranscriptional suppressor of NRF2, and epidemiologic plus toxicologic analyses linked higher acrylamide biomarkers with increased miR-128-1 and explored its role in β-cell oxidative injury and impaired glucose-stimulated insulin secretion 42107271May. In diabetic retinopathy, physalin A was tested for its ability to engage NRF2 to restore redox and mitochondrial homeostasis and restrain ferroptosis in retinal pigment epithelial cells and diabetic mice 42104733May. Additional metabolic studies reported that DL-norvaline restored NRF2-associated antioxidant genes in high-fat diet-fed mice 42105997May, while curcumin-loaded liver-targeting liposomes reduced NRF2 degradation, promoted NRF2 nuclear translocation, and alleviated mitochondrial ROS-mediated ferroptosis in steatohepatitis 41725216Feb. Anthocyanin-rich purple highland barley bran extract also showed partial involvement of NRF2 activation in protecting against NAFLD-related oxidative stress and inflammation 41794448Mar.

NRF2 was also repeatedly implicated in renal protection and ferroptosis-related injury. In membranous nephropathy, ferrostatin-1 reduced proteinuria and renal damage while restoring NRF2/HO-1 pathway expression, and the study used the NRF2 inhibitor ML385 to probe pathway involvement 42044765Apr. In diabetic nephropathy, recombinant human ADAMTS13 was reported to inhibit ROS generation by activating NRF2/GPX4 signaling, thereby suppressing mitophagy and ferroptosis and improving renal injury 41912450Mar. Forest-cultivated Epimedium koreanum Nakai was examined in organotin-exacerbated diabetic nephropathy, where network toxicology and validation experiments identified the SIRT1/NRF2/PPARγ axis as a central node of protection 42142608May. QingShen granules were also reported to suppress renal tubular epithelial-mesenchymal transition through the miR-23b-5p/Nrf2/PINK1 axis 41794259Mar, and nicotiflorin was evaluated in septic acute kidney injury for its effects on mitochondrial restoration and oxidative stress reduction 41730753Feb. In a related renal inflammation context, a bioinspired lipid droplet nanoplatform for periodontitis was reported to activate NRF2/NF-κB-mediated antioxidant signaling while restoring oxidative stress-damaged mitochondria 41624519Feb.

Several publications examined NRF2 in neuroprotection, immune injury, and cancer-related stress resistance. Poliumoside was shown to activate the Keap1/NRF2 pathway, promote NRF2 nuclear translocation, and increase downstream HO-1 and NQO1 in ischemic stroke models 42134761May. Sulforaphane was studied in Parkinson’s disease models, where Nrf2 silencing was used to clarify its role in promoting CBS expression, H2S synthesis, mitophagy, and inhibition of NLRP3 inflammasome activation and caspase-1 41797134Mar. quercetin was investigated in broiler thymus injury, with the study focusing on Nrf2/PERK signaling in LPS-induced necroptosis 42046449Apr. In cancer, NAT10 was reported to stabilize Nrf2 mRNA in hepatocellular carcinoma, maintaining antioxidant capacity and reducing ROS, while NAT10 inhibition increased oxidative stress and sensitized cells to sorafenib 41692399Feb. In head and neck and esophageal cancer cells, CRISPR-directed gene editing of NRF2 was explored as a strategy to restore chemosensitivity, with the study highlighting the importance of target site selection and exon skipping in determining editing outcomes 41624405Feb. A review on the NRF2 readout beyond genotyping further emphasized that NRF2 activation state may be more informative than mutation status alone for understanding resistance phenotypes and therapeutic liabilities in non-small cell lung cancer 41944556Apr.

What Changes, What Holds

1. NRF2 remains a broad stress-response node, now tied more explicitly to metabolic and ferroptotic injury pathways
REINFORCES These studies mostly extend the established view of NRF2 as a defense factor against oxidative stress and inflammation, showing it being probed in hyperglycemia, NAFLD, and diabetic retinal injury. The added value is mechanistic sharpening: NRF2 is being linked not just to antioxidant defense but also to mitochondrial homeostasis and ferroptosis control 42334690Jun42104733May. That strengthens the baseline rather than changing it.

2. Renal protection is increasingly framed through NRF2-linked ferroptosis and mitochondrial control
REINFORCES The new work keeps NRF2 in the same protective lane described in the Overview, but in kidney disease it is now being used to explain resistance to proteinuria, tubular injury, and inflammatory damage. What changes is the pathway detail: NRF2/HO-1, NRF2/GPX4, and related axes are being positioned as convergent mediators of renal rescue, with ferroptosis and mitophagy as key intermediates 42044765Apr41912450Mar. This is an extension, not a reversal.

3. NRF2 is being used as a mechanistic handle for neuroprotection, immune injury, and drug resistance
REINFORCES The new studies reinforce the Overview’s claim that NRF2 matters in neurodegeneration and cancer, while broadening the list of contexts in which its activation state appears functionally important. They also sharpen the therapeutic implication: NRF2 can support survival programs that are beneficial in stroke or Parkinsonian models, yet in cancer it may sustain antioxidant capacity and treatment resistance, making it a liability to inhibit in some settings 42134761May41692399Feb. That duality fits the baseline and makes it more clinically nuanced.

Overview update candidates: NRF2’s links to ferroptosis; mitophagy; and mitochondrial homeostasis in metabolic; renal; and neuroprotective settings; its role in treatment resistance in cancer.