Nrf2-associated antioxidant genes

Overview

Nrf2-associated antioxidant genes refer to the downstream gene network regulated by nuclear factor erythroid 2-related factor 2 (Nrf2, also written NRF2), a redox-sensitive transcription factor that coordinates cellular defense against oxidative stress. In the basal state, Nrf2 activity is restrained by KEAP1-mediated degradation; when activated, Nrf2 promotes expression of antioxidant and cytoprotective genes such as hemeoxygenase-1 (HO-1), superoxide dismutase, catalase-related programs, and glutathione-associated defenses. This pathway is widely studied in inflammation, ferroptosis, metabolic dysfunction, neurodegeneration, fibrosis, and toxicant exposure.

Biomedically, Nrf2-associated antioxidant genes are not a single protein but a functional gene set and signaling axis. Their activity is often interpreted through changes in Nrf2 abundance, KEAP1, GPX4, HO-1, ferritin, and related oxidative stress markers. Recent studies have examined this axis as a therapeutic target or readout in contexts involving berberine, caffeic acid, melatonin-treated BMSC-Exos, grape seed oil nanoemulsion, kaempferide, QingShen granules, DL-norvaline, and miR-128-1, often in relation to carbon tetrachloride injury, acrylamide toxicity, hyperglycemia, glucocorticoid-induced osteoporosis, metabolic dysfunction-associated fatty liver disease, and renal epithelial-mesenchymal transition.

Focus of Latest Publications

Recent publications consistently position Nrf2-associated antioxidant genes as a central protective program that is suppressed during disease and restored by diverse interventions.

In a mouse study of berberine and hyperglycemia-induced neurodegeneration, the authors specifically tested whether Nrf2 was essential to berberine’s neuroprotective action. This work framed Nrf2 as a redox-associated factor linked to neuronal survival under hyperglycemic stress, supporting the idea that activation of the Nrf2 antioxidant program contributes to protection against neurodegeneration.

In a rat model of carbon tetrachloride-induced liver fibrosis, melatonin-treated bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) improved liver function and oxidative balance. The reported effects included restoration of albumin, improved liver enzymes, increased superoxide dismutase activity, higher Nrf2 levels, and reduced malondialdehyde (MDA). This suggests that the exosome-based intervention countered fibrotic injury in part by enhancing Nrf2-linked antioxidant defenses and reducing lipid peroxidation.

A study in Nile tilapia exposed to acrylamide toxicity found that grape seed oil nanoemulsion improved growth, immune competence, and antioxidant capacity in a dose-dependent manner. The intervention was associated with marked upregulation of NRF2 expression, alongside IL-6, IL-8, and cathepsin-B. In this setting, NRF2 appears to have been used as a molecular indicator of improved antioxidant and stress-response signaling in a toxicology model.

In adult rats with l-methionine-induced hyperhomocysteinemia, caffeic acid reversed decreases in hippocampal Nrf2 protein expression, together with Sox-2 and BDNF. This links Nrf2-associated antioxidant genes to neurogenesis-related outcomes and oxidative stress control in the hippocampus, suggesting that caffeic acid may protect neural tissue by restoring antioxidant transcriptional signaling.

An epidemiological and toxicological analysis examined miR-128-1 as a posttranscriptional suppressor of NRF2 in the context of acrylamide exposure and type 2 diabetes risk. The study proposed that miR-128-1 may connect environmental acrylamide exposure with diabetes susceptibility by dampening the NRF2 antioxidant pathway. This is notable because it places Nrf2-associated antioxidant genes at the intersection of pollutant exposure, metabolic disease risk, and posttranscriptional regulation.

In patients with metabolic dysfunction-associated fatty liver disease, serum Nrf2 levels were decreased while KEAP1, HO-1, ferritin, TNF-α, IL-6, and ACSL4 were increased relative to controls. The pattern is consistent with impaired antioxidant defense and enhanced ferroptosis-related signaling. Here, Nrf2-associated antioxidant genes were evaluated in a human disease context alongside ferroptosis-related proteins, reinforcing their relevance to metabolic liver injury.

Kaempferide was reported to alleviate glucocorticoid-induced osteoporosis by targeting ferroptosis through the GSK3β/Nrf2/GPX4 pathway. The study found increased GSK3β phosphorylation, Nrf2 upregulation, and elevated GPX4 expression, with these effects reversed by the GSK3β agonist DIF-3. This indicates that Nrf2-associated antioxidant genes can be engaged downstream of GSK3β signaling to suppress ferroptotic damage in a rat GIOP model.

QingShen granules were reported to activate mitophagy and suppress renal tubular epithelial-mesenchymal transition via the miR-23b-5p/Nrf2/PINK1 axis. This places Nrf2 within a broader mitochondrial quality-control network, linking antioxidant signaling to PINK1-associated mitophagy and renal fibrosis-related remodeling.

A mechanistic study on ALDH18A1 showed that phosphorylation of Cullin3 disrupts KEAP1-mediated NRF2 degradation. This work addressed why NRF2 declines during aging and suggested that altered KEAP1-Cullin3 regulation can impair NRF2 stability. The finding is important because it identifies a post-translational control point that governs the availability of Nrf2-associated antioxidant genes.

Finally, DL-norvaline was reported to attenuate high-fat-diet-induced metabolic inflammation and dysfunction, reducing LPS-driven inflammatory signaling and restoring Nrf2-associated antioxidant genes. This study connected the Nrf2 program with suppression of MyD88/NF-κB signaling and broader metabolic protection, emphasizing its role in inflammatory-metabolic homeostasis.

Across these studies, Nrf2-associated antioxidant genes repeatedly appear as a protective transcriptional module that is reduced in oxidative stress, fibrosis, ferroptosis, and metabolic injury, and increased by natural products, exosomes, and pathway-directed interventions. Related molecules such as HO-1, GPX4, ferritin, KEAP1, ACSL4, and transforming growth factor-beta often serve as mechanistic readouts or linked effectors.

Key Publications

Jun Berberine attenuates hyperglycemia induced neurodegeneration in mice by modulation of Nrf2 expression. (Molecular biology reports, 2026, PMID 42334690): "Herein, we investigated whether nuclear factor erythroid 2-related factor 2 (Nrf2), a redox-associated factor, is essential to the neuroprotective action of BBR."
Jun Melatonin-treated bone marrow mesenchymal stem cell-derived exosomes reverse liver fibrosis induced by CCl4 in male wistar albino rats. (Scientific reports, 2026, PMID 42324293): "Treated rats showed restoration of albumin levels, significant improvements in liver enzymes, notable elevations in SOD activity and Nrf2 levels, and a marked reduction in MDA levels."
Jun Immune-antioxidant potential, splenic cytokines regulation, and tissue architecture restoration by grape seed oil nanoemulsion in Nile tilapia subjected to acrylamide toxicity. (Fish physiology and biochemistry, 2026, PMID 42310230): "Conversely, GON supplementation significantly improved growth performance, immune competence, and antioxidant capacity in a dose-dependent manner, accompanied by marked upregulation (p<0.0001), of IL-6, IL-8, cathepsin-B, and NRF2 expression."
Jun Caffeic Acid Ameliorates l-Methionine-Induced Hyperhomocysteinemia, Leading to Decreased Adult Neurogenesis and Oxidative Stress Status in Adult Rats. (ACS chemical neuroscience, 2026, PMID 42216877): "CA also reversed the l-met-induced decreases in hippocampal protein expression of Nrf2, Sox-2, and BDNF, as determined by Western blotting."
Jun Potential role of miR-128-1 modulating antioxidant NRF2 pathway in linking acrylamide exposure with type 2 diabetes risk: Insight from epidemiological and toxicological evidence. (Ecotoxicology and environmental safety, 2026, PMID 42107271): "Role of miR-128-1, an emerging therapeutic target of type 2 diabetes (T2D) and a targeted posttranscriptional suppressor of the antioxidant master nuclear factor erythroid 2-related factor 2 (NRF2), in linking acrylamide (ACR), a worldwide-concerning and lifelong-exposed pollutant, with T2D is unclear and warrants urgent elucidation."
Jun Association of Serum Angiopoietin-Like Protein 7 With Ferroptosis-Related Proteins in Patients With Metabolic Dysfunction-Associated Fatty Liver Disease. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42247282): "Serum levels of ANGPTL7, TNF-α, IL-6, ACSL4, Keap-1, HO-1, and ferritin were significantly increased, while IL-10, GPX4, and Nrf2 levels were decreased in MAFLD patients when compared with the Con group (MAFLD vs. Con, all p < 0.001)."
Jun Kaempferide alleviates glucocorticoid-induced osteoporosis by targeting ferroptosis through the GSK3β/Nrf-2/GPX4 pathway. (International immunopharmacology, 2026, PMID 41962468): "Mechanistically, KF activated the GSK3β/Nrf2/GPX4 signaling pathway, evidenced by increased GSK3β phosphorylation, Nrf2 upregulation, and elevated GPX4 expression; importantly, these protective effects were reversed by the GSK3β agonist DIF-3."
Jun QingShen granules activates mitophagy to suppress renal tubular epithelial-mesenchymal transition via the miR-23b-5p/Nrf2/PINK1 axis. (Journal of ethnopharmacology, 2026, PMID 41794259): "QingShen granules activates mitophagy to suppress renal tubular epithelial-mesenchymal transition via the miR-23b-5p/Nrf2/PINK1 axis."
Jun Phosphorylation of Cullin3 by the pseudokinase ALDH18A1 disrupts KEAP1-mediated NRF2 degradation. (Biochemical and biophysical research communications, 2026, PMID 41996736): "The decline of the transcription factor NRF2 during aging contributes to impaired oxidative stress defense, yet the underlying mechanisms remain incompletely understood."
Jun DL-norvaline attenuated HFD-induced metabolic inflammation and dysfunction with integrated pharmacokinetic, biodistribution, and safety evaluation. (European journal of pharmacology, 2026, PMID 42105997): "DL-norvaline lowered LPS and inflammatory mediators, attenuated hepatic activation of multiple toll-like receptors and downstream MyD88/NF-κB signaling, and restored Nrf2-associated antioxidant genes."