Yuchen Yang1
Haidong Zou1,2,3,4*- 1Shanghai Eye Diseases Prevention & Treatment Center/Shanghai Eye Hospital, School of Medicine, Tongji University, Shanghai, China
- 2Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 3Department of Ophthalmology, National Clinical Research Center for Eye Diseases, Shanghai, China
- 4Department of Ophthalmology, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
Diabetic retinopathy (DR) is a primary cause of vision loss among individuals with diabetes and represents the most prevalent microvascular complication of diabetes mellitus. Its pathophysiological mechanisms involve processes such as oxidative stress, chronic inflammation, cell apoptosis, and angiogenesis. As a core transcription factor in the antioxidant response, Nrf2 upregulates the expression of antioxidant genes through the Keap1-Nrf2-ARE pathway, hence reducing reactive oxygen species (ROS) levels in retinal cells and alleviating oxidative stress and correlated damage. By activating Nrf2, the release of pro-inflammatory cytokines is inhibited, which helps mitigate inflammation and delays DR progression through anti-apoptotic effects, suppression of angiogenesis and ferroptosis inhibition. This review highlights the Nrf2-related regulatory mechanisms and the latest research progress regarding its function in DR, offering a theoretical foundation for Nrf2-targeted DR therapies.
1 Introduction
Diabetic retinopathy (DR) is a prevailing microvascular complication associated with diabetes mellitus and is a primary cause of vision loss and blindness in diabetic individuals globally (1). The development of DR is intricate, involving potential risk factors including hyperglycemia, hypertension, dyslipidemia, disease continuation and pregnancy (2). It is closely associated with pathophysiological processes such as oxidative stress, inflammatory reactions, cell apoptosis, and angiogenesis. Clinically, DR is generally classified into non-proliferative stages (NPDR) and proliferative stages (PDR). The retinal changes in NPDR primarily include microaneurysms, retinal hemorrhages, hard exudates and cotton-wool spots, whereas the features of PDR comprise the formation of neovascularization in the retina, pre-retinal hemorrhages, vitreous hemorrhage, fibrous proliferation and tractional retinal detachment. Early-stage DR may be asymptomatic, with vision impairment becoming apparent only once the disease progresses to PDR or diabetic macular edema (DME). DME can occur at any stage of DR and is positively correlated with the severity of DR (3). Once DR advances to the PDR stage, the prognosis for surgical intervention is generally poor. Anti-vascular endothelial growth factor (VEGF) agents administered via intravitreal injections effectively address some diabetic microvascular changes such as retinal neovascularization and also DME; however, a significant proportion of patients show inadequate or no response to anti-VEGF therapy (3). Hence, the pursuit of developing novel therapeutic approaches for early DR intervention remains a key focus of ophthalmic research.
Oxidative stress is a fundamental mechanism underlying the onset of DR. Recent studies indicate that the nuclear factor E2-related factor 2 (Nrf2) signaling pathway, as a crucial mediator of intracellular antioxidant defense, regulates antioxidant genes like catalase (CAT) and heme oxygenase-1 (HO-1). Nrf2 is also implicated in various pathological mechanisms, including inflammation, cell apoptosis, and angiogenesis (4). Consequently, Nrf2 can be anticipated to be a promising therapeutic target for early DR intervention. This article thoroughly reviews recent advancements in related research.
2 The composition of the Keap1-Nrf2-ARE signaling pathway
Kelch-like ECH-associated protein 1 (Keap1) functions as a substrate adaptor protein of the Cullin3 (Cul3)-dependent E3 ubiquitin ligase complex, forming the Keap1-Cul3-E3 complex with Cul3 (4). Under normal conditions, the Keap1-Cul3-E3 complex binds to Nrf2, sequestering it in the cytoplasm and promoting its ubiquitination and subsequent proteasomal degradation, thereby keeping Nrf2 at low levels. Upon oxidative stress, a conformational change occurs in the Keap1-Cul3-E3 complex, leading to the dissociation of Nrf2, which reduces its degradation and facilitates the nuclear translocation of Nrf2. In the nucleus, Nrf2 binds with small musculoaponeurotic fibrosarcoma protein (sMaf), forming the Nrf2-sMaf heterodimer, which then associates with the antioxidant response element (ARE) to initiate the transcription of antioxidant genes (4). These genes predominantly encode endogenous antioxidants, such as glutathione peroxidase (GPX), NAD(P)H:quinone oxidoreductase 1 (NQO1), superoxide dismutase (SOD) and various peroxidases such as CAT, all of which collaborate to preserve cellular redox balance and alleviate damage induced by oxidative stress. (See Figure 1)
Figure 1. Upstream pathways of Nrf2 and downstream regulatory functions. (a) The mechanism of the Keap1-Nrf2-ARE pathway and interventions targeting the upstream pathways of Nrf2. (b) The effects induced by Nrf2. The colored blocks are arranged from top to bottom and from left to right, representing anti-oxidative stress, anti-ferroptosis, anti-apoptosis, anti-angiogenesis, anti-autophagy, anti-ER stress, and anti-inflammation effects, respectively. The upregulation or downregulation of corresponding molecules by Nrf2 is indicated by a red upward arrow or a blue downward arrow respectively next to the corresponding molecules.
3 Nrf2-mediated oxidative stress mechanisms in DR intervention
The onset and progression of DR are significantly influenced by oxidative stress, which refers to the disparity between oxidant production and the ability of the antioxidant system to neutralize them, which leads to redox dysregulation and the accumulation of excessive reactive oxygen species (ROS), such as hydroxyl radicals (·OH), triggering lipid peroxidation, protein oxidation and nucleic acid damage. Excessive ROS damages retinal blood vessels and surrounding tissues, inducing cell apoptosis, inflammatory responses, mitochondrial dysfunction and microvascular changes, ultimately leading to DR (5). In both DR patients and animal models, elevated levels of ROS in the retina and reduced levels of antioxidants such as SOD and reduced glutathione (GSH) have been observed (6), indicating that inhibiting ROS production and enhancing their elimination are critical strategies for DR treatment.
As a pivotal transcription factor in the oxidative stress defense system, Nrf2 mediates critical regulatory functions in DR pathogenesis. At the cellular level, high glucose treatment significantly elevates ROS levels in retinal pigment epithelial cells, while platycodin D (PLD) usage can reduce ROS levels and ameliorate DR by upregulating the Nrf2 pathway (7). Mesenchymal stem cells-derived exosomes (MSCs-EXOs) activate the PI3K/Akt pathway to govern Nrf2, leading to the upregulation of HO-1 and NQO1, thereby alleviating oxidative damage and cellular senescence in retinal pigment epithelial cells, as well as improving retinal structural damage (8). In animal models, diabetic mice exhibit reduced expression of Nrf2 in the eye, and topical application of the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin can restore Nrf2 and its downstream genes (e.g., CAT, SOD and GPX), with short-term (2 weeks) application improving early-stage DR in mice (9). Compared to anti-VEGF therapy, topical administration of DPP-4 inhibitors offers a non-invasive treatment approach that not only reduces the risk of complications but also alleviates the economic burden on patients, thus presenting a promising option for early DR prevention and intervention. Although currently the role of Nrf2 in antioxidant defense has been well established, the exact mechanisms underlying its regulation of ROS production pathways remain obscure, and further research should be conducted to delve into the differential mechanisms of oxidative stress and Nrf2 regulation across different retinal cell types. See Table 1 for additional interventions of Nrf2 to alleviate oxidative stress. In conclusion, Nrf2 could ameliorate DR by countering oxidative stress through ROS reduction and antioxidant genes upregulation.
Table 1. Summary of drugs or treatments modulating Nrf2 pathways in DR intervention.
4 Nrf2-mediated apoptotic mechanisms in DR intervention
Beyond oxidative stress, Nrf2 also regulates apoptosis mechanisms in DR. Cell apoptosis, the earliest identified pattern of programmed cell death, occurs via two essential mechanisms: the intrinsic and extrinsic pathways. BAX and Bak, as pro-apoptotic elements, increase mitochondrial permeability, which facilitates cytochrome c to be released into the cytoplasm, subsequently initiating a caspase cascade reaction, resulting in intrinsic apoptosis (10). Meanwhile, the binding of Fas ligand (FasL) and tumor necrosis factor-alpha (TNF-α) to their respective receptors activates a caspase cascade reaction, thereby inducing extrinsic apoptosis (11, 12).
Retinal cell apoptosis can occur in the early phases of DR, which often precedes other histopathological alterations (5). Studies on Nrf2-related apoptotic mechanisms in DR intervention have been conducted in recent years. In DR rat models, BAX expression is elevated, whereas Bcl-2 (as an anti-apoptotic factor) expression is reduced. Astaxanthin can trigger the Nrf2 signaling pathway to reverse these changes, thereby inhibiting apoptosis as well as thickening the retina and preserving retinal ganglion cell number, ultimately ameliorating DR (13). Senescence marker protein 30 (SMP30) is an aging-associated protein whose overexpression reduces high glucose-induced ganglion cell apoptosis via the Akt/GSK-3β/Nrf2 pathway, thereby exerting a protective effect on the retina (14). MiR-93 upregulation negatively regulates Nrf2 under hyperglycemic conditions, promoting apoptosis in retinal pigment epithelial cells, whereas long non-coding RNA (lncRNA) MEG3 enhances Nrf2 activity by complementarily interacting with miR-93, thereby reducing cell apoptosis (15). Additionally, miR-221 inhibits Nrf2 activation by suppressing Sirt1 expression, which results in elevated BAX and reduced Bcl-2 levels, thereby enhancing apoptosis in retinal microvascular endothelial cells (16). Given the differential gene expression among various retinal cell types, the overall impact of miRNA on retinal cell apoptosis requires further investigation. In a hyperglycemic environment, retinal pigment epithelial cells exhibit increased expression of ALK7 and GCN2 genes, while their knockdown suppresses cell apoptosis by activating the Nrf2/HO-1 pathway (17, 18). Future research should aim at delineating the interactions between Nrf2 and key apoptosis-related molecules, in order to provide more precise therapeutic targets for DR treatment. See Table 1 for additional interventions of Nrf2 to inhibit cell apoptosis. In summary, Nrf2 exerts cytoprotective effects in DR by balancing pro- and anti-apoptotic factors to hinder cell apoptosis in retinal cells.
5 Nrf2-mediated inflammatory mechanisms in DR intervention
Apart from its anti-apoptotic effects, Nrf2 further demonstrates therapeutic potential by orchestrating an anti-inflammatory role. Both diabetic patients and animal models show the signs of chronic retinal inflammation, which could lead to vascular occlusion, neovascularization and macular edema, thereby accelerating the progression from NPDR to PDR (6, 19). In a hyperglycemic environment, excessive expression of pro-inflammatory molecules activates additional inflammatory cytokines and chemokines, leading to leukocyte aggregation, cell apoptosis and capillary leakage, thereby exacerbating tissue damage (20, 21). Current studies have linked various inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-8, IL-12, IL-13, IL-17A, and TNF-α, to the severity of DR (6, 21, 22). Retinal cell dysfunction further amplifies inflammatory responses, which is a phenomenon that can be observed even in the early stages of DR (21).
Some progress has been made on Nrf2-related inflammatory mechanisms in DR intervention. In diabetic rats retinas, tilianin inhibits the elevation of thioredoxin interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), caspase-1 and IL-1β levels via the Nrf2/TXNIP/NLRP3 inflammasome pathway, thereby mitigating retinal damage (23). MSC-derived small extracellular vesicles (MSC-sEV) can deliver miR-143-3p, which inhibits the neural precursor cell-expressed developmentally down-regulated 8 (NEDD8) neddylation of Cul3, thus preventing the proteasomal degradation of the Keap1-Cul3-E3-Nrf2 complex. This stabilizes Nrf2 and reduces the expression of NLRP3 and pro-inflammatory cytokines, exerting anti-inflammatory effects (24). The impact of other components within MSC-sEV on Nrf2 still requires further investigation. Sulforaphane, as an Nrf2 activator, could regulate Nrf2 signaling to suppress NLRP3 inflammasome formation, thus reducing levels of inflammatory cytokines to alleviate high-glucose-induced inflammatory damage in DR (25). In addition to causing the release of inflammatory cytokines, NLRP3 inflammasome could also trigger pyroptosis, a pattern of inflammation-driven cell death. LncRNA HOTAIR could inhibit Nrf2 under high glucose, resulting in NLRP3 inflammasome activation which subsequently induces pyroptosis, indicating that suppressing pyroptosis via Nrf2 activation could be an important therapeutic strategy for DR (26). In retinal ganglion cells exposed to high glucose, sulfiredoxin-1 (Srxn1) activates Nrf2 through the Akt/GSK-3β pathway, inhibiting the release of IL-1β, IL-6 and TNF-α (27). Additionally, chlorogenic acid (CGA) can reverse TNF-α-induced epithelial-mesenchymal transition (EMT), endothelial-mesenchymal transition (EndoMT) and blood-retinal barrier damage via Nrf2, with these effects being abolished when Nrf2 is inhibited (28). The molecular mechanisms linking Nrf2 with inflammatory factors, as well as the signaling pathways related to EMT and EndoMT, still require further exploration to determine the potential of Nrf2 as a therapeutic target in DR. See Table 1 for additional interventions of Nrf2 to mitigate inflammation. In short, Nrf2-mediated downregulation of inflammatory cytokines highlights its anti-inflammatory potential, rendering Nrf2 an adequate target for alleviating chronic inflammation in DR.
6 Nrf2-mediated angiogenesis mechanisms in DR intervention
Beyond mitigating inflammation, Nrf2 activation exerts an essential function on retinal neovascularization, which is a key indicator of the transition from NPDR to PDR. VEGF is crucial in angiogenesis, facilitating endothelial cell migration and proliferation, enhancing leukocyte adhesion in the retina, and compromising the blood-retinal barrier. This disruption can result in endothelial cell damage, capillary hypoperfusion and the development of DME (22). Furthermore, VEGF increases vascular permeability by weakening intercellular tight junctions, thereby exacerbating blood-retinal barrier damage (29).
Previous studies have shown that nitro-oleic acid (NO2-OA) inhibits the expression of VEGF-A in retinal Müller cells via Nrf2, thereby attenuating angiogenesis induced by hypoxia and inflammation (30). Tricin activates the Sestrin2/Nrf2 pathway and downregulates the expression of VEGF receptor 2 (VEGFR2), which subsequently suppresses retinal morphological changes and neovascularization in diabetic rats. In vitro research has validated the anti-angiogenic effects of this pathway in retinal pigment epithelial cells (31). Research has also demonstrated that acidic polysaccharides from Buddleja officinalis (APBOM) significantly improve retinal pathological changes and neovascularization in diabetic mice by modulating the Nrf2 pathway (32). Future studies are required to further validate the role of these compounds in preventing retinal neovascularization via the Nrf2 pathway, in order to assess their clinical application potential. To conclude, pharmacological Nrf2 activation could attenuate retinal neovascularization, positioning Nrf2 agonists as promising adjuvants to conventional anti-VEGF therapies in DR management.
7 Nrf2-mediated ferroptosis mechanisms in DR intervention
Other than the above-mentioned cell death modes including apoptosis and pyroptosis, Nrf2 could also modulate ferroptosis, which is a unique type of cell death characterized by iron accumulation and lipid peroxidation (33). Iron ions induce massive ROS production via the Fenton reaction, initiating lipid peroxidation that drives cell ferroptosis ultimately (34). The system xc- (composed of the subunits xCT and SLC3A2) and GPX4 are essential in regulating ferroptosis. The system xc- imports cystine into cells, which is then utilized by γ-glutamate-cysteine ligase (γ-GCL), composed of the subunits GCLC and GCLM, to synthesize GSH. GPX4 catalyzes the elimination of lipid peroxides while converting GSH to its oxidized form (GSSG), thus safeguarding cells against ferroptosis (22).
Nrf2 is a key regulator of ferroptosis, which is involved in processes such as the synthesis and metabolism of GSH and GPX4, iron metabolism and lipid peroxidation (35). There has been abundant progress being made during recent years on Nrf2-related ferroptosis in DR intervention. High glucose treatment in retinal pigment epithelial cells elevates miR-138-5p expression, inhibiting the Sirt1/Nrf2 pathway and leading to ferroptosis. However, astragaloside-IV downregulates miR-138-5p, thereby activating the Sirt1/Nrf2 pathway, upregulating GPX4 and GCLC/GCLM and significantly alleviating ferroptosis (36). Corilagin can also inhibit ferroptosis by activating Nrf2, reducing cell tight junction damage. After silencing Nrf2, xCT and GPX4 levels decrease, while transferrin receptor (TFR) and ferritin heavy chain (FTH) levels increase (37). Furthermore, in both in vivo and in vitro experiments, Maresin-1 significantly inhibits high glucose-induced ferroptosis by activating the Nrf2/HO-1/GPX4 pathway, which is manifested by increased GPX4 levels and downregulation of the ferroptosis-promoting factor acyl-CoA synthetase long-chain family member 4 (ACSL4) (38). By activating Nrf2 in retinal endothelial cells, amygdalin suppresses ferroptosis and delays the progression of DR in rats (39). Future research should further explore the potential of targeting Nrf2 to regulate ferroptosis in various retinal cell types and investigate the interactions between Nrf2 and other ferroptosis-associated pathways to expand therapeutic strategies for DR. See Table 1 for additional interventions of Nrf2 to reduce ferroptosis. Overall, Nrf2 safeguards retinal cells against ferroptosis by modulating GPX4-mediated elimination of lipid peroxidation resulted from iron accumulation, designating inhibition of ferroptosis via Nrf2 as a possible means of improving DR.
8 Nrf2-mediated endoplasmic reticulum stress and autophagy in DR intervention
The multifaceted protective role of Nrf2 could also extend to the regulation of endoplasmic reticulum (ER) stress and autophagy, further expanding its therapeutic landscape in DR. Misfolded or unfolded proteins are typically degraded via the ubiquitin-proteasome system or autophagy to maintain protein homeostasis. However, when these proteins cannot be cleared promptly, ER stress can be subsequently induced by three transmembrane proteins in the ER: inositol-requiring enzyme 1 (IRE1), protein kinase R-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) (40). ER stress in the pathophysiology of DR is primarily associated with blood-retinal barrier disruption, retinal neovascularization and neuronal injury (41). Liraglutide has been shown to inhibit ER stress, positioning it as a potential candidate for DR prevention and therapies. Under high-glucose conditions in Neuro2a cells treated with liraglutide, the activation of the p-Erk/Nrf2/Trx pathway decreases ER stress proteins such as IRE1 and PERK (42). Similarly, in high-glucose-treated Müller cells, liraglutide significantly inhibits ER stress through activation of this pathway (40). See Table 1 for additional interventions of Nrf2 to reduce ER stress. In brief, ER stress inhibition by Nrf2 activation may emerge as a novel means of combating DR.
Autophagy is a cellular protective mechanism, through which the lysosome degrades cytoplasm, proteins and damaged organelles as well as metabolic waste and aging by-products, and subsequently the resulting products can be recycled in cells. This process is vital for cellular homeostasis and significantly influences the pathogenesis and progression of DR (43–45). The selective autophagy receptor p62 can competitively bind to Keap1, thereby promoting Nrf2 activation. It has been demonstrated that high-glucose-treated human retinal pigment epithelial cells exhibit reduced CKIP-1 levels, elevated autophagy markers, and diminished p62 accumulation, indicating autophagy activation, whereas CKIP-1 overexpression activates the p62/Keap1/Nrf2 axis and significantly suppresses cell autophagy (46). Thus, modulating autophagy through the p62/Keap1/Nrf2 pathway offers a promising approach to improving the progression of DR.
9 Conclusions and future perspectives
DR has become one of the leading causes of vision loss in diabetic patients, with its pathogenesis involving processes such as oxidative stress and chronic inflammation. Nrf2 alleviates oxidative damage by activating antioxidant genes and reducing intracellular ROS accumulation. Nrf2 also inhibits inflammatory responses, cell apoptosis, angiogenesis and ferroptosis, thereby improving retinal damage. It is noteworthy that these mechanisms regulated by Nrf2 are interconnected and exhibit mutual interactions, implying that intervention of Nrf2 may yield multiple ameliorative effects on DR rather than exerting a single mechanism separately. Table 1 summarizes the effects of pharmacological interventions targeting Nrf2 in improving DR, along with its upstream pathways and downstream molecules. Figure 1 illustrates the mechanism of the Keap1-Nrf2-ARE pathway, along with interventions targeting its upstream pathways and the effects on Nrf2.
Given the limited efficacy of current treatment options (such as anti-VEGF therapy) in certain patients, Nrf2, as a pleiotropic target, holds potential as a complementary therapeutic strategy alongside conventional treatments, rather than as a replacement. Notably, most of the research cited in this review is based on preclinical studies, and currently no clinical trials have been conducted on the use of Nrf2 modulators for the treatment of DR, which is primarily due to the challenges associated with translating Nrf2 activators to clinical applications. For example, the toxicity and adverse effects of Nrf2 activators have not been fully elucidated. Further studies focusing on Nrf2-related animal models are warranted to better characterize the toxicological profiles, pharmacokinetics and pharmacodynamics of these compounds. In addition, the development of Nrf2 activator analogs with reduced toxicity and side effects would be crucial for advancing Nrf2-mediated therapies for DR. To translate Nrf2-based therapies to clinical application, more clinical trials should be conducted. Among the strategies of intervening Nrf2, some safe nutraceuticals such as lutein and curcumin stand out to be more promising for early clinical trials compared to therapies based on gene regulation, owing to their relative safety and easy accessibility from daily diet. To date, no drugs specifically targeting Nrf2 have been developed. Future studies should investigate the regulatory roles of Nrf2 throughout various stages of DR, focusing on its interactions with cell apoptosis, autophagy, ferroptosis and angiogenesis, to further elucidate the signaling pathways involved, thereby offering innovative therapeutic strategies for DR prevention and treatment.
Author contributions
YY: Conceptualization, Writing – original draft, Writing – review & editing. HZ: Conceptualization, Supervision, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. Chinese National Nature Science Foundation (Project number 82371110); Key disciplinary projects of the three-year action plan to strengthen the construction of the public health system in Shanghai (Project number GWVI-11.1-30); Shanghai engineering research center of precise diagnosis and treatment of eye diseases, Shanghai, China (Project No. 19DZ2250100).
Acknowledgments
We appreciate the invaluable assistance given by all members of Zou lab. The figure was illustrated with Adobe Illustrator.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Glossary
ACSL4: Acyl-CoA synthetase long-chain family member 4
APAF-1: Apoptotic protease activating factor-1
ARE: Antioxidant response element
ATF: Activating transcription factor
BAEC: Bovine aortic endothelial cell
CAT: Catalase
CGA: Chlorogenic acid
CKIP-1: Casein kinase 2-interacting protein-1
COX-2: Cyclooxygenase-2
CTRP: C1q/TNF-related protein
DME: Diabetic macular edema
DPP-4: Dipeptidyl peptidase-4
DR: Diabetic retinopathy
EMT: Epithelial-mesenchymal transition
EndoMT: Endothelial-mesenchymal transition
FasL: Fas ligand
FTH: Ferritin heavy chain
γ-GCL: γ-Glutamate-cysteine ligase
GCLC: Glutamate-cysteine ligase catalytic subunit
GCLM: Glutamate-cysteine ligase modifier subunit
GPX: Glutathione peroxidase
GR: Glutathione reductase
GSDMD: Gasdermin D
GSH: Reduced glutathione
GSSG: Oxidized glutathione
HO-1: Heme oxygenase-1
HREC: Human retinal endothelial cell
hRMEC: Human retinal microvascular endothelial cell
HRPs: Human retinal pericytes
HRVECs: Human retinal vascular endothelial cell
HUVECs: Human umbilical vein endothelial cells
IRE1: Inositol-requiring enzyme 1
Keap1: Kelch-like ECH-associated protein 1
lncRNA: Long non-coding RNA
MIC-1: Macrophage inhibitory cytokine-1
miRNA: microRNA
MSC-sEV: Mesenchymal stem cells-derived small extracellular vesicles
MSCs-EXOs: Mesenchymal stem cells-derived exosomes
NO2-OA: Nitro-oleic acid
NPDR: Non-proliferative DR
NQO1: NAD(P)H:quinone oxidoreductase 1
Nrf2: Nuclear factor E2-related factor 2
PDR: Proliferative DR
PERK: Protein kinase R-like endoplasmic reticulum kinase
PLD: Platycodin D
PTGS2: Prostaglandin-endoperoxide synthase 2
PUFAs: Polyunsaturated fatty acids
RGCs: Retinal ganglion cells
ROS: Reactive oxygen species
RPE: Retinal pigment epithelial cells
rRMEC: Rat retinal microvascular endothelial cell
RRPs: Rat retinal pericytes
shRNA: Short hairpin RNA
siRNA: Small interfering RNA
SMP30: Senescence marker protein 30
SOD: Superoxide dismutase
Srxn1: Sulfiredoxin-1
STK25: Serine/threonine protein kinase 25
TFR: Transferrin receptor
TNF-α: Tumor necrosis factor-alpha
TNFR: TNF receptor
TXNIP: Thioredoxin interacting protein
VEGF: Vascular endothelial growth factor.
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Keywords: diabetic retinopathy, Nrf2, oxidative stress, inflammation, apoptosis, angiogenesis, ferroptosis, endoplasmic reticulum stress
Citation: Yang Y and Zou H (2025) Research progress on Nrf2 intervention in the treatment of diabetic retinopathy. Front. Endocrinol. 16:1587231. doi: 10.3389/fendo.2025.1587231
Received: 04 March 2025; Accepted: 05 May 2025;
Published: 21 May 2025.
Edited by:
Kapil Upadhyay, University of Michigan, United StatesReviewed by:
Jacques C. Mbongue, Oakwood University, United StatesCopyright © 2025 Yang and Zou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Haidong Zou, em91aGFpZG9uZ0BzanR1LmVkdS5jbg==