Title Oxidative Stress in Age-Related Macular Degeneration: From Molecular Mechanisms to Emerging Therapeutic Targets

Tatsuya Mimura; Hidetaka Noma

doi:10.3390/antiox14101251

journal article Open Access Oct 18, 2025

Title Oxidative Stress in Age-Related Macular Degeneration: From Molecular Mechanisms to Emerging Therapeutic Targets

Tatsuya Mimura Hidetaka Noma

Antioxidants Vol. 14 No. 10 pp. 1251 · MDPI AG

View at Publisher Save 10.3390/antiox14101251

Abstract

Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment in the elderly, and oxidative stress, primarily mediated by reactive oxygen species (ROS), is widely recognized as a central driver of its onset and progression. The retina is highly susceptible to oxidative damage due to its elevated oxygen consumption, abundant polyunsaturated fatty acids, and continuous exposure to light. Recent studies have elucidated molecular mechanisms in which mitochondrial dysfunction, disruption of redox homeostasis, inflammation, and complement activation interact to promote degeneration of retinal pigment epithelium (RPE) and photoreceptor cells. In addition to age-related oxidative stress, environmental factors such as motor vehicle exhaust and volatile organic compounds (VOCs) can accelerate the accumulation of lipofuscin and drusen, thereby fostering a chronic pro-inflammatory milieu. From a therapeutic perspective, beyond conventional antioxidant supplementation, emerging strategies targeting oxidative stress-related pathways have gained attention, including mitochondrial protectants, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, anti-inflammatory agents, and gene therapy. Importantly, several innovative approaches are under investigation, such as saffron supplementation with neuroprotective properties, drug repositioning of levodopa, and nanotechnology-based delivery systems to enhance retinal bioavailability of antioxidants and gene therapies. This review summarizes the pathophysiological role of oxidative stress in AMD from a molecular mechanistic perspective and discusses recent advances in research and novel therapeutic targets.

Topics

No keywords indexed for this article. Browse by subject →

References

116

[1]

Hadziahmetovic, M., and Malek, G. (2021). Age-related macular degeneration revisited: From pathology and cellular stress to potential therapies. Front. Cell Dev. Biol., 8. 10.3389/fcell.2020.612812

[2]

Joachim "The incidence and progression of age-related macular degeneration over 15 years: The Blue Mountains Eye Study" Ophthalmology (2015) 10.1016/j.ophtha.2015.08.002

[3]

Parmar, U.P.S., Surico, P.L., Mori, T., Singh, R.B., Cutrupi, F., Premkishore, P., Gallo Afflitto, G., Di Zazzo, A., Coassin, M., and Romano, F. (2025). Antioxidants in age-related macular degeneration: Lights and shadows. Antioxidants, 14. 10.3390/antiox14020152

[4]

Maurya "Oxidative stress in retinal pigment epithelium degeneration: From pathogenesis to therapeutic targets in dry age-related macular degeneration" Neural Regen. Res. (2023) 10.4103/1673-5374.369098

[5]

Ochoa Hernández, M.E., Lewis-Luján, L.M., Burboa Zazueta, M.G., Del Castillo Castro, T., De La Re Vega, E., Gálvez-Ruiz, J.C., Trujillo-López, S., López Torres, M.A., and Iloki-Assanga, S.B. (2025). Role of oxidative stress and inflammation in age-related macular degeneration: Insights into the retinal pigment epithelium (RPE). Int. J. Mol. Sci., 26. 10.3390/ijms26083463

[6]

Abokyi "Central role of oxidative stress in age-related macular degeneration: Evidence from a review of the molecular mechanisms and animal models" Oxidative Med. Cell. Longev. (2020) 10.1155/2020/7901270

[7]

Fritsche "Seven new loci associated with age-related macular degeneration" Nat. Genet. (2013) 10.1038/ng.2578

[8]

The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD

Sayantan Datta, Marisol Cano, Katayoon Ebrahimi et al.

Progress in Retinal and Eye Research 2017 10.1016/j.preteyeres.2017.03.002

[9]

Heesterbeek "Risk factors for progression of age-related macular degeneration" Ophthalmic Physiol. Opt. (2020) 10.1111/opo.12675

[10]

Bell "Human organoids for the study of retinal development and disease" Annu. Rev. Vis. Sci. (2020) 10.1146/annurev-vision-121219-081855

[11]

Ruan, Y., Jiang, S., and Gericke, A. (2021). Age-related macular degeneration: Role of oxidative stress and blood vessels. Int. J. Mol. Sci., 22. 10.3390/ijms22031296

[12]

Sparrow "The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells" Investig. Ophthalmol. Vis. Sci. (2000)

[13]

Marie "Light action spectrum on oxidative stress and mitochondrial damage in A2E-loaded retinal pigment epithelium cells" Cell Death Dis. (2018) 10.1038/s41419-018-0331-5

[14]

Role of Mitochondria in Retinal Pigment Epithelial Aging and Degeneration

Yao Tong, Zunyi Zhang, Shusheng Wang

Frontiers in Aging 10.3389/fragi.2022.926627

[15]

Downie "Blue-light filtering intraocular lenses (IOLs) for protecting macular health" Cochrane Database Syst. Rev. (2018)

[16]

The Age-Related Eye Disease Study 2 Research Group (2013). Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: The Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA, 309, 2005–2015. 10.1001/jama.2013.4997

[17]

Wei "Interferon-γ induces retinal pigment epithelial cell ferroptosis by a JAK1-2/STAT1/SLC7A11 signaling pathway in age-related macular degeneration" FEBS J. (2022) 10.1111/febs.16272

[18]

Grenell "Loss of MPC1 Reprograms Retinal Metabolism to Impair Visual Function" Proc. Natl. Acad. Sci. USA (2019) 10.1073/pnas.1812941116

[19]

Fisher "Perspective on AMD pathobiology: A bioenergetic crisis in the RPE" Investig. Ophthalmol. Vis. Sci. (2018) 10.1167/iovs.18-24289

[20]

Mehrzadi "Mitochondrial dysfunction in age-related macular degeneration: Melatonin as a potential treatment" Expert Opin. Ther. Targets (2020) 10.1080/14728222.2020.1737015

[21]

Bellezza, I. (2018). Oxidative stress in age-related macular degeneration: Nrf2 as therapeutic target. Front. Pharmacol., 9. 10.3389/fphar.2018.01280

[22]

Jarrett "Consequences of oxidative stress in age-related macular degeneration" Mol. Aspects Med. (2012) 10.1016/j.mam.2012.03.009

[23]

Lenin, R.R., Koh, Y.H., Zhang, Z., Yeo, Y.Z., Parikh, B.H., Seah, I., Wong, W., and Su, X. (2023). Dysfunctional autophagy, proteostasis, and mitochondria as a prelude to age-related macular degeneration. Int. J. Mol. Sci., 24. 10.3390/ijms24108763

[24]

Yang, B., Yang, K., Chen, Y., Li, Q., Chen, J., Li, S., and Wu, Y. (2025). Exposure of A2E to blue light promotes ferroptosis in the retinal pigment epithelium. Cell Mol. Biol. Lett., 30. 10.1186/s11658-025-00700-2

[25]

Velilla "Smoking and age-related macular degeneration: Review and update" J. Ophthalmol. (2013) 10.1155/2013/895147

[26]

Wu, J., Zhang, Y., and Xu, X. (2024). Association between ambient air pollution and age-related macular degeneration: A meta-analysis. BMC Ophthalmol., 24. 10.1186/s12886-024-03465-y

[27]

Chua "UK Biobank Eye and Vision Consortium. Association of ambient air pollution with age-related macular degeneration and retinal thickness in UK Biobank" Br. J. Ophthalmol. (2022) 10.1136/bjophthalmol-2020-316218

[28]

Wang, Z., Chen, D., Peng, L., Wang, X., Ding, Q., Li, L., and Xu, T. (2024). Exposure to volatile organic compounds is a risk factor for diabetes retinopathy: A cross-sectional study. Front. Public Health, 12. 10.3389/fpubh.2024.1347671

[29]

Writing Committee for the OPTOS PEripheral RetinA (OPERA) Study Research Group, Domalpally, A., Clemons, T.E., Danis, R.P., Sadda, S.R., Cukras, C.A., Toth, C.A., Friberg, T.R., and Chew, E.Y. (2017). Peripheral retinal changes associated with age-related macular degeneration in the Age-Related Eye Disease Study 2: Age-Related Eye Disease Study 2 Report Number 12 by the Age-Related Eye Disease Study 2 Optos PEripheral RetinA (OPERA) Study Research Group. Ophthalmology, 124, 479–487. 10.1016/j.ophtha.2016.12.004

[30]

Broadhead "Saffron therapy for the treatment of mild/moderate age-related macular degeneration: A randomised clinical trial" Graefes Arch. Clin. Exp. Ophthalmol. (2019) 10.1007/s00417-018-4163-x

[31]

Karimi, P., Gheisari, A., Gasparini, S.J., Baharvand, H., Shekari, F., Satarian, L., and Ader, M. (2020). Crocetin Prevents RPE Cells from Oxidative Stress through Protection of Cellular Metabolic Function and Activation of ERK1/2. Int. J. Mol. Sci., 21. 10.3390/ijms21082949

[32]

Moldogazieva "Oxidative stress and advanced lipoxidation and glycation end products (ALEs and AGEs) in aging and age-related diseases" Oxidative Med. Cell. Longev. (2019) 10.1155/2019/3085756

[33]

Mol, M., Degani, G., Coppa, C., Baron, G., Popolo, L., Carini, M., Aldini, G., Vistoli, G., and Altomare, A. (2019). Advanced lipoxidation end products (ALEs) as RAGE binders: Mass spectrometric and computational studies to explain the reasons why. Redox Biol., 23. 10.1016/j.redox.2018.101083

[34]

Complement Activation and Inflammatory Processes in Drusen Formation and Age Related Macular Degeneration

Lincoln V Johnson, William P Leitner, Michelle K Staples et al.

Experimental Eye Research 2001 10.1006/exer.2001.1094

[35]

Park, Y.G., Park, Y.S., and Kim, I.B. (2021). Complement system and potential therapeutics in age-related macular degeneration. Int. J. Mol. Sci., 22. 10.3390/ijms22136851

[36]

Pivtoraiko "Oxidative stress and autophagy in the regulation of lysosome-dependent neuron death" AntiOxidative Redox Signal. (2009) 10.1089/ars.2008.2263

[37]

Mitter "Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD" Autophagy (2014) 10.4161/auto.36184

[38]

Wang "Autophagy dysfunction, cellular senescence, and abnormal immune-inflammatory responses in AMD: From mechanisms to therapeutic potential" Oxidative Med. Cell. Longev. (2019)

[39]

Nita "Interplay between reactive oxygen species and autophagy in the course of age-related macular degeneration" EXCLI J. (2020)

[40]

Brown "Mitochondria: Potential targets for protection in age-related macular degeneration" Adv. Exp. Med. Biol. (2018) 10.1007/978-3-319-75402-4_2

[41]

Lambros "Oxidative stress and the Nrf2 anti-oxidant transcription factor in age-related macular degeneration" Adv. Exp. Med. Biol. (2016) 10.1007/978-3-319-17121-0_10

[42]

Hu "Regulatory factors of Nrf2 in age-related macular degeneration pathogenesis" Int. J. Ophthalmol. (2024) 10.18240/ijo.2024.07.21

[43]

Kauppinen "Inflammation and its role in age-related macular degeneration" Cell Mol. Life Sci. (2016) 10.1007/s00018-016-2147-8

[44]

Ferroptosis: molecular mechanisms and health implications

Daolin Tang, Xin Chen, Rui Kang et al.

Cell Research 2021 10.1038/s41422-020-00441-1

[45]

Zhu "Salidroside alleviates ferroptosis in FAC-induced age-related macular degeneration models by activating Nrf2/SLC7A11/GPX4 axis" Int. Immunopharmacol. (2024) 10.1016/j.intimp.2024.113041

[46]

Natoli "Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment" Mol. Vis. (2018)

[47]

Feumi "CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration" J. Clin. Investig. (2007) 10.1172/jci31692

[48]

Ozawa, Y. (2020). Oxidative stress in the light-exposed retina and its implication in age-related macular degeneration. Redox Biol., 37. 10.1016/j.redox.2020.101779

[49]

Li "Role of microglia/macrophage polarisation in intraocular diseases: A review" Int. J. Mol. Med. (2024) 10.3892/ijmm.2024.5369

[50]

Khademi "Macrophages in age-related macular degeneration: A narrative review" Aging Adv. (2024) 10.4103/agingadv.agingadv-d-24-00007

Showing 50 of 116 references

Metrics

6

Citations

116

References

Details

Published: Oct 18, 2025
Vol/Issue: 14(10)
Pages: 1251
License: View

Authors

T

Tatsuya Mimura

Department of Ophthalmology, Tsurumi University School of Dental Medicine, Yokohama 230-0063, Japan

H

Hidetaka Noma

Department of Ophthalmology, Tokyo Medical University Ibaraki Medical Center, Ami-cho 300-0395, Japan

Cite This Article

Tatsuya Mimura, Hidetaka Noma (2025). Title Oxidative Stress in Age-Related Macular Degeneration: From Molecular Mechanisms to Emerging Therapeutic Targets. Antioxidants, 14(10), 1251. https://doi.org/10.3390/antiox14101251

Title Oxidative Stress in Age-Related Macular Degeneration: From Molecular Mechanisms to Emerging Therapeutic Targets

You May Also Like