Targeting the Nrf2-Keap1 Pathway to Suppress Ferroptosis in Ischemic Stroke: Repurposed Therapeutics and Translational Perspectives
DOI:
https://doi.org/10.62382/71pktn38Keywords:
Ischemic stroke, Ferroptosis, Nrf2-Keap1 signaling, Drug repurposing, Pharmacological intervention, NeuroprotectionAbstract
Globally, ischemic stroke is the leading cause of mortality and long-term disability. Although reperfusion therapies have improved the patient outcomes, their benefits remain limited by narrow therapeutic windows and ischemia-reperfusion injury. Oxidative stress is the main contributor to the secondary neuronal damage, aggravating the lipid peroxidation, mitochondrial dysfunction, neuroinflammation, and ferroptosis. Therefore, targeting the Nrf2-Keap1 pathway has become a promising strategy for neuroprotection. The present review critically examines the molecular interaction between the oxidative stress, ferroptosis, and Nrf2 signaling, with particular emphasis on the translational potential of Nrf2-targeted pharmacotherapy. The repurposed and emerging Nrf2 modulators, including dimethyl fumarate, edaravone, N-acetylcysteine, and sulforaphane were evaluated for their mechanisms of action, preclinical and clinical evidence, and translational challenges. The review integrates mechanistic, preclinical, pharmacological, pharmacokinetic, safety, and available clinical evidence, with particular attention to therapeutic timing, Central Nervous System (CNS) exposure, combination strategies, biomarkers, and barriers to clinical translation. Overall, Nrf2-targeted modulation represents a promising mechanistic strategy for limiting ferroptosis and oxidative secondary injury after ischemic stroke, although its clinical therapeutic potential remains to be established.
References
[1]GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: A systematic analysis for the Global Burden of Disease Study 2019. The Lancet Neurology, 2021, 20(10), 795-820. DOI: 10.1016/S1474-4422(21)00252-0
[2]GBD 2021 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2021: A systematic analysis for the Global Burden of Disease Study 2021. The Lancet Neurology, 2024, 23(10), 973-1003. DOI: 10.1016/S1474-4422(24)00369-7
[3]Campbell BC, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. New England Journal of Medicine, 2018, 378(17), 1573-1582. DOI: 10.1056/NEJMoa1716405
[4]Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 2019, 50(12), e344-e418. DOI: 10.1161/STR.0000000000000211
[5]Chamorro Á, Dirnagl U, Urra X, Planas AM. Neuroprotection in acute stroke: Targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. The Lancet Neurology, 2016, 15(8), 869-881. DOI: 10.1016/S1474-4422(16)00114-9
[6]Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5), 1060-1072. DOI: 10.1016/j.cell.2012.03.042
[7]Stockwell BR, Angeli JPF, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell, 2017, 171(2), 273-285. DOI: 10.1016/j.cell.2017.09.021
[8]Fan J, Chen M, Cao S, Yao Q, Zhang X, Du S, et al. Identification of a ferroptosis-related gene pair biomarker with immune infiltration landscapes in ischemic stroke: A bioinformatics-based comprehensive study. BMC Genomics, 2022, 23(1), 59. DOI: 10.1186/s12864-022-08295-0
[9]Zhang LM, Liang XL, Xiong GF, Xing XL, Zhang QJ, Zhang BR, et al. Analysis and identification of oxidative stress-ferroptosis related biomarkers in ischemic stroke. Scientific Reports, 2024, 14(1), 3803. DOI: 10.1038/s41598-024-54555-2
[10]Yeh SJ, Chen CH, Lin YH, Tsai LK, Lee CW, Sun Y, et al. Ferroptosis biomarkers predict the outcomes of patients with acute ischemic stroke undergoing endovascular thrombectomy. Scientific Reports, 2025, 15(1), 39510. DOI: 10.1038/s41598-025-23289-0
[11]Farina M, Vieira LE, Buttari B, Profumo E, Saso L. The Nrf2 pathway in ischemic stroke: A review. Molecules, 2021, 26(16), 5001. DOI: 10.3390/molecules26165001.
[12]Dodson M, de la Vega MR, Cholanians AB, Schmidlin CJ, Chapman E, Zhang DD. Modulating NRF2 in disease: Timing is everything. Annual Review of Pharmacology and Toxicology, 2019, 59(1), 555-575. DOI: 10.1146/annurev-pharmtox-010818-021856
[13]Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP, Rumsey WL, et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nature Reviews Drug Discovery, 2019, 18(4), 295-317. DOI: 10.1038/s41573-018-0008-x
[14]Deng X, Chu W, Zhang H, Peng Y. Nrf2 and ferroptosis: A new research direction for ischemic stroke. Cellular and Molecular Neurobiology, 2023, 43(8), 3885-3896. DOI: 10.1007/s10571-023-01411-y
[15]Kleinschnitz C, Grund H, Wingler K, Armitage ME, Jones E, Mittal M, et al. Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and tissue injury. PLoS Biology, 2010, 8(9), e1000479. DOI: 10.1371/journal.pbio.1000479
[16]Casas AI, Dao VTV, Daiber A, Maghzal GJ, Di Lisa F, Kaludercic N, et al. Reactive oxygen-related diseases: Therapeutic targets and emerging clinical indications. Antioxidants & Redox Signaling, 2015, 23(14), 1171-1185. DOI: 10.1089/ars.2015.6433
[17]Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Medicine and Cellular Longevity, 2014, 2014, 360438. DOI: 10.1155/2014/360438
[18]Yang C, Hawkins KE, Doré S, Candelario-Jalil E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. American Journal of Physiology-Cell Physiology, 2019, 316(2), C135-C153. DOI: 10.1152/ajpcell.00136.2018
[19]Jiang X, Stockwell BR, Conrad M. Ferroptosis: Mechanisms, biology and role in disease. Nature Reviews Molecular Cell Biology, 2021, 22(4), 266-282. DOI: 10.1038/s41580-020-00324-8
[20]Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nature Chemical Biology, 2017, 13(1), 91-98. DOI: 10.1038/nchembio.2239
[21]Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, et al. Ferroptosis: Past, present and future. Cell Death & Disease, 2020, 11(2), 88. DOI: 10.1038/s41419-020-2298-2
[22]Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature, 2019, 575(7784), 688-692. DOI: 10.1038/s41586-019-1705-2
[23]Kraft VA, Bezjian CT, Pfeiffer S, Ringelstetter L, Müller C, Zandkarimi F, et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Central Science, 2019, 6(1), 41-53. DOI: 10.1021/acscentsci.9b01063
[24]Feng X, Huang C, Ye L, Xu Z. Identification of five characteristic ferroptosis-related genes as novel biomarkers for ischemic stroke using bioinformatic and machine learning strategies. bioRxiv, 2023. DOI: 10.1101/2023.07.20.549866
[25]Nishizawa H, Yamanaka M, Igarashi K. Ferroptosis: Regulation by competition between NRF2 and BACH1 and propagation of the death signal. The FEBS Journal, 2023, 290(7), 1688-1704. DOI: 10.1111/febs.16382
[26]Chiang SK, Chen SE, Chang LC. A dual role of heme oxygenase-1 in cancer cells. International Journal of Molecular Sciences, 2019, 20(1), 39. DOI: 10.3390/ijms20010039
[27]Veeckmans G, Van San E, Vanden Berghe T. A guide to ferroptosis, the biological rust of cellular membranes. The FEBS Journal, 2024, 291(13), 2767-2783. DOI: 10.1111/febs.16993
[28]Bereczki D Jr, Balla J, Bereczki D. Heme oxygenase-1: Clinical relevance in ischemic stroke. Current Pharmaceutical Design, 2018, 24(20), 2229-2235. DOI: 10.2174/1381612824666180717101104
[29]Safari A, Badeli-Sarkala H, Namavar MR, Kargar-Abarghoue E, Anssari N, Izadi S, et al. Neuroprotective effect of dimethyl fumarate in stroke: The role of nuclear factor erythroid 2-related factor 2. Iranian Journal of Neurology, 2019, 18(3), 108-113.
[30]Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain, 2011, 134(3), 678-692. DOI: 10.1093/brain/awq386
[31]Fan W, Chen H, Li M, Fan X, Jiang F, Xu C, et al. NRF2 activation ameliorates blood-brain barrier injury after cerebral ischemic stroke by regulating ferroptosis and inflammation. Scientific Reports, 2024, 14(1), 5300. DOI: 10.1038/s41598-024-53836-0
[32]Wu N, Luo Z, Deng R, Zhang Z, Zhang J, Liu S, et al. Sulforaphane: An emerging star in neuroprotection and neurological disease prevention. Biochemical Pharmacology, 2025, 233, 116797. DOI: 10.1016/j.bcp.2025.116797
[33]Li Q, Fadoul G, Ikonomovic M, Yang T, Zhang F. Sulforaphane promotes white matter plasticity and improves long-term neurological outcomes after ischemic stroke via the Nrf2 pathway. Free Radical Biology and Medicine, 2022, 193(Pt 1), 292-303. DOI: 10.1016/j.freeradbiomed.2022.10.001.
[34]Dang R, Wang M, Li X, Wang H, Liu L, Wu Q, et al. Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway. Journal of Neuroinflammation, 2022, 19(1), 41. DOI: 10.1186/s12974-022-02400-6
[35]Chen C, Li M, Lin L, Chen S, Chen Y, Hong L. Clinical effects and safety of edaravone in treatment of acute ischaemic stroke: A meta-analysis of randomized controlled trials. Journal of Clinical Pharmacy and Therapeutics, 2021, 46(4), 907-917. DOI: 10.1111/jcpt.13392
[36]Fidalgo M, Pires JR, Viseu I, Magalhaes P, Gregorio H, Afreixo V, et al. Edaravone for acute ischemic stroke: Systematic review with meta-analysis. Clinical Neurology and Neurosurgery, 2022, 219, 107299. DOI: 10.1016/j.clineuro.2022.107299
[37]Komakula S, Bhatia R, Sahib A, Upadhyay A, S LJ, Garg A, et al. Safety and efficacy of N-acetylcysteine (NAC) as an adjunct to standard treatment in patients with acute ischemic stroke: A randomized controlled pilot trial (NACTLYS). Scientific Reports, 2024, 14(1), 1103. DOI: 10.1038/s41598-023-49054-9
[38]Zhang S, Pavic NV, Maloof AG, Goh R, Priglinger M, Garcia-Esperon C, et al. N-Acetylcysteine in the treatment of ischemic stroke: A systematic review. Neurology Open Access, 2026, 2(2), e000079. DOI: 10.1212/WN9.0000000000000079
[39]Wang J, Gao S, Lenahan C, Gu Y, Wang X, Fang Y, et al. Melatonin as an antioxidant agent in stroke: An updated review. Aging and Disease, 2022, 13(6), 1823-1844. DOI: 10.14336/AD.2022.0405
[40]Wei L, Ren H, Zhao M, Xu T, Yang J, Deng X, et al. Curcumin reduces neuroinflammation and oxidative stress in a stroke model by epigenetically regulating ADRB2 methylation through JAK2/STAT3 and Nrf2/HO-1 pathways. Journal of Neuroinflammation, 2026, 23(1), 109. DOI: 10.1186/s12974-026-03729-y
[41]Sun Y, Yang X, Xu L, Jia M, Zhang L, Li P, et al. The role of Nrf2 in relieving cerebral ischemia-reperfusion injury. Current Neuropharmacology, 2023, 21(6), 1405-1420. DOI: 10.2174/1570159X21666221129100308
[42]Takagi T, Kitashoji A, Iwawaki T, Tsuruma K, Shimazawa M, Yoshimura S, et al. Temporal activation of Nrf2 in the penumbra and Nrf2 activator-mediated neuroprotection in ischemia-reperfusion injury. Free Radical Biology and Medicine, 2014, 72, 124-133. DOI: 10.1016/j.freeradbiomed.2014.04.009
[43]Yang K, Zeng L, Yuan X, Wang S, Ge A, Xu H, et al. The mechanism of ferroptosis regulating oxidative stress in ischemic stroke and the regulation mechanism of natural pharmacological active components. Biomedicine & Pharmacotherapy, 2022, 154, 113611. DOI: 10.1016/j.biopha.2022.113611
[44]Millán M, DeGregorio-Rocasolano N, Pérez de la Ossa N, Reverté S, Costa J, Giner P, et al. Targeting pro-oxidant iron with deferoxamine as a treatment for ischemic stroke: Safety and optimal dose selection in a randomized clinical trial. Antioxidants, 2021, 10(8), 1270. DOI: 10.3390/antiox10081270
[45]Sui H, Sun Z, Liu C, Xi H. Ferritinophagy promotes microglia ferroptosis to aggravate neuroinflammation induced by cerebral ischemia-reperfusion injury via activation of the cGAS-STING signaling pathway. Neurochemistry International, 2025, 183, 105920. DOI: 10.1016/j.neuint.2024.105920
[46]Lewczuk A, Boratyńska-Jasińska A, Charzewski Ł, Beręsewicz-Haller M, Zabłocka B. Integrated computational and experimental approach to identify Nrf2-regulated molecular targets in cerebral ischemia. Pharmacological Reports, 2025, 77(6), 1639-1656. DOI: 10.1007/s43440-025-00792-9
[47]Dirnagl U. Thomas Willis lecture: Is translational stroke research broken, and if so, how can we fix it? Stroke, 2016, 47(8), 2148-2153. DOI: 10.1161/STROKEAHA.116.013244
[48]Nitti M, Piras S, Brondolo L, Marinari UM, Pronzato MA, Furfaro AL. Heme oxygenase 1 in the nervous system: Does it favor neuronal cell survival or induce neurodegeneration? International Journal of Molecular Sciences, 2018, 19(8), 2260. DOI: 10.3390/ijms19082260
[49]Duo K, Feng X, Tian X, Wang F, Zhao Y, Yu J, et al. Ferroptosis inhibitors: Mechanisms of action and therapeutic potential. Cellular and Molecular Life Sciences, 2025, 82(1), 441. DOI: 10.1007/s00018-025-05958-5
[50]Zhang L, Luo YL, Xiang Y, Bai XY, Qiang RR, Zhang X, et al. Ferroptosis inhibitors: Past, present and future. Frontiers in Pharmacology, 2024, 15, 1407335. DOI: 10.3389/fphar.2024.1407335
[51]Zhao L, Li Y, Wang W, Qi X, Wang S, Song W, et al. Regulating NCOA4-mediated ferritinophagy for therapeutic intervention in cerebral ischemia-reperfusion injury. Neurochemical Research, 2024, 49(7), 1806-1822. DOI: 10.1007/s11064-024-04146-4
[52]Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, et al. Drug repurposing: Progress, challenges and recommendations. Nature Reviews Drug Discovery, 2019, 18(1), 41-58. DOI: 10.1038/nrd.2018.168
[53]Wu Q, Chen C, Liu W, Zhou Y, Weng G, Gu Y. Network-based drug repurposing for potential stroke therapy. Computational and Structural Biotechnology Journal, 2023, 21, 2809-2823. DOI: 10.1016/j.csbj.2023.04.018
[54]Sun Y, Yang T, Mao L, Zhang F. Sulforaphane protects against brain diseases: Roles of cytoprotective enzymes. Austin Journal of Cerebrovascular Disease & Stroke, 2017, 4(1), 1054. DOI: 10.26420/austinjcerebrovascdisstroke.2017.1054
[55]Ye Y, Xie X, Bi Y, Liu Q, Qiu L, Zhao H, et al. Nrf2 alleviates acute ischemic stroke induced ferroptosis via regulating xCT/GPX4 pathway. Free Radical Biology and Medicine, 2025, 231, 153-162. DOI: 10.1016/j.freeradbiomed.2025.02.040
[56]Wang Y, Huang Y, Xu Y, Ruan W, Wang H, Zhang Y, et al. A dual AMPK/Nrf2 activator reduces brain inflammation after stroke by enhancing microglia M2 polarization. Antioxidants & Redox Signaling, 2018, 28(2), 141-163. DOI: 10.1089/ars.2017.7003
[57]Ashabi G, Khalaj L, Khodagholi F, Goudarzvand M, Sarkaki A. Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia. Metabolic Brain Disease, 2015, 30(3), 747-754. DOI: 10.1007/s11011-014-9632-2
[58]Mansouri A, Reiner Ž, Ruscica M, Tedeschi-Reiner E, Radbakhsh S, Ekta MB, et al. Antioxidant effects of statins by modulating Nrf2 and Nrf2/HO-1 signaling in different diseases. Journal of Clinical Medicine, 2022, 11(5), 1313. DOI: 10.3390/jcm11051313
[59]Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proceedings of the National Academy of Sciences, 1998, 95(15), 8880-8885. DOI: 10.1073/pnas.95.15.8880
[60]Amarenco P, Kim JS, Labreuche J, Charles H, Abtan J, Béjot Y, et al. A comparison of two LDL cholesterol targets after ischemic stroke. New England Journal of Medicine, 2020, 382(1), 9-19. DOI: 10.1056/NEJMoa1910355
[61]Pardridge WM. Drug transport across the blood-brain barrier. Journal of Cerebral Blood Flow & Metabolism, 2012, 32(11), 1959-1972. DOI: 10.1038/jcbfm.2012.126
[62]Okada T, Suzuki H, Travis ZD, Zhang JH. The stroke-induced blood-brain barrier disruption: Current progress of inspection technique, mechanism, and therapeutic target. Current Neuropharmacology, 2020, 18(12), 1187-1212. DOI: 10.2174/1570159X18666200528143301
[63]Shimizu H, Nishimura Y, Shiide Y, Matsuda H, Akimoto M, Matsuda M, et al. Evaluation of pharmacokinetics, safety, and drug-drug interactions of an oral suspension of edaravone in healthy adults. Clinical Pharmacology in Drug Development, 2021, 10(10), 1174-1187. DOI: 10.1002/cpdd.925
[64]Park J, Riew TR. Nanoparticle-mediated nose-to-brain delivery for ischemic stroke therapy: Preclinical insights. Pharmaceutics, 2025, 17(11), 1447. DOI: 10.3390/pharmaceutics17111447
[65]Koo J, Lim C, Oh KT. Recent advances in intranasal administration for brain-targeting delivery: A comprehensive review of lipid-based nanoparticles and stimuli-responsive gel formulations. International Journal of Nanomedicine, 2024, 1767-1807. DOI: 10.2147/IJN.S439181
[66]Ronaldson PT, Williams EI, Betterton RD, Stanton JA, Nilles KL, Davis TP. CNS drug delivery in stroke: Improving therapeutic translation from the bench to the bedside. Stroke, 2024, 55(1), 190-202. DOI: 10.1161/STROKEAHA.123.043764
[67]Ha D, Yang N, Nadithe V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: Current perspectives and future challenges. Acta Pharmaceutica Sinica B, 2016, 6(4), 287-296. DOI: 10.1016/j.apsb.2016.02.001
[68]Parvez S, Kaushik M, Ali M, Alam MM, Ali J, Tabassum H, et al. Dodging blood brain barrier with “nano” warriors: Novel strategy against ischemic stroke. Theranostics, 2022, 12(2), 689-719. DOI: 10.7150/thno.64806
[69]Thamizhoviya G. Intranasal herbal neurotherapeutics in neurodegenerative disorders: Preclinical advances and translational implications. Neuroscience Research and Clinical Practice, 2025, 1(1), 57-66. DOI: 10.64229/ps9nz775
[70]Casas AI, Nogales C, Szepanowski RD, Elbatreek MH, Anastasi E, Sadegh S, et al. Synergistic network pharmacology: Preclinical validation and clinical safety in acute ischemic stroke. Journal of the American Heart Association, 2025, 14(10), e039098. DOI: 10.1161/JAHA.124.039098
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