Oxidative Stress: Molecular Mechanisms, Diseases, and Therapeutic Targets

Abstract

Although the physiological level of reactive oxygen species (ROS) is crucial for governing life processes through redox signaling, the excessive accumulation of ROS can contribute to biomolecular damage and pathological state, namely, oxidative stress. This review systematically summarizes the molecular mechanisms underlying the dynamic equilibrium of cellular redox state, including the intracellular sources of ROS and the multilayered antioxidant defense network. When ROS production exceeds the regulatory limits of the antioxidant system, excessive ROS will act on a series of molecular targets and participate in the pathogenesis of diseases. Therapeutic targeting of the redox balance is regarded as an effective strategy for treating oxidative stress-related diseases, such as supplementation of direct antioxidants and enhancement of endogenous antioxidant defense network. Nevertheless, clinical trials that attempt to delay the onset or progression of such diseases are mostly negative. This review discusses the challenges encountered in the clinical application of antioxidant therapy and highlights the opportunities brought by novel technologies such as intelligent drug delivery system and personalized medicine. By adopting these new technologies, it is expected to overcome the limitations of traditional antioxidant therapy.

Keywords

oxidative damage / oxidative stress / reactive oxygen species / redox signaling / therapeutic targets

References

[1] B. Li, H. Ming, S. Qin, et al., “Redox Regulation: Mechanisms, Biology and Therapeutic Targets in Diseases,” Signal Transduction and Targeted Therapy 10, no. 1 (2025): 72.

[2] H. Sies and D. P. Jones, “Reactive Oxygen Species (ROS) as Pleiotropic Physiological Signalling Agents,” Nature Reviews Molecular Cell Biology 21, no. 7 (2020): 363–383.

[3] H. Jiang, H. Wang, and M. De Ridder, “Targeting Antioxidant Enzymes as a Radiosensitizing Strategy,” Cancer Letters 438 (2018): 154–164.

[4] B. J. Day, “Antioxidant Therapeutics: Pandora's Box,” Free Radical Biology and Medicine 66 (2013): 58–64.

[5] Y. Zhang, Y. Zhang, R. Liang, et al., “Targeted ROS Scavenging for Disease Therapies Using Nanomaterials,” Advanced Materials 37, no. 50 (2025): e04435.

[6] L. Flohé, “Looking Back at the Early Stages of Redox Biology,” Antioxidants 9, no. 12 (2020): 1254.

[7] Y. Yao, Y. Luo, X. Liang, et al., “The Role of Oxidative Stress-Mediated Fibro-Adipogenic Progenitor Senescence in Skeletal Muscle Regeneration and Repair,” Stem Cell Research & Therapy 16, no. 1 (2025): 104.

[8] T. von Zglinicki, “Oxidative Stress and Cell Senescence as Drivers of Ageing: Chicken and Egg,” Ageing Research Reviews 102 (2024): 102558.

[9] F. C. E. Vogel, A. B. Chaves-Filho, and A. Schulze, “Lipids as Mediators of Cancer Progression and Metastasis,” Nature Cancer 5, no. 1 (2024): 16–29.

[10] G. Vitale, S. Salvioli, and C. Franceschi, “Oxidative Stress and the Ageing Endocrine System,” Nature Reviews Endocrinology 9, no. 4 (2013): 228–240.

[11] A. Tratenšek, I. Locatelli, I. Grabnar, et al., “Oxidative Stress-Related Biomarkers as Promising Indicators of Inflammatory Bowel Disease Activity: A Systematic Review and Meta-Analysis,” Redox Biology 77 (2024): 103380.

[12] M. R. Miller, “Oxidative Stress and the Cardiovascular Effects of Air Pollution,” Free Radical Biology and Medicine 151 (2020): 69–87.

[13] Y.-F. Li, S.-H. Ouyang, L.-F. Tu, et al., “Caffeine Protects Skin From Oxidative Stress-Induced Senescence Through the Activation of Autophagy,” Theranostics 8, no. 20 (2018): 5713–5730.

[14] M. Kuntic, I. Kuntic, D. Cleppien, et al., “Differential Inflammation, Oxidative Stress and Cardiovascular Damage Markers of Nano- and Micro-Particle Exposure in Mice: Implications for Human Disease Burden,” Redox Biology 83 (2025): 103644.

[15] A. Q. Khan, M. V. Agha, K. S. A. M. Sheikhan, et al., “Targeting Deregulated Oxidative Stress in Skin Inflammatory Diseases: An Update on Clinical Importance,” Biomedicine & Pharmacotherapy 154 (2022): 113601.

[16] F. M. F. Cornelis, S. Monteagudo, L.-A. K. A. Guns, et al., “ANP32A Regulates ATM Expression and Prevents Oxidative Stress in Cartilage, Brain, and Bone,” Science Translational Medicine 10, no. 458 (2018): eaar8426.

[17] R. P. Bowler and J. D. Crapo, “Oxidative Stress in Allergic Respiratory Diseases,” Journal of Allergy and Clinical Immunology 110, no. 3 (2002): 349–356.

[18] A. Bhattacharyya, R. Chattopadhyay, S. Mitra, and S. E. Crowe, “Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases,” Physiological Reviews 94, no. 2 (2014): 329–354.

[19] C. C. Benz and C. Yau, “Ageing, Oxidative Stress and Cancer: Paradigms in Parallax,” Nature Reviews Cancer 8, no. 11 (2008): 875–879.

[20] R. Bai, J. Guo, X.-Y. Ye, et al., “Oxidative Stress: The Core Pathogenesis and Mechanism of Alzheimer's Disease,” Ageing Research Reviews 77 (2022): 101619.

[21] M. S. Alam and D. M. Czajkowsky, “SARS-CoV-2 Infection and Oxidative Stress: Pathophysiological Insight Into Thrombosis and Therapeutic Opportunities,” Cytokine & Growth Factor Reviews 63 (2021): 44–57.

[22] W. Ahmad, B. Ijaz, K. Shabbiri, et al., “Oxidative Toxicity in Diabetes and Alzheimer's Disease: Mechanisms Behind ROS/RNS Generation,” Journal of Biomedical Science 24, no. 1 (2017): 76.

[23] K. Aramouni, R. Assaf, A. Shaito, et al., “Biochemical and Cellular Basis of Oxidative Stress: Implications for Disease Onset,” Journal of Cellular Physiology 238, no. 9 (2023): 1951–1963.

[24] Y. Qin, Z. Zhang, X. Guo, et al., “A Bone-Targeting Hydrogen Sulfide Delivery System for Treatment of Osteoporotic Fracture via Macrophage Reprogramming and Osteoblast-Osteoclast Coupling,” Advanced Functional Materials 35, no. 17 (2025): 2418822.

[25] S. Ray, A. A. Abugable, J. Parker, et al., “A Mechanism for Oxidative Damage Repair at Gene Regulatory Elements,” Nature 609, no. 7929 (2022): 1038–1047.

[26] M. Pajares, N. Jiménez-Moreno, I. H. K. Dias, et al., “Redox Control of Protein Degradation,” Redox Biology 6 (2015): 409–420.

[27] W. Yang, H. Yue, G. Lu, et al., “Advances in Delivering Oxidative Modulators for Disease Therapy,” Research 2022 (2022): 9897464.

[28] S. Li, H. Li, X. Xu, et al., “Nanocarrier-Mediated Antioxidant Delivery for Liver Diseases,” Theranostics 10, no. 3 (2020): 1262–1280.

[29] X. Huang, X. Liu, Q. Luo, et al., “Artificial Selenoenzymes: Designed and Redesigned,” Chemical Society Reviews 40, no. 3 (2010): 1171–1184.

[30] H. J. Forman, K. J. A. Davies, and F. Ursini, “How Do Nutritional Antioxidants Really Work: Nucleophilic Tone and Para-Hormesis Versus Free Radical Scavenging in Vivo,” Free Radical Biology and Medicine 66 (2013): 24–35.

[31] H. J. Forman and H. Zhang, “Targeting Oxidative Stress in Disease: Promise and Limitations of Antioxidant Therapy,” Nature Reviews Drug Discovery 20, no. 9 (2021): 689–709.

[32] J. Dan Dunn, L. A. Alvarez, X. Zhang, and T. Soldati, “Reactive Oxygen Species and Mitochondria: A Nexus of Cellular Homeostasis,” Redox Biology 6 (2015): 472–485.

[33] E. Niki, “Assessment of Antioxidant Capacity in Vitro and in Vivo,” Free Radical Biology and Medicine 49, no. 4 (2010): 503–515.

[34] A. Varesi, L. I. M. Campagnoli, A. Carrara, et al., “Non-Enzymatic Antioxidants Against Alzheimer's Disease: Prevention, Diagnosis and Therapy,” Antioxidants 12, no. 1 (2023): 180.

[35] G. C. Brown and V. Borutaite, “There Is no Evidence That Mitochondria Are the Main Source of Reactive Oxygen Species in Mammalian Cells,” Mitochondrion 12, no. 1 (2012): 1–4.

[36] M. P. Johnson, “Structure, Regulation and Assembly of the Photosynthetic Electron Transport Chain,” Nature Reviews Molecular Cell Biology 26, no. 9 (2025): 667–690.

[37] X. Xu, Y. Pang, and X. Fan, “Mitochondria in Oxidative Stress, Inflammation and Aging: From Mechanisms to Therapeutic Advances,” Signal Transduction and Targeted Therapy 10, no. 1 (2025): 190.

[38] J. Hirst, “Mitochondrial Complex I,” Annual Review of Biochemistry 82 (2013): 551–575.

[39] T. Kalogeris, Y. Bao, and R. J. Korthuis, “Mitochondrial Reactive Oxygen Species: A Double Edged Sword in Ischemia/Reperfusion vs Preconditioning,” Redox Biology 2 (2014): 702–714.

[40] J. Grujicic and A. R. Allen, “Manganese Superoxide Dismutase: Structure, Function, and Implications in Human Disease,” Antioxidants 14, no. 7 (2025): 848.

[41] M. B. H. Youdim, D. Edmondson, and K. F. Tipton, “The Therapeutic Potential of Monoamine Oxidase Inhibitors,” Nature Reviews Neuroscience 7, no. 4 (2006): 295–309.

[42] X. Wu, W. Hao, S. Yan, et al., “Selective Nanopore Detection of Monoamine Oxidase A and B in a Single Sample,” Angewandte Chemie 64, no. 35 (2025): e202505138.

[43] N. Kaludercic, R. J. Arusei, and F. Di Lisa, “Recent Advances on the Role of Monoamine Oxidases in Cardiac Pathophysiology,” Basic Research in Cardiology 118, no. 1 (2023): 41.

[44] S. S. Bhat, D. Anand, and F. A. Khanday, “p66Shc as a Switch in Bringing About Contrasting Responses in Cell Growth: Implications on Cell Proliferation and Apoptosis,” Molecular Cancer 14 (2015): 76.

[45] S. X. Zhang, J. J. Wang, C. R. Starr, et al., “The Endoplasmic Reticulum: Homeostasis and Crosstalk in Retinal Health and Disease,” Progress in Retinal and Eye Research 98 (2024): 101231.

[46] G. Ong and S. E. Logue, “Unfolding the Interactions Between Endoplasmic Reticulum Stress and Oxidative Stress,” Antioxidants 12, no. 5 (2023): 981.

[47] A. Delaunay-Moisan and C. Appenzeller-Herzog, “The Antioxidant Machinery of the Endoplasmic Reticulum: Protection and Signaling,” Free Radical Biology and Medicine 83 (2015): 341–351.

[48] A. Veith and B. Moorthy, “Role of Cytochrome P450s in the Generation and Metabolism of Reactive Oxygen Species,” Current Opinion in Toxicology 7 (2018): 44–51.

[49] J. Yuan, Z. Liao, X. Zhu, et al., “PM2.5 Exacerbates Nasal Epithelial Barrier Dysfunction in Allergic Rhinitis by Inducing NLRP3-Mediated Pyroptosis via the AhR/CYP1A1/ROS Axis,” Journal of Hazardous Materials 492 (2025): 138145.

[50] J. Kim and H. Bai, “Peroxisomal Stress Response and Inter-Organelle Communication in Cellular Homeostasis and Aging,” Antioxidants 11, no. 2 (2022): 192.

[51] N. A. Bonekamp, A. Völkl, H. D. Fahimi, and M. Schrader, “Reactive Oxygen Species and Peroxisomes: Struggling for Balance,” Biofactors 35, no. 4 (2009): 346–355.

[52] R. J. A. Wanders, H. R. Waterham, and S. Ferdinandusse, “Metabolic Interplay Between Peroxisomes and Other Subcellular Organelles Including Mitochondria and the Endoplasmic Reticulum,” Frontiers in Cell and Developmental Biology 3 (2015): 83.

[53] V. D. Antonenkov, S. Grunau, S. Ohlmeier, and J. K. Hiltunen, “Peroxisomes Are Oxidative Organelles,” Antioxidants & Redox Signaling 13, no. 4 (2010): 525–537.

[54] M. Schrader, M. Kamoshita, and M. Islinger, “Organelle Interplay-Peroxisome Interactions in Health and Disease,” Journal of Inherited Metabolic Disease 43, no. 1 (2020): 71–89.

[55] Y. Sargsyan and S. Thoms, “Staying in Healthy Contact: How Peroxisomes Interact With Other Cell Organelles,” Trends in Molecular Medicine 26, no. 2 (2020): 201–214.

[56] L. F. DiGiovanni, P. K. Khroud, R. E. Carmichael, et al., “ROS Transfer at Peroxisome-Mitochondria Contact Regulates Mitochondrial Redox,” Science 389, no. 6756 (2025): 157–162.

[57] A. Panday, M. K. Sahoo, D. Osorio, and S. Batra, “NADPH Oxidases: An Overview From Structure to Innate Immunity-Associated Pathologies,” Cellular & Molecular Immunology 12, no. 1 (2015): 5–23.

[58] D. Kračun, L. R. Lopes, E. Cifuentes-Pagano, and P. J. Pagano, “NADPH Oxidases: Redox Regulation of Cell Homeostasis and Disease,” Physiological Reviews 105, no. 3 (2025): 1291–1428.

[59] A. Vermot, I. Petit-Härtlein, S. M. E. Smith, and F. Fieschi, “NADPH Oxidases (NOX): An Overview From Discovery, Molecular Mechanisms to Physiology and Pathology,” Antioxidants 10, no. 6 (2021): 890.

[60] A. Cipriano, M. Viviano, A. Feoli, et al., “NADPH Oxidases: From Molecular Mechanisms to Current Inhibitors,” Journal of Medicinal Chemistry 66, no. 17 (2023): 11632–11655.

[61] K. Y. Hood, A. C. Montezano, A. P. Harvey, et al., “Nicotinamide Adenine Dinucleotide Phosphate Oxidase-Mediated Redox Signaling and Vascular Remodeling by 16α-Hydroxyestrone in Human Pulmonary Artery Cells: Implications in Pulmonary Arterial Hypertension,” Hypertension 68, no. 3 (2016): 796–808.

[62] J. P. Taylor and H. M. Tse, “The Role of NADPH Oxidases in Infectious and Inflammatory Diseases,” Redox Biology 48 (2021): 102159.

[63] P. Chaudhary, P. Janmeda, A. O. Docea, et al., “Oxidative Stress, Free Radicals and Antioxidants: Potential Crosstalk in the Pathophysiology of Human Diseases,” Frontiers in Chemistry 11 (2023): 1158198.

[64] H. J. Forman and H. Zhang, “Targeting Oxidative Stress in Disease: Promise and Limitations of Antioxidant Therapy,” Nature Reviews Drug Discovery 20, no. 9 (2021): 689–709.

[65] M. Che, R. Wang, X. Li, et al., “Expanding Roles of Superoxide Dismutases in Cell Regulation and Cancer,” Drug Discovery Today 21, no. 1 (2016): 143–149.

[66] T. Liu, J. Shang, and Q. Chen, “Superoxide Dismutases in Immune Regulation and Infectious Diseases,” Antioxidants 14, no. 7 (2025): 809.

[67] S. Abdalbagemohammedabdalsadeg, B.-L. Xiao, X.-X. Ma, et al., “Catalase Immobilization: Current Knowledge, Key Insights, Applications, and Future Prospects—A Review,” International Journal of Biological Macromolecules 276, no. Pt 2 (2024): 133941.

[68] E. Lubos, J. Loscalzo, and D. E. Handy, “Glutathione Peroxidase-1 in Health and Disease: From Molecular Mechanisms to Therapeutic Opportunities,” Antioxidants & Redox Signaling 15, no. 7 (2011): 1957–1997.

[69] M. U. Ghani, Z. Yang, T. Feng, et al., “Comprehensive Review on Glucose 6 Phosphate Dehydrogenase: A Critical Immunometabolic and Redox Switch in Insects,” International Journal of Biological Macromolecules 273, no. Pt 2 (2024): 132867.

[70] E. Fuentes-Lemus, J. S. Reyes, J. D. Figueroa, et al., “The Enzymes of the Oxidative Phase of the Pentose Phosphate Pathway as Targets of Reactive Species: Consequences for NADPH Production,” Biochemical Society Transactions 51, no. 6 (2023): 2173–2187.

[71] D. Lapenna, “Glutathione and Glutathione-dependent Enzymes: From Biochemistry to Gerontology and Successful Aging,” Ageing Research Reviews 92 (2023): 102066.

[72] Y. Wang, N. Lilienfeldt, and S. Hekimi, “Understanding Coenzyme Q,” Physiological Reviews 104, no. 4 (2024): 1533–1610.

[73] A. Meščić Macan, T. Gazivoda Kraljević, and S. Raić-Malić, “Therapeutic Perspective of Vitamin C and Its Derivatives,” Antioxidants 8, no. 8 (2019): 247.

[74] E. Niki, “Role of Vitamin E as a Lipid-Soluble Peroxyl Radical Scavenger: In Vitro and in Vivo Evidence,” Free Radical Biology and Medicine 66 (2013): 3–12.

[75] H. Tapiero, D. M. Townsend, and K. D. Tew, “The Role of Carotenoids in the Prevention of Human Pathologies,” Biomedicine & Pharmacotherapy 58, no. 2 (2004): 100–110.

[76] A. Varela-López, P. Bullón, F. Giampieri, and J. L. Quiles, “Non-Nutrient, Naturally Occurring Phenolic Compounds With Antioxidant Activity for the Prevention and Treatment of Periodontal Diseases,” Antioxidants 4, no. 3 (2015): 447–481.

[77] S. Geertsema, A. R. Bourgonje, R. R. Fagundes, et al., “The NRF2/Keap1 Pathway as a Therapeutic Target in Inflammatory Bowel Disease,” Trends in Molecular Medicine 29, no. 10 (2023): 830–842.

[78] Q. Ma, “Role of nrf2 in Oxidative Stress and Toxicity,” Annual Review of Pharmacology and Toxicology 53 (2013): 401–426.

[79] E. Bobrovnikova-Marjon, C. Grigoriadou, D. Pytel, et al., “PERK Promotes Cancer Cell Proliferation and Tumor Growth by Limiting Oxidative DNA Damage,” Oncogene 29, no. 27 (2010): 3881–3895.

[80] T. Ishii, E. Warabi, and G. E. Mann, “Stress Activated MAP Kinases and Cyclin-Dependent Kinase 5 Mediate Nuclear Translocation of Nrf2 via Hsp90α-Pin1-Dynein Motor Transport Machinery,” Antioxidants 12, no. 2 (2023): 274.

[81] M. J. Morgan and Z.-G. Liu, “Crosstalk of Reactive Oxygen Species and NF-κB Signaling,” Cell Research 21, no. 1 (2011): 103–115.

[82] J. M. Heilman, T. J. Burke, C. J. McClain, and W. H. Watson, “Transactivation of Gene Expression by NF-κB Is Dependent on Thioredoxin Reductase Activity,” Free Radical Biology and Medicine 51, no. 8 (2011): 1533–1542.

[83] H. Sies, C. Berndt, and D. P. Jones, “Oxidative Stress,” Annual Review of Biochemistry 86 (2017): 715–748.

[84] E. Casper, “The Crosstalk Between Nrf2 and NF-κB Pathways in Coronary Artery Disease: Can It be Regulated by SIRT6?,” Life Sciences 330 (2023): 122007.

[85] S. Reuter, S. C. Gupta, M. M. Chaturvedi, and B. B. Aggarwal, “Oxidative Stress, Inflammation, and Cancer: How Are They Linked?,” Free Radical Biology and Medicine 49, no. 11 (2010): 1603–1616.

[86] B. D. Freudenthal, W. A. Beard, L. Perera, et al., “Uncovering the Polymerase-Induced Cytotoxicity of an Oxidized Nucleotide,” Nature 517, no. 7536 (2015): 635–639.

[87] H. E. Krokan and M. Bjørås, “Base Excision Repair,” Cold Spring Harbor Perspectives in Biology 5, no. 4 (2013): a012583.

[88] A. Prasad and A. Kanakkanthara, “An ATM D-compartmentalization in DNA Damage Response,” Trends in Cell Biology 34, no. 3 (2024): 173–175.

[89] C. Cirotti, S. Rizza, P. Giglio, et al., “Redox Activation of ATM Enhances GSNOR Translation to Sustain Mitophagy and Tolerance to Oxidative Stress,” Embo Reports 22, no. 1 (2021): e50500.

[90] A. Nandi and D. K. Chowdhuri, “Cadmium Mediated Redox Modulation in Germline Stem Cells Homeostasis Affects Reproductive Health of Drosophila Males,” Journal of Hazardous Materials 402 (2021): 123737.

[91] L. Zheng, B. Tsai, and N. Gao, “Structural and Mechanistic Insights Into the DNA Glycosylase AAG-Mediated Base Excision in Nucleosome,” Cell Discovery 9, no. 1 (2023): 62.

[92] J. Y. Hahm, J. Park, E.-S. Jang, and S. W. Chi, “8-Oxoguanine: From Oxidative Damage to Epigenetic and Epitranscriptional Modification,” Experimental & Molecular Medicine 54, no. 10 (2022): 1626–1642.

[93] H. E. Poulsen, E. Specht, K. Broedbaek, et al., “RNA Modifications by Oxidation: A Novel Disease Mechanism?,” Free Radical Biology and Medicine 52, no. 8 (2012): 1353–1361.

[94] M. Pagès-Gallego, K. van Soest D M, N. J. M. Besselink, et al., “Direct Detection of 8-oxo-dG Using Nanopore Sequencing,” Nature Communications 16, no. 1 (2025): 5236.

[95] A. M. Fleming, Y. Ding, and C. J. Burrows, “Oxidative DNA Damage Is Epigenetic by Regulating Gene Transcription via Base Excision Repair,” PNAS 114, no. 10 (2017): 2604–2609.

[96] D. V. Maltseva, A. A. Baykov, A. Jeltsch, and E. S. Gromova, “Impact of 7,8-Dihydro-8-oxoguanine on Methylation of the CpG Site by Dnmt3a,” Biochemistry 48, no. 6 (2009): 1361–1368.

[97] V. Valinluck, H.-H. Tsai, D. K. Rogstad, et al., “Oxidative Damage to Methyl-CpG Sequences Inhibits the Binding of the Methyl-CpG Binding Domain (MBD) of Methyl-CpG Binding Protein 2 (MeCP2),” Nucleic Acids Research 32, no. 14 (2004): 4100–4108.

[98] X. Zhou, Z. Zhuang, W. Wang, et al., “OGG1 is Essential in Oxidative Stress Induced DNA Demethylation,” Cell Signalling 28, no. 9 (2016): 1163–1171.

[99] C. López-Otín, M. A. Blasco, L. Partridge, et al., “Hallmarks of Aging: An Expanding Universe,” Cell 186, no. 2 (2023): 243–278.

[100] M. Radzinski, T. Oppenheim, N. Metanis, and D. Reichmann, “The Cys Sense: Thiol Redox Switches Mediate Life Cycles of Cellular Proteins,” Biomolecules 11, no. 3 (2021): 469.

[101] S. Hanzén, K. Vielfort, J. Yang, et al., “Lifespan Control by Redox-Dependent Recruitment of Chaperones to Misfolded Proteins,” Cell 166, no. 1 (2016): 140–151.

[102] L. J. Alcock, M. V. Perkins, and J. M. Chalker, “Chemical Methods for Mapping Cysteine Oxidation,” Chemical Society Reviews 47, no. 1 (2018): 231–268.

[103] A. Ulfig and U. Jakob, “Cellular Oxidants and the Proteostasis Network: Balance Between Activation and Destruction,” Trends in Biochemical Sciences 49, no. 9 (2024): 761–774.

[104] S.-M. Hwang, S. Chang, P. C. Rodriguez, and J. R. Cubillos-Ruiz, “Endoplasmic Reticulum Stress Responses in Anticancer Immunity,” Nature Reviews Cancer 25, no. 9 (2025): 684–702.

[105] J. Pei, X. Pan, G. Wei, and Y. Hua, “Research Progress of Glutathione Peroxidase Family (GPX) in Redoxidation,” Frontiers in Pharmacology 14 (2023): 1147414.

[106] L. Wang and C.-C. Wang, “Oxidative Protein Folding Fidelity and Redoxtasis in the Endoplasmic Reticulum,” Trends in Biochemical Sciences 48, no. 1 (2023): 40–52.

[107] H. A. Bustamante, A. E. González, C. Cerda-Troncoso, et al., “Interplay Between the Autophagy-Lysosomal Pathway and the Ubiquitin-Proteasome System: A Target for Therapeutic Development in Alzheimer's Disease,” Frontiers in Cellular Neuroscience 12 (2018): 126.

[108] E. Desideri, G. Filomeni, and M. R. Ciriolo, “Glutathione Participates in the Modulation of Starvation-Induced Autophagy in Carcinoma Cells,” Autophagy 8, no. 12 (2012): 1769–1781.

[109] D. Denton and S. Kumar, “Autophagy-Dependent Cell Death,” Cell Death and Differentiation 26, no. 4 (2018): 605–616.

[110] Z. Qi, W. Yang, B. Xue, et al., “ROS-Mediated Lysosomal Membrane Permeabilization and Autophagy Inhibition Regulate Bleomycin-Induced Cellular Senescence,” Autophagy 20, no. 9 (2024): 2000–2016.

[111] T. Shibata, K. Shimizu, K. Hirano, et al., “Adductome-Based Identification of Biomarkers for Lipid Peroxidation,” Journal of Biological Chemistry 292, no. 20 (2017): 8223–8235.

[112] E. Gianazza, M. Brioschi, A. M. Fernandez, and C. Banfi, “Lipoxidation in Cardiovascular Diseases,” Redox Biology 23 (2019): 101119.

[113] P. Wójcik, A. Gęgotek, N. Žarković, and E. Skrzydlewska, “Oxidative Stress and Lipid Mediators Modulate Immune Cell Functions in Autoimmune Diseases,” International Journal of Molecular Sciences 22, no. 2 (2021): 723.

[114] Y. Zheng, J. Sun, Z. Luo, et al., “Emerging Mechanisms of Lipid Peroxidation in Regulated Cell Death and Its Physiological Implications,” Cell Death & Disease 15, no. 11 (2024): 859.

[115] M. Kist and D. Vucic, “Cell Death Pathways: Intricate Connections and Disease Implications,” Embo Journal 40, no. 5 (2021): e106700.

[116] S. S. Davies, A. V. Pontsler, G. K. Marathe, et al., “Oxidized Alkyl Phospholipids Are Specific, High Affinity Peroxisome Proliferator-Activated Receptor Gamma Ligands and Agonists,” Journal of Biological Chemistry 276, no. 19 (2001): 16015–16023.

[117] J.-P. Després and I. Lemieux, “Abdominal Obesity and Metabolic Syndrome,” Nature 444, no. 7121 (2006): 881–887.

[118] S.-K. Myung, W. Ju, B. Cho, et al., “Efficacy of Vitamin and Antioxidant Supplements in Prevention of Cardiovascular Disease: Systematic Review and Meta-Analysis of Randomised Controlled Trials,” Bmj 346 (2013): f10.

[119] D. Farhat and H. Lincet, “Lipoic Acid a Multi-Level Molecular Inhibitor of Tumorigenesis,” Biochimica et Biophysica Acta (BBA) – Reviews on Cancer 1873, no. 1 (2019): 188317.

[120] K. Borowiec, A. Stachniuk, D. Szwajgier, and A. Trzpil, “Polyphenols Composition and the Biological Effects of Six Selected Small Dark Fruits,” Food Chemistry 391 (2022): 133281.

[121] T. Bohn, E. Balbuena, H. Ulus, et al., “Carotenoids in Health as Studied by Omics-Related Endpoints,” Advances in Nutrition 14, no. 6 (2023): 1538–1578.

[122] K. D. Copps and M. F. White, “Regulation of Insulin Sensitivity by Serine/Threonine Phosphorylation of Insulin Receptor Substrate Proteins IRS1 and IRS2,” Diabetologia 55, no. 10 (2012): 2565–2582.

[123] M. Sharma and C. S. Dey, “AKT ISOFORMS-AS160-GLUT4: The Defining Axis of Insulin Resistance,” Reviews in Endocrine & Metabolic Disorders 22, no. 4 (2021): 973–986.

[124] J. Sastre, S. Pérez, L. Sabater, and S. Rius-Pérez, “Redox Signaling in the Pancreas in Health and Disease,” Physiological Reviews 105, no. 2 (2024): 593–650.

[125] L. Dilworth, D. Stennett, A. Facey, et al., “Diabetes and the Associated Complications: The Role of Antioxidants in Diabetes Therapy and Care,” Biomedicine & Pharmacotherapy 181 (2024): 117641.

[126] Q. Kang and C. Yang, “Oxidative Stress and Diabetic Retinopathy: Molecular Mechanisms, Pathogenetic Role and Therapeutic Implications,” Redox Biology 37 (2020): 101799.

[127] M. A. Hill, Y. Yang, L. Zhang, et al., “Insulin Resistance, Cardiovascular Stiffening and Cardiovascular Disease,” Metabolism 119 (2021): 154766.

[128] M. A. Hill, F. Jaisser, and J. R. Sowers, “Role of the Vascular Endothelial Sodium Channel Activation in the Genesis of Pathologically Increased Cardiovascular Stiffness,” Cardiovascular Research 118, no. 1 (2022): 130–140.

[129] A. R. Aroor, S. McKarns, V. G. Demarco, et al., “Maladaptive Immune and Inflammatory Pathways Lead to Cardiovascular Insulin Resistance,” Metabolism 62, no. 11 (2013): 1543–1552.

[130] K. K. Griendling, L. L. Camargo, F. J. Rios, et al., “Oxidative Stress and Hypertension,” Circulation Research 128, no. 7 (2021): 993–1020.

[131] A. A. da Silva, J. M. do Carmo, X. Li, et al., “Role of Hyperinsulinemia and Insulin Resistance in Hypertension: Metabolic Syndrome Revisited,” Canadian Journal of Cardiology 36, no. 5 (2020): 671–682.

[132] S. Saez-Atienzar and E. Masliah, “Cellular Senescence and Alzheimer Disease: The Egg and the Chicken Scenario,” Nature Reviews Neuroscience 21, no. 8 (2020): 433–444.

[133] A. Pezone, F. Olivieri, M. V. Napoli, et al., “Inflammation and DNA Damage: Cause, Effect or Both,” Nature Reviews Rheumatology 19, no. 4 (2023): 200–211.

[134] N. Y. Ngoi, A. Q. Liew, S. J. F. Chong, et al., “The Redox-Senescence Axis and Its Therapeutic Targeting,” Redox Biology 45 (2021): 102032.

[135] X. Hao, C. Wang, and R. Zhang, “Chromatin Basis of the Senescence-Associated Secretory Phenotype,” Trends in Cell Biology 32, no. 6 (2022): 513–526.

[136] A. Salminen, A. Kauppinen, and K. Kaarniranta, “Emerging Role of NF-κB Signaling in the Induction of Senescence-Associated Secretory Phenotype (SASP),” Cell Signalling 24, no. 4 (2011): 835–845.

[137] L. S. Melo Dos Santos, M. Trombetta-Lima, B. Eggen, and M. Demaria, “Cellular Senescence in Brain Aging and Neurodegeneration,” Ageing Research Reviews 93 (2023): 102141.

[138] R. M. Liu, “Aging, Cellular Senescence, and Alzheimer's Disease,” International Journal of Molecular Sciences 23, no. 4 (2022): 1989.

[139] M. Xu, E. W. Bradley, M. M. Weivoda, et al., “Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice,” Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 72, no. 6 (2017): 780–785.

[140] M. Wan, E. F. Gray-Gaillard, and J. H. Elisseeff, “Cellular Senescence in Musculoskeletal Homeostasis, Diseases, and Regeneration,” Bone Research 9, no. 1 (2021): 41.

[141] J. Riegger, A. Schoppa, L. Ruths, et al., “Oxidative Stress as a Key Modulator of Cell Fate Decision in Osteoarthritis and Osteoporosis: A Narrative Review,” Cellular & Molecular Biology Letters 28, no. 1 (2023): 76.

[142] D. Li, Q. Yu, R. Wu, et al., “Interactions Between Oxidative Stress and Senescence in Cancer: Mechanisms, Therapeutic Implications, and Future Perspectives,” Redox Biology 73 (2024): 103208.

[143] X. Liang, J. Weng, Z. You, et al., “Oxidative Stress in Cancer: From Tumor and Microenvironment Remodeling to Therapeutic Frontiers,” Molecular Cancer 24, no. 1 (2025): 219.

[144] J. D. Hayes, A. T. Dinkova-Kostova, and K. D. Tew, “Oxidative Stress in Cancer,” Cancer Cell 38, no. 2 (2020): 167–197.

[145] J. N. Moloney and T. G. Cotter, “ROS Signalling in the Biology of Cancer,” Seminars in Cell & Developmental Biology 80 (2017): 50–64.

[146] P. Saharinen, L. Eklund, K. Pulkki, et al., “VEGF and Angiopoietin Signaling in Tumor Angiogenesis and Metastasis,” Trends in Molecular Medicine 17, no. 7 (2011): 347–362.

[147] S. Kiri and T. Ryba, “Cancer, Metastasis, and the Epigenome,” Molecular Cancer 23, no. 1 (2024): 154.

[148] J. Jiang, K. Wang, Y. Chen, et al., “Redox Regulation in Tumor Cell Epithelial-Mesenchymal Transition: Molecular Basis and Therapeutic Strategy,” Signal Transduction and Targeted Therapy 2 (2017): 17036.

[149] C. Glorieux, S. Liu, D. Trachootham, and P. Huang, “Targeting ROS in Cancer: Rationale and Strategies,” Nature Reviews Drug Discovery 23, no. 8 (2024): 583–606.

[150] N. V. Ivanisenko, K. Seyrek, L. K. Hillert-Richter, et al., “Regulation of Extrinsic Apoptotic Signaling by c-FLIP: Towards Targeting Cancer Networks,” Trends in Cancer 8, no. 3 (2021): 190–209.

[151] L. Dorstyn, C. W. Akey, and S. Kumar, “New Insights Into Apoptosome Structure and Function,” Cell Death and Differentiation 25, no. 7 (2018): 1194–1208.

[152] Y. Wang, H. Qi, Y. Liu, et al., “The Double-Edged Roles of ROS in Cancer Prevention and Therapy,” Theranostics 11, no. 10 (2021): 4839–4857.

[153] Q. Zhou, Y. Meng, D. Li, et al., “Ferroptosis in Cancer: From Molecular Mechanisms to Therapeutic Strategies,” Signal Transduction and Targeted Therapy 9, no. 1 (2024): 55.

[154] J. Tschopp and K. Schroder, “NLRP3 Inflammasome Activation: The Convergence of Multiple Signalling Pathways on ROS Production?,” Nature Reviews Immunology 10, no. 3 (2010): 210–215.

[155] J. Wang, Z. Wu, M. Zhu, et al., “ROS Induced Pyroptosis in Inflammatory Disease and Cancer,” Frontiers in Immunology 15 (2024): 1378990.

[156] E. Dubois-Deruy, V. Peugnet, A. Turkieh, and F. Pinet, “Oxidative Stress in Cardiovascular Diseases,” Antioxidants 9, no. 9 (2020): 864.

[157] J. H. Yi, D. H. Kim, T. M. Piers, et al., “Postsynaptic p47phox Regulates Long-Term Depression in the Hippocampus,” Cell Discovery 4 (2018): 44.

[158] W. Zhang, W. Li, J. Du, et al., “Dnmt3a-Mediated Hypermethylation of FoxO3 Promotes Redox Imbalance During Osteoclastogenesis,” PNAS 122, no. 12 (2025): e2418023122.

[159] S. Jin, L. Zhu, R. Bao, et al., “Helicobacter Hepaticus Promotes Hepatic Steatosis Through CdtB-Induced Mitochondrial Stress and Lipid Metabolism Reprogramming,” Nature Communications 16, no. 1 (2025): 7954.

[160] B. Halliwell, “Understanding Mechanisms of Antioxidant Action in Health and Disease,” Nature Reviews Molecular Cell Biology 25, no. 1 (2023): 13–33.

[161] J. Zuo, Z. Zhang, M. Luo, et al., “Redox Signaling at the Crossroads of Human Health and Disease,” MedComm 3, no. 2 (2022): e127.

[162] D. Albanes, O. P. Heinonen, P. R. Taylor, et al., “Alpha-Tocopherol and Beta-Carotene Supplements and Lung Cancer Incidence in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: Effects of Base-Line Characteristics and Study Compliance,” JNCI: Journal of the National Cancer Institute 88, no. 21 (1996): 1560–1570.

[163] H. Al-Madhagi and A. Masoud, “Limitations and Challenges of Antioxidant Therapy,” Phytotherapy Research 38, no. 12 (2024): 5549–5566.

[164] A. G. Pearson, J. M. Pullar, J. Cook, et al., “Peroxiredoxin 2 Oxidation Reveals Hydrogen Peroxide Generation Within Erythrocytes During High-Dose Vitamin C Administration,” Redox Biology 43 (2021): 101980.

[165] D. Praticò, “Evidence of Oxidative Stress in Alzheimer's Disease Brain and Antioxidant Therapy: Lights and Shadows,” Annals of the New York Academy of Sciences 1147 (2008): 70–78.

[166] A. Lloret, M.-C. Badía, N. J. Mora, et al., “Vitamin E Paradox in Alzheimer's Disease: It Does Not Prevent Loss of Cognition and May Even be Detrimental,” Journal of Alzheimer's Disease 17, no. 1 (2009): 143–149.

[167] X. G. Lei, J.-H. Zhu, W.-H. Cheng, et al., “Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications,” Physiological Reviews 96, no. 1 (2016): 307–364.

[168] D. D. Zhang, “Thirty Years of NRF2: Advances and Therapeutic Challenges,” Nature Reviews Drug Discovery 24, no. 6 (2025): 421–444.

[169] A. R. Mallard, J. G. Spathis, and J. S. Coombes, “Nuclear Factor (Erythroid-Derived 2)-Like 2 (Nrf2) and Exercise,” Free Radical Biology and Medicine 160 (2020): 471–479.

[170] L. Ma, K. Li, W. Wei, et al., “Exercise Protects Aged Mice Against Coronary Endothelial Senescence via FUNDC1-Dependent Mitophagy,” Redox Biology 62 (2023): 102693.

[171] D. de Zeeuw, T. Akizawa, P. Audhya, et al., “Bardoxolone Methyl in Type 2 Diabetes and Stage 4 Chronic Kidney Disease,” New England Journal of Medicine 369, no. 26 (2013): 2492–2503.

[172] S. Gopal, A. Mikulskis, R. Gold, et al., “Evidence of Activation of the Nrf2 Pathway in Multiple Sclerosis Patients Treated With Delayed-Release Dimethyl Fumarate in the Phase 3 DEFINE and CONFIRM Studies,” Multiple Sclerosis 23, no. 14 (2017): 1875–1883.

[173] K. L. Madsen, A. E. Buch, B. H. Cohen, et al., “Safety and Efficacy of Omaveloxolone in Patients With Mitochondrial Myopathy: MOTOR Trial,” Neurology 94, no. 7 (2020): e687–e698.

[174] M. Ribeiro, L. Alvarenga, K. S. Coutinho-Wolino, et al., “Sulforaphane Upregulates the mRNA Expression of NRF2 and NQO1 in Non-Dialysis Patients With Chronic Kidney Disease,” Free Radical Biology and Medicine 221 (2024): 181–187.

[175] M. Ge, H. Chen, Q. Zhu, et al., “Propofol Post-Conditioning Alleviates Hepatic Ischaemia Reperfusion Injury via BRG1-Mediated Nrf2/HO-1 Transcriptional Activation in Human and Mice,” Journal of Cellular and Molecular Medicine 21, no. 12 (2017): 3693–3704.

[176] H. Zhang, K. J. A. Davies, and H. J. Forman, “Oxidative Stress Response and Nrf2 Signaling in Aging,” Free Radical Biology and Medicine 88, no. Pt B (2015): 314–336.

[177] T. Zakic, J. Jevtic, M. Vukobratovic, et al., “Nrf2-Driven Redox Coupling of Tumour and Associated Adipose Tissue During Early Tumour Growth in an Orthotopic Breast Cancer Model,” Free Radical Biology and Medicine 239 (2025): 63–79.

[178] M. Che, W. Wei, X. Yang, et al., “Radiation-Induced Upregulation of Itaconate in Macrophages Promotes the Radioresistance of Non-Small Cell Lung Cancer by Stabilizing NRF2 Protein and Suppressing Immune Response,” Redox Biology 85 (2025): 103711.

[179] D. Ren, N. F. Villeneuve, T. Jiang, et al., “Brusatol Enhances the Efficacy of Chemotherapy by Inhibiting the Nrf2-Mediated Defense Mechanism,” PNAS 108, no. 4 (2011): 1433–1438.

[180] Y. Li, W. Chen, J. Yin, et al., “Biomineralized ZIF-8 Encapsulating SOD From Hydrogenobacter Thermophilus: Maintaining Activity in the Intestine and Alleviating Intestinal Oxidative Stress,” Small 20, no. 50 (2024): e2402812.

[181] J. Yayun, G. Qianqian, S. Xihang, et al., “Metal-Organic Framework-Mediated Antioxidant Enzyme Delivery in Disease Treatment,” Redox Biology 85 (2025): 103778.

[182] R. Zhang, B. Jiang, K. Fan, et al., “Designing Nanozymes for in Vivo Applications,” Nature Reviews Bioengineering 2, no. 10 (2024): 849–868.

[183] W. Won, E. H. Lee, L. Gotina, et al., “Hemoglobin as a Pseudoperoxidase and Drug Target for Oxidative Stress-Related Diseases,” Signal Transduction and Targeted Therapy 10, no. 1 (2025): 270.

[184] J. Bolaños-Cardet, B. Pepió-Tárrega, J. Saiz-Poseu, et al., “The Redox Properties of Polyphenols and Their Role in ROS Generation for Biomedical Applications,” Angewandte Chemie 65, no. 3 (2026): e13698.

[185] J. R. Chong, C. de Lucia, D. A. Tovar-Rios, et al., “A Randomised, Double-Blind, Placebo-Controlled, Cross-Over Clinical Trial to Evaluate the Biological Effects and Safety of a Polyphenol Supplement on Healthy Ageing,” Antioxidants 13, no. 8 (2024): 995.

[186] B. Salehi, Y. Berkay Yılmaz, G. Antika, et al., “Insights on the Use of α-Lipoic Acid for Therapeutic Purposes,” Biomolecules 9, no. 8 (2019): 356.

[187] A. Solmonson and R. J. DeBerardinis, “Lipoic Acid Metabolism and Mitochondrial Redox Regulation,” Journal of Biological Chemistry 293, no. 20 (2017): 7522–7530.

[188] R. I. Spain, M. M. Paz Soldán, M. S. Freedman, et al., “Lipoic Acid for Treatment of Progressive Multiple Sclerosis: A Phase 2 Randomized Clinical Trial,” Neurology 106, no. 1 (2025): e214454.

[189] E. Domínguez-Álvarez, B. Rácz, M. A. Marć, et al., “Selenium and Tellurium in the Development of Novel Small Molecules and Nanoparticles as Cancer Multidrug Resistance Reversal Agents,” Drug Resistance Updates 63 (2022): 100844.

[190] S. Menon, S. D. Ks, R. Santhiya, et al., “Selenium Nanoparticles: A Potent Chemotherapeutic Agent and an Elucidation of Its Mechanism,” Colloids and Surfaces B, Biointerfaces 170 (2018): 280–292.

[191] J. S. Walsh, R. M. Jacques, L. Schomburg, et al., “Effect of Selenium Supplementation on Musculoskeletal Health in Older Women: A Randomised, Double-Blind, Placebo-Controlled Trial,” Lancet Healthy Longev 2, no. 4 (2021): e212–e221.

[192] B. Pedre, U. Barayeu, D. Ezeriņa, and T. P. Dick, “The Mechanism of Action of N-acetylcysteine (NAC): The Emerging Role of H2S and Sulfane Sulfur Species,” Pharmacology & Therapeutics 228 (2021): 107916.

[193] D. Ezeriņa, Y. Takano, K. Hanaoka, et al., “N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production,” Cell Chemical Biology 25, no. 4 (2018): 447–459.e4.

[194] Y. Zhou, F. Wu, Z. Shi, et al., “Effect of High-Dose N-Acetylcysteine on Exacerbations and Lung Function in Patients With Mild-to-Moderate COPD: A Double-Blind, Parallel Group, Multicentre Randomised Clinical Trial,” Nature Communications 15, no. 1 (2024): 8468.

[195] Y. Kato, M. Iwase, S. Ichihara, et al., “Beneficial Effects of Growth Hormone-Releasing Peptide on Myocardial Oxidative Stress and Left Ventricular Dysfunction in Dilated Cardiomyopathic Hamsters,” Circulation Journal 74, no. 1 (2009): 163–170.

[196] T. Brioche, R. A. Kireev, S. Cuesta, et al., “Growth Hormone Replacement Therapy Prevents Sarcopenia by a Dual Mechanism: Improvement of Protein Balance and of Antioxidant Defenses,” Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 69, no. 10 (2013): 1186–1198.

[197] Y. Gong, K. Zhang, D. Xiong, et al., “Growth Hormone Alleviates Oxidative Stress and Improves the IVF Outcomes of Poor Ovarian Responders: A Randomized Controlled Trial,” Reproductive Biology and Endocrinology 18, no. 1 (2020): 91.

[198] L. Zhang, Y. Lu, H. Jiang, et al., “Additional Use of Trimetazidine in Patients With Chronic Heart Failure: A Meta-Analysis,” Journal of the American College of Cardiology 59, no. 10 (2012): 913–922.

[199] A. van Eijk R P, F. J. Steyn, M. R. Janse van Mantgem, et al., “An Open-Label Phase 2a Study to Assess the Safety and Tolerability of Trimetazidine in Patients With Amyotrophic Lateral Sclerosis,” Brain Communications 7, no. 1 (2025): fcaf063.

[200] H. Geng, Q.-Z. Zhong, J. Li, et al., “Metal Ion-Directed Functional Metal-Phenolic Materials,” Chemical Reviews 122, no. 13 (2022): 11432–11473.

[201] H. Deng, Y. Qu, B. Chu, et al., “Macrophage Membrane-Biomimetic ROS-Responsive Platinum Nanozyme Clusters for Acute Kidney Injury Treatment,” Biomaterials 317 (2024): 123072.

[202] Q. Wang, X. Peng, X. Gao, et al., “Peptide-Oligonucleotide Nanohybrids Designed for Precise Gene Therapy of Rheumatoid Arthritis,” Advanced Materials 37, no. 18 (2025): e2500883.

[203] X. Zhao, Y. Yu, X. Xu, et al., “Machine Learning-Assisted High-Throughput Screening of Nanozymes for Ulcerative Colitis,” Advanced Materials 37, no. 9 (2025): e2417536.

[204] F. Dai, J. Zhang, F. Chen, et al., “A Multi-Responsive Hydrogel Combined With Mild Heat Stimulation Promotes Diabetic Wound Healing by Regulating Inflammatory and Enhancing Angiogenesis,” Advanced Science 11, no. 46 (2024): e2408783.

[205] G. Block, C. D. Jensen, J. D. Morrow, et al., “The Effect of Vitamins C and E on Biomarkers of Oxidative Stress Depends on Baseline Level,” Free Radical Biology and Medicine 45, no. 4 (2008): 377–384.

[206] S. Quattrini, S. Gatti, A. Palpacelli, et al., “P549 Oxidative Stress and Antioxidant Capacity Biomarkers in Adults and Children With IBD: Current Update From OxIBDiet Trial,” Journal of Crohn's and Colitis 16, no. supplement S1 (2022): i496.

[207] D. Ho, S. R. Quake, E. R. B. McCabe, et al., “Enabling Technologies for Personalized and Precision Medicine,” Trends in Biotechnology 38, no. 5 (2020): 497–518.

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