Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy
Open accessAbstract
Oxidative stress is a component of many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer disease and cancer. Although numerous small molecules evaluated as antioxidants have exhibited therapeutic potential in preclinical studies, clinical trial results have been disappointing. A greater understanding of the mechanisms through which antioxidants act and where and when they are effective may provide a rational approach that leads to greater pharmacological success. Here, we review the relationships between oxidative stress, redox signalling and disease, the mechanisms through which oxidative stress can contribute to pathology, how antioxidant defences work, what limits their effectiveness and how antioxidant defences can be increased through physiological signalling, dietary components and potential pharmaceutical intervention.
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NO crosses the membranes of parenchymal cells, elevating the synthesis of intracellular GSH, thereby improving the parenchymal cells' capacity to combat oxidative stress, maintain intracellular redox homeostasis, and secure the stability of cell cycle regulation, cellular proliferation, and overall physiological functions.
“The resulting NO crosses the membranes of parenchymal cells, elevating the synthesis of intracellular GSH, thereby improving the parenchymal cells’ capacity to combat oxidative stress, maintain intracellular redox homeostasis, and secure the stability of cell cycle regulation, cellular proliferation, and overall physiological functions.”
From Decellularized liver scaffolds for constructing drug-metabolically functional ex vivo human liver models (2025) · cites this paper as [50]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredNO, as a lipophilic small molecule, can directly diffuse into hepatocytes, where an elevation within a certain range can enhance the enzymatic activity of glutamate-cysteine ligase within the liver cells, leading to the production of higher levels of GSH and mitigating the increase in intracellular oxidative stress products, thereby enhancing cellular functions.
“NO, as a lipophilic small molecule, can directly diffuse into hepatocytes, where an elevation within a certain range can enhance the enzymatic activity of glutamate-cysteine ligase within the liver cells, leading to the production of higher levels of GSH and mitigating the increase in intracellular oxidative stress products, thereby enhancing cellular functions [49,50].”
From Decellularized liver scaffolds for constructing drug-metabolically functional ex vivo human liver models (2025) · cites this paper as [50]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredOxidative stress is a component of many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer's disease and cancer.
“Oxidative stress is a component of many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer’s disease and cancer, among others [2].”
From Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity (2023) · cites this paper as [2]
Evidence of efficacy of natural antioxidant compounds has been limited possibly due to poor bioavailability or treatment timing.
“evidence of their efficacy has been quite limited thus far possibly due to a poor bioavailability or to the time point in which the treatment is undertaken (Forman and Zhang, 2021)”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Forman and Zhang, 2021
Ebselen and its modified analog BXT-51072 delay neurological deficits and acute ischemic stroke, inhibit the inflammatory response, suppress oxidative damage, and have other beneficial oxidative stress-reducing properties.
“This compound and its modified analog BXT-51072 were able to delay neurological deficits, and acute ischemic stroke, inhibit the inflammatory response, suppress oxidative damage, and other beneficial oxidative stress-reducing properties (Forman and Zhang 2021).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Forman and Zhang 2021
Apart from vitamin E, other antioxidants such as carotenoids, ascorbic acid, and flavonoids have been shown to have a very mild effect on preventing oxidative damage.
“With respect to antioxidant interventions, apart from vitamin E, other antioxidants such as carotenoids, ascorbic acid, and flavonoids have been shown to have a very mild effect on preventing oxidative damage (Halliwell 2020; Forman and Zhang 2021; Mangione et al. 2022).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Forman and Zhang 2021
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References 302 · Cited by 2,900
Research works printed but not linked: 4
- [1]Sies, H. Oxidative Stress (ed. Sies, H.) 1–8 (Academic Press, 1985). This article introduces the concept of oxidative stress.
- [74]Chakraborty, R. K. & Burns, B. Systemic Inflammatory Response Syndrome (StatPearls 2020). 31613449
- [225]Maxfield, L. & Crane, J. S. Vitamin C Deficiency. StatPearls [online] https://www.ncbi.nlm.nih.gov/books/NBK493187/ (updated 2 Jul 2020).
- [249]Bianca R Superoxide dismutase mimetic with catalase activity, EUK-134, attenuates the multiple organ injury and dysfunction caused by endotoxin in the rat Med. Sci. Monit. 2002 8 BR1 BR7 11796957
- Authors
- Forman, H. J., & Zhang, H.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Forman, Henry Jay
- Venue
- Nature Reviews Drug Discovery
- Published
- 2021-06-30
- Volume
- 20
- Issue
- 9
- Pages
- 689-709
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- PMC
- PMC8243062
- OpenAlex
- W3173948537
- Cited by
- 2,900
- References
- 302
- Citations by year
- 2026: 499 · 2025: 699 · 2024: 723 · 2023: 571 · 2022: 358 · 2021: 49
- FWCI
- 38.67
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-07-13)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (AG055367)
- National Institute on Aging (P01AG055367)
- Topics
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Keywords
- oxidative stress, antioxidant therapy, redox signaling, antioxidant defense, atherosclerosis, chronic obstructive pulmonary disease, Alzheimer's disease, cancer, dietary antioxidants, clinical trial limitations, pharmacological interventions
- MeSH terms
- Drug Development, Animals, Antioxidants, Drug Evaluation, Preclinical, Humans, Oxidation-Reduction, Signal Transduction, Oxidative Stress, Molecular Targeted Therapy
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