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Targeting oxidative stress in disease: promise and limitations of antioxidant therapy

Nature Reviews Drug Discovery volume 20, pages 689–709 (2021)Cite this article

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An Author Correction to this article was published on 13 July 2021

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Abstract

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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Fig. 1: Reactive species in the extracellular space and defences by SOD or catalase mimics and NOX inhibitors.
Fig. 2: Glutathione metabolism and strategies to increase glutathione.
Fig. 3: NRF2 signalling pathway and antioxidant therapeutic approaches.

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Acknowledgements

The authors thank their many colleagues with whom conversations and collaborations concerning antioxidants have occurred over decades. The authors’ work in this area was supported by several past NIH grants and currently by P01 AG055367.

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  1. University of California Merced, Merced, CA, USA

    Henry Jay Forman

  2. Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA

    Henry Jay Forman & Hongqiao Zhang

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Glossary

Oxidative stress

Imbalance between generation of oxidants and the ability to prevent oxidative damage favouring the latter process.

Redox signalling

Signal transduction in which oxidants act as second messengers.

Antioxidant defence

Prevention or repair of oxidative damage.

Antioxidant enzymes

Strictly, enzymes that remove oxidants; broadly, enzymes that contribute to the prevention or repair of oxidative damage. The broader definition is used in this Review.

NRF2 transcription factor

Nuclear factor E2-related factor 2, which coordinates both the baseline and stress-inducible activation of a great many antioxidant enzymes.

Antioxidant therapy

Treatment with agents that enhance antioxidant defence.

Pneumonitis

Inflammation of the lungs caused by irritation of lung tissue, disease, infection, radiation therapy or allergy.

Ischaemia–reperfusion

Cessation followed by restoration of blood flow.

Autophagy

A mechanism through which unnecessary or damaged cellular components are degraded.

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Forman, H.J., Zhang, H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov 20, 689–709 (2021). https://doi.org/10.1038/s41573-021-00233-1

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