Oxidative Stress and COVID-19: A Mechanistic and Translational Review

Abstract

This review aimed to explain how oxidative stress contributes to COVID-19 pathogenesis, assess whether redox biomarkers may help predict clinical risk, and discuss whether redox-targeted therapies have a credible role in future research or care.
Evidence suggests that oxidative stress is not simply a by-product of severe infection. SARS-CoV-2 can disturb redox balance through ACE2 downregulation, angiotensin II accumulation, NADPH oxidase activation, mitochondrial injury, inflammasome signaling, endothelial dysfunction, and immunothrombosis. Together, these processes increase reactive oxygen and nitrogen species, reduce nitric oxide availability, weaken antioxidant defenses, and help connect viral pneumonia with vascular injury, microthrombosis, and multiorgan damage.
Clinical studies show that several oxidative stress markers are associated with worse COVID-19 outcomes. Higher levels of hydrogen peroxide, total oxidative stress, malondialdehyde, 8-isoprostanes, nitrotyrosine, protein carbonyls, and oxidized LDL have been linked to severe disease, ICU admission, respiratory failure, and mortality. Lower levels of glutathione, superoxide dismutase, catalase, glutathione peroxidase, and thiols suggest reduced antioxidant reserve. Even so, these markers are not ready for routine clinical use because studies differ in timing, assays, samples, patient populations, and outcomes.
Redox-related genetic variants may help explain why some patients develop greater oxidative injury, but this field remains exploratory. Persistent redox imbalance may also contribute to long COVID, especially fatigue, brain fog, cardiovascular dysfunction, dysautonomia, and exercise intolerance. Antioxidant or redox-modulating therapies, including N-acetylcysteine, vitamin C, selenium, zinc, and NRF2 activators, remain biologically plausible but clinically unproven. Future studies should use serial biomarker panels and phenotype-driven trials to identify patients most likely to benefit.