Oxidative stress is a shared characteristic of ME/CFS and Long COVID.
Shankar, Vishnu, Wilhelmy, Julie, Curtis, Ellis J et al. · Proceedings of the National Academy of Sciences of the United States of America · 2025 · DOI
Quick Summary
Researchers found that both ME/CFS and Long COVID patients have higher levels of oxidative stress—a harmful buildup of unstable molecules—in their immune cells, particularly in a type of white blood cell called memory T cells. The study identified specific problems with how the body clears this oxidative stress and showed that the existing medication metformin might help reduce overgrowth of these immune cells. Importantly, they discovered these problems show different patterns in men and women, suggesting that sex-specific treatment approaches may be needed.
Why It Matters
This study provides the first molecular evidence that ME/CFS and Long COVID share an underlying oxidative stress mechanism, validating the clinical observation that these conditions are similar. Identifying metformin as a potential treatment with sex-specific efficacy offers a concrete lead for clinical trials and suggests a path toward precision medicine approaches. Understanding these mechanisms could enable development of better diagnostic blood tests and more targeted therapies for both conditions.
Observed Findings
- Both ME/CFS and Long COVID patients showed elevated oxidative stress markers in blood lymphocytes, with particular prominence in memory T cells.
- Males and females with ME/CFS exhibited different patterns: females had higher total reactive oxygen species (ROS) and mitochondrial calcium, while males showed normal ROS but pronounced mitochondrial lipid oxidative damage.
- Impaired ROS clearance pathways were identified, including elevated glutathione, decreased mitochondrial superoxide dismutase protein, and increased glutathione peroxidase 4-mediated lipid oxidative damage.
- In female patients, elevated ROS correlated with increased T cell hyperproliferation when lymphocytes were stimulated.
- Metformin reduced T cell hyperproliferation in laboratory assays, particularly in female samples.
Inferred Conclusions
- ME/CFS and Long COVID share a common molecular mechanism involving oxidative stress and impaired cellular antioxidant defenses.
- The redox abnormalities show sex-specific patterns that may require different therapeutic approaches for males and females.
- Metformin, an FDA-approved medication, warrants clinical investigation as a potential treatment for reducing immune cell proliferation in these conditions.
- Quantitative blood cell measurements and lymphocyte stimulation assays could serve as biomarkers for disease detection and personalized drug discovery.
Remaining Questions
- Does oxidative stress cause the symptoms of ME/CFS and Long COVID, or is it a consequence of other underlying disease processes?
- Will metformin show clinical benefit in actual ME/CFS and Long COVID patients, and do the sex-specific laboratory patterns predict treatment response in people?
- How do the redox abnormalities in blood lymphocytes relate to dysfunction in other tissues and organ systems affected by these conditions?
- Can the identified oxidative stress markers be developed into reliable clinical diagnostic tests that help differentiate ME/CFS/Long COVID from other conditions?
What This Study Does Not Prove
This study does not prove that oxidative stress is the primary cause of ME/CFS or Long COVID—it may be secondary to other pathological processes. The findings are from isolated blood cells stimulated in the laboratory, so they may not fully reflect what happens in the patient's living body. The sex-specific differences observed require larger studies to confirm and do not yet establish whether metformin will be effective in actual patients, only that it works in laboratory assays.
Topics
Tags
Metadata
- DOI
- 10.1073/pnas.2426564122
- PMID
- 40627396
- Review status
- Editor reviewed
- Evidence level
- Early hypothesis, preprint, editorial, or weak support
- Last updated
- 7 April 2026