Decreased Glutathione in COVID-19 and Viral Pathogenesis

By Tim Guilford, MD

Biological Role of Glutathione (GSH)

Glutathione (GSH) is the body’s primary intracellular antioxidant (composed of glutamate, cysteine, and glycine) concentrated heavily in the liver, lungs, and immune cells (7). It neutralizes reactive oxygen species (ROS) and regulates immune cell function to prevent hyper-inflammatory cytokine production (1–4, 7).

During neutralizations, reduced GSH oxidizes into glutathione disulfide (GSSG), which must be continuously recycled back to GSH by glutathione reductase (GSR) or synthesized anew via glutamate-cysteine ligase enzymes (GCLC/GCLM) (7, 8). This synthesis and recycling system is controlled by NRF2, the master switch for cellular antioxidant defense (6–8).

Pathophysiology in COVID-19

SARS-CoV-2 creates a cycle of sustained oxidative stress, uncontrolled inflammation, and GSH depletion through specific pathways:

  • NRF2 Suppression: SARS-CoV-2 directly inhibits NRF2 signaling in airway epithelial and lung cells, reducing expression of enzymes needed to synthesize and recycle GSH (6).
  • Cytokine Elevation: Inflammatory cytokines like IL-6 and TGF-? promote ROS generation and directly inhibit GSH synthesis pathways (1–3).
  • Cellular & Endothelial Damage: GSH depletion impairs immune cell function, causes damage to type II/I pneumocytes (limiting oxygen diffusion) (1), and drives endothelial dysfunction. This depletion directly correlates with elevated D-dimer levels and increased risk of immunothrombosis (2, 3, 18).

Clinical & Multi-Viral Evidence

  • COVID-19 Disease Severity: Clinical studies link baseline or acquired GSH deficiency directly to severe COVID-19 outcomes (2–4, 13–15, 17, 18). NIH studies showed significant intracellular GSH depletion in peripheral blood mononuclear cells (PBMCs) that persisted ? 50 days post-infection, even in mild/moderate cases, suggesting a potential role in Long COVID (5).
  • Shared Viral Pathway: NRF2 suppression and GSH depletion are common mechanisms observed in other respiratory viruses, including Influenza A and Respiratory Syncytial Virus (RSV) (6, 11, 12, 16).

Liposomal Glutathione Research

Because oral delivery of standard antioxidants often suffers from poor absorption, researchers are investigating liposomal glutathione:

  • Preclinical and clinical models show liposomal delivery restores intracellular GSH and improves immune cell function more effectively than precursors like N-acetylcysteine (NAC) alone (1).
  • In models testing SARS-CoV-2 spike protein exposure, liposomal GSH reduced pro-inflammatory cytokines and markers of immunothrombosis (9).
  • In RSV models, liposomal GSH reduced viral replication and mitigated acute lung injury (10).

References

  1. Guloyan V, Oganesian B, Baghdasaryan N, et al. Glutathione Supplementation as an Adjunctive Therapy in COVID-19. Antioxidants. 2020;9(10):937.
  2. Yegiazaryan A, Abnousian A, Alexander LJ, et al. Recent Developments in the Understanding of Immunity, Pathogenesis and Management of COVID-19. Int J Mol Sci. 2022;23(16):8972.
  3. Glassman I, Le N, Mirhosseini M, et al. The Role of Glutathione in Prevention of COVID-19 Immunothrombosis: A Review. Front Biosci (Landmark Ed). 2023;28(3):59.
  4. Polonikov A. Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS Infect Dis. 2020;6(7):1558–1562.
  5. Lage SL, Amaral EP, Hilligan KL, Laidlaw E, Rupert A, Namasivayan S, et al. Persistent Oxidative Stress and Inflammasome Activation in CD14(high)CD16(-) Monocytes From COVID-19 Patients. Front Immunol. 2021;12:799558. PMCID: PMC8795739. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8795739/
  6. Qu Y, Haas de Mello A, Morris DR, et al. SARS-CoV-2 Inhibits NRF2-Mediated Antioxidant Responses in Airway Epithelial Cells and in the Lung of a Murine Model of Infection. Microbiol Spectr. 2023;11(3):e0037823.
  7. Lu SC. Regulation of Glutathione Synthesis. Mol Aspects Med. 2009;30(1–2):42–59.
  8. Harvey CJ, Thimmulappa RK, Singh A, et al. Nrf2-regulated Glutathione Recycling Independent of Biosynthesis Is Critical for Cell Survival During Oxidative Stress. Free Radic Biol Med. 2009;46(4):443–453.
  9. Norris B, Chorbajian A, Dawi J, et al. Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced Immunothrombosis and Cytokine Dysregulation. Antioxidants. 2024;13(3):271.
  10. Gauthier TW, Ping X-D, Harris FL, Brown LAS. Liposomal Glutathione Augments Immune Defenses against Respiratory Syncytial Virus in Neonatal Mice Exposed in Utero to Ethanol. Antioxidants. 2024;13(2):137.
  11. Rashid MU, Gao A, Coombs KM. Influenza A Virus Uses PSMA2 for Downregulation of the NRF2-Mediated Oxidative Stress Response. J Virol. 2022;96(5):e0199021.
  12. Komaravelli N, Ansar M, Garofalo RP, Casola A. Respiratory Syncytial Virus Induces NRF2 Degradation Through a Promyelocytic Leukemia Protein–Ring Finger Protein 4 Dependent Pathway. Free Radic Biol Med. 2017;113:494–504.
  13. Dodson M, Shakya A, Anandhan A, et al. NRF2 and Diabetes: The Good, the Bad, and the Complex. Diabetes. 2022;71(12):2463–2476.
  14. Neagu M, Constantin C, Surcel M, et al. Diabetic Neuropathy: A NRF2 Disease? J Diabetes. 2024;16(9):e13524.
  15. Ebrahimi R, Mohammadpour A, Medoro A, et al. Exploring the Links Between Polyphenols, NRF2, and Diabetes: A Review. Biomed Pharmacother. 2025;186:118020.
  16. Kayesh MEH, Kohara M, Tsukiyama-Kohara K. Effects of Oxidative Stress on Viral Infections: An Overview. npj Viruses. 2025;3(1):27.
  17. Gregory JM, Slaughter JC, Duffus SH, et al. COVID-19 Severity Is Tripled in the Diabetes Community: A Prospective Analysis of the Pandemic’s Impact in Type 1 and Type 2 Diabetes. Diabetes Care. 2021;44(2):526–532.
  18. Georgieva E, Ananiev J, Yovchev Y, Arabadzhiev G, Abrashev H, Abrasheva D, et al. COVID-19 Complications: Oxidative Stress, Inflammation, and Mitochondrial and Endothelial Dysfunction. Int J Mol Sci. 2023;24(19). PMCID: PMC10573237. https://pmc.ncbi.nlm.nih.gov/articles/PMC10573237/