Glutathione

Overview

Glutathione, often referred to as the body’s “master antioxidant,” is a tripeptide composed of three amino acids: glutamine, cysteine, and glycine.^[1] It exists predominantly in two forms: the reduced (GSH) and oxidized (GSSG) forms, with the ratio between these two forms serving as a key indicator of the cell’s redox state.^[2] Glutathione is produced mainly in the liver and is involved in a wide variety of cellular functions, including antioxidant defense, detoxification, immune modulation, and regulation of cellular processes like apoptosis and cell division.^[3] At the biochemical level, glutathione’s core role lies in its ability to neutralize reactive oxygen species (ROS) and reactive nitrogen species (RNS) that cause oxidative damage.^[4] But beyond its antioxidant function, glutathione regulates important cellular signaling pathways by maintaining cellular redox balance.^[5] This balance is pivotal for cellular functions like DNA synthesis, protein folding, cellular signaling, and immune responses.

Glutathione in Immune Function

Glutathione also plays an active role in immune cell function, signal transduction, and cytokine regulation, and not just passive protection against oxidative stress.^[6] The levels influence both innate and adaptive immune responses.

Glutathione in Innate Immunity

The innate immune response is the body’s first line of defense against infections, involving immune cells such as neutrophils, macrophages, and dendritic cells.^[7] These cells require glutathione to perform functions like ROS production to kill pathogens and cytokine release to initiate inflammation.^[8] Neutrophils produce ROS in response to pathogen invasion. The production of these highly reactive molecules is controlled by glutathione. Excessive oxidative burst can lead to tissue damage, while inadequate ROS production compromises pathogen clearance.^[9] Glutathione, therefore, modulates the intensity of this oxidative burst to balance immune defense and minimize collateral damage. Macrophages are responsible for phagocytosing pathogens and presenting antigens to T-cells.^[10] Glutathione influences their migration, phagocytosis, and cytokine production.^[11] Low glutathione levels have been shown to impair macrophage function, making the body more susceptible to infections.^[12][13][14]

Glutathione in Adaptive Immunity

In adaptive immunity, glutathione influences the function of T-cells and B-cells. T-cells, which are essential for recognizing and eliminating infected or cancerous cells, depend on glutathione for their proliferation and activation.^[15] Adequate glutathione is necessary for the optimal proliferation of T-cells upon encountering pathogens. It regulates the production of cytokines like IL-2 and IFN-γ, which are crucial for orchestrating a Th1 immune response.^[16] In contrast, glutathione depletion leads to impaired cytokine production, resulting in weakened T-cell responses to infections.^[17] Glutathione also plays a regulatory role in immune tolerance, maintaining a balance between effective immune responses and the prevention of excessive inflammation. For example, it helps prevent autoimmune responses by modulating the function of T-regulatory cells (Tregs), which maintain immune homeostasis.^[18] Without sufficient glutathione, the balance shifts toward inflammatory Th17 responses, promoting autoimmune diseases like rheumatoid arthritis.

Nutritional Immunity and Glutathione

Nutritional immunity is a host defense strategy in which the body actively restricts access to essential nutrients that pathogens need for survival and proliferation.^[19] The term was historically coined in the context of metal sequestration, especially iron, which hosts withhold from invading microbes to limit their ability to thrive.^[20] Nutritional immunity is about competition for scarce resources: the host sequesters micronutrients (Fe, Zn, Mn, Cu) and other metabolic substrates to starve pathogens, while pathogens evolve mechanisms to overcome these defenses.^[21] Traditionally, nutritional immunity has been discussed in terms of trace metals and vitamins. Still, emerging evidence supports broadening the concept to include other nutrient and redox systems, especially those involving primary thiol redox buffers like glutathione.^[22]

Concept within Nutritional Immunity	Role of Glutathione
Nutrient Restriction as Host Defense	Glutathione modulates nutrient availability indirectly by influencing cysteine allocation. Cysteine is the rate‑limiting precursor for GSH synthesis.[23] During infection, the host prioritizes cysteine for immune cell GSH production, limiting availability to pathogens that also rely on sulfur amino acids for their own redox defenses.[24] This metabolic tug‑of‑war affects pathogen survival and replication, positioning glutathione synthesis as a major control point in redox‑related nutritional immunity.
Redox Regulation of Pathogen Survival	GSH influences the oxidative environment that pathogens face. Many pathogens require an oxidant‑tolerant state to survive.[25] GSH in host immune cells buffers excessive oxidative stress, allowing controlled ROS generation that kills pathogens without inducing systemic damage.[26] When GSH is low, ROS are either excessive (causing tissue damage) or insufficiently regulated (reducing pathogen killing).
Pathogen Redox Evasion and Adaptation	Some pathogens manipulate host GSH pathways directly or indirectly to evade immune killing. Examples include HIV’s association with systemic GSH depletion, which weakens host defense against opportunistic pathogens like M. tb, illustrating how pathogen‑driven redox changes can undermine nutritional immunity.[27]
Metal Sequestration Interactions	Although classic nutritional immunity focuses on metals, glutathione intersects these systems by maintaining host redox states that regulate metal sequestration proteins and inflammatory signaling pathways.[28] GSH ensures redox conditions favorable for optimal deployment of these metal‑withholding defenses.
Signaling for Immune Prioritization	GSH influences immune cell signaling thresholds, tipping responses toward pathogen clearance modes and fine‑tuning inflammation.[29] This ensures nutrient resources are allocated efficiently toward effective responses rather than maladaptive chronic inflammation.

Glutathione Depletion in Chronic Inflammatory Diseases

Chronic inflammatory diseases such as rheumatoid arthritis, endometriosis, and Crohn’s disease are often characterized by glutathione depletion in affected tissues.^[30] In these conditions, chronic oxidative stress leads to an imbalance between ROS production and antioxidant defenses, which contributes to tissue damage, excessive inflammation, and immune dysfunction.

In rheumatoid arthritis, for example, glutathione depletion is associated with joint inflammation, cartilage degradation, and bone erosion.^[31] The low levels of glutathione in synovial fluid impair the ability of immune cells to regulate inflammation, resulting in persistent autoimmune attacks on joint tissues.^[32][33]

In endometriosis, glutathione depletion contributes to the chronic inflammation and oxidative stress that are hallmark features of the disease.^[34] Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus, which leads to inflammation, pain, and fertility issues.^[35] The low levels of glutathione in the peritoneal fluid of women with endometriosis lead to an increase in ROS, which further exacerbates inflammation and immune dysfunction in the pelvic cavity.^[36][37] This oxidative stress disrupts the function of immune cells such as macrophages, which play a key role in tissue repair and inflammation resolution. With insufficient glutathione, macrophages become dysregulated, promoting persistent inflammation and immune dysfunction.

Pathogen Interactions with Host Glutathione Systems

Pathogens do not exist in isolation of host metabolism; many directly interact with glutathione (GSH) pathways, exploiting, resisting, or modulating them to enhance survival.^[38] These interactions form a crucial part of how nutritional immunity operates beyond metal sequestration, incorporating redox competition and nutrient flux control.

Pathogen / Group	How It Interacts with Glutathione
Mycobacterium tuberculosis	Competes with host GSH for redox balance; host GSH enhances Th1 and macrophage killing.[39][40]
Influenza virus	High GSH inhibits viral replication in host cells.[41]
SARS‑CoV‑2	Some virulence factors target thiol redox systems, including GSH.[42]
HIV	Chronic infection depletes GSH; GSH restoration improves immune responses and co‑infection control.[43]
Gram‑negative bacteria (Francisella)	GSH modulates neutrophil migration and ROS balance.

The relationship of glutathione with nutritional immunity transcends its role as a simple antioxidant. It is intricately involved in metabolic competition with pathogens, immune cell nutrient management, redox‑dependent immune modulation, and maintenance of immune efficiency under nutrient stress. Understanding these connections reframes glutathione from a cellular defender to a core component of nutritional immune strategies, with implications for infection biology, host defense, and therapeutic innovation.

Research Feed

Update History

References

1. Glutathione: A Samsonian life-sustaining small molecule that protects against oxidative stress, ageing and damaging inflammation.. Labarrere, C. A., & Kassab, G. S. (2022).. (Frontiers in Nutrition, 9, 1007816.)
2. Glutathione-Related Enzymes and Proteins: A Review.. Vašková, J., Kočan, L., Vaško, L., & Perjési, P. (2023).. (Molecules, 28(3).)
3. GLUTATHIONE SYNTHESIS.. Lu, S. C. (2012).. (Biochimica et Biophysica Acta, 1830(5), 3143.)
4. Glutathione Homeostasis and Functions: Potential Targets for Medical Interventions.. Lushchak, V. I. (2012).. (Journal of Amino Acids, 2012, 736837.)
5. Natural Compounds and Glutathione: Beyond Mere Antioxidants.. Giacomo, C. D., Malfa, G. A., Tomasello, B., Bianchi, S., & Acquaviva, R. (2023).. (Antioxidants, 12(7), 1445.)
6. Glutathione Fine-Tunes the Innate Immune Response toward Antiviral Pathways in a Macrophage Cell Line Independently of Its Antioxidant Properties.. Diotallevi, M., Checconi, P., Palamara, A. T., Celestino, I., Coppo, L., Holmgren, A., Abbas, K., Peyrot, F., Mengozzi, M., & Ghezzi, P. (2017).. (Frontiers in Immunology, 8, 289507.)
7. ROS signaling in innate immunity via oxidative protein modifications.. Manoharan, R. R., Prasad, A., Pospíšil, P., & Kzhyshkowska, J. (2024).. (Frontiers in Immunology, 15, 1359600.)
8. ROS signaling in innate immunity via oxidative protein modifications.. Manoharan, R. R., Prasad, A., Pospíšil, P., & Kzhyshkowska, J. (2024).. (Frontiers in Immunology, 15, 1359600.)
9. Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance.. Nguyen, G. T., Green, E. R., & Mecsas, J. (2017).. (Frontiers in Cellular and Infection Microbiology, 7, 373.)
10. Macrophages in immunoregulation and therapeutics.. Chen, S., Saeed, A. F., Liu, Q., Jiang, Q., Xu, H., Xiao, G. G., Rao, L., & Duo, Y. (2023).. (Signal Transduction and Targeted Therapy, 8(1), 207.)
11. Glutathione Induced Immune-Stimulatory Activity by Promoting M1-Like Macrophages Polarization via Potential ROS Scavenging Capacity.. Kwon, D. H., Lee, H., Park, C., Hong, H., Hong, S. H., Kim, Y., Cha, J., Kim, S., Kim, S., Hwang, J., & Choi, Y. H. (2019).. (Antioxidants, 8(9), 413.)
12. Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease.. Labarrere, C. A., & Kassab, G. S. (2022).. (Frontiers in Microbiology, 13, 979719.)
13. Glutathione Depletion Exacerbates Hepatic Mycobacterium tuberculosis Infection.. Sasaninia, K., Mohan, A. S., Badaoui, A., Glassman, I., Yoon, S., Karapetyan, A., Kolloli, A., Kumar, R., Ramasamy, S., Subbian, S., Venketaraman, V., Sasaninia, K., Mohan, A. S., Badaoui, A., Glassman, I., Yoon, S., Karapetyan, A., Kolloli, A., Kumar, R., . . . Venketaraman, V. (2025).. (Biology, 14(2).)
14. Targeting Oxidative Stress Involved in Endometriosis and Its Pain.. Clower, L., Fleshman, T., Geldenhuys, W. J., & Santanam, N. (2022).. (Biomolecules, 12(8), 1055.)
15. Glutathione Modulates Efficacious Changes in the Immune Response against Tuberculosis.. Abnousian, A., Vasquez, J., Sasaninia, K., Kelley, M., & Venketaraman, V. (2023).. (Biomedicines, 11(5), 1340.)
16. Glutathione Modulates Efficacious Changes in the Immune Response against Tuberculosis.. Abnousian, A., Vasquez, J., Sasaninia, K., Kelley, M., & Venketaraman, V. (2023).. (Biomedicines, 11(5), 1340.)
17. The Role of Glutathione in the Management of Cell-Mediated Immune Responses in Individuals with HIV.. Lin, N., Erdos, T., Louie, C., Desai, R., Lin, N., Ayzenberg, G., & Venketaraman, V. (2024).. (International Journal of Molecular Sciences, 25(5), 2952.)
18. Glutathione restricts serine metabolism to preserve regulatory T cell function.. Kurniawan, H., Franchina, D. G., Guerra, L., Bonetti, L., Soriano-Baguet, L., Grusdat, M., Schlicker, L., Hunewald, O., Dostert, C., Merz, M. P., Binsfeld, C., Duncan, G. S., Farinelle, S., Nonnenmacher, Y., Haight, J., Gupta, D. D., Ewen, A., Taskesen, R., Halder, R., . . . Brenner, D. (2020).. (Cell Metabolism, 31(5), 920.)
19. Nutritional immunity: the battle for nutrient metals at the host–pathogen interface.. Murdoch CC, Skaar EP.. (Nat Rev Microbiol. 2022;20(11):657-670.)
20. Beyond nutritional immunity: Immune-stressing challenges basic paradigms of immunometabolism and immunology.. LeGrand, E. K. (2025).. (Frontiers in Nutrition, 12, 1508767.)
21. Nutritional immunity: the battle for nutrient metals at the host–pathogen interface.. Murdoch CC, Skaar EP.. (Nat Rev Microbiol. 2022;20(11):657-670.)
22. Nutritional immunity: the battle for nutrient metals at the host–pathogen interface.. Murdoch CC, Skaar EP.. (Nat Rev Microbiol. 2022;20(11):657-670.)
23. How to Increase Cellular Glutathione.. Giustarini, D., Milzani, A., Dalle-Donne, I., Rossi, R., Giustarini, D., Milzani, A., Dalle-Donne, I., & Rossi, R. (2023).. (Antioxidants, 12(5).)
24. Amino Assets: How Amino Acids Support Immunity.. Kelly, B., & Pearce, E. L. (2020).. (Cell Metabolism, 32(2), 154-175.)
25. The role of glutathione for oxidative stress and pathogenicity of Streptococcus suis.. Peng, W., Jiang, Q., Wu, Y., He, L., Li, B., Bei, W., & Yang, X. (2025).. (Virulence, 16(1), 2474866.)
26. Protective Effect of Glutathione against Oxidative Stress-induced Cytotoxicity in RAW 264.7 Macrophages through Activating the Nuclear Factor Erythroid 2-Related Factor-2/Heme Oxygenase-1 Pathway.. Kwon, D. H., Cha, J., Lee, H., Hong, H., Park, C., Park, H., Kim, Y., Kim, S., Kim, S., Hwang, J., & Choi, Y. H. (2019).. (Antioxidants, 8(4), 82.)
27. The Role of Glutathione in the Management of Cell-Mediated Immune Responses in Individuals with HIV.. Lin, N., Erdos, T., Louie, C., Desai, R., Lin, N., Ayzenberg, G., & Venketaraman, V. (2024).. (International Journal of Molecular Sciences, 25(5), 2952.)
28. Glutathione Is a Key Player in Metal-Induced Oxidative Stress Defenses.. Jozefczak, M., Remans, T., Vangronsveld, J., & Cuypers, A. (2012).. (International Journal of Molecular Sciences, 13(3), 3145.)
29. Glutathione Fine-Tunes the Innate Immune Response toward Antiviral Pathways in a Macrophage Cell Line Independently of Its Antioxidant Properties.. Diotallevi, M., Checconi, P., Palamara, A. T., Celestino, I., Coppo, L., Holmgren, A., Abbas, K., Peyrot, F., Mengozzi, M., & Ghezzi, P. (2017).. (Frontiers in Immunology, 8, 289507.)
30. The Role of Glutathione Metabolism in Chronic Illness Development and Its Potential Use as a Novel Therapeutic Target.. Hristov, B. D. (2022).. (Cureus, 14(9), e29696.)
31. The glutathione defense system in the pathogenesis of rheumatoid arthritis.. Hassan, M & Hadi, R & Al-Rawi, Ziad & Padron, Victor & Stohs, Sidney. (2001).. (Journal of Applied Toxicology. 21. 69-73.)
32. The glutathione defense system in the pathogenesis of rheumatoid arthritis.. Hassan, M & Hadi, R & Al-Rawi, Ziad & Padron, Victor & Stohs, Sidney. (2001).. (Journal of Applied Toxicology. 21. 69-73.)
33. Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis.. Qiu, J., Wu, B., Goodman, S. B., Berry, G. J., Goronzy, J. J., & Weyand, C. M. (2021).. (Frontiers in Immunology, 12, 652771.)
34. Targeting Oxidative Stress Involved in Endometriosis and Its Pain.. Clower, L., Fleshman, T., Geldenhuys, W. J., & Santanam, N. (2022).. (Biomolecules, 12(8), 1055.)
35. Endometriosis.. Zondervan, K. T., Becker, C. M., Koga, K., Missmer, S. A., Taylor, R. N., & Viganò, P. (2018).. (Nature Reviews Disease Primers, 4(1), 9.)
36. Can Endometriosis-Related Oxidative Stress Pave the Way for New Treatment Targets?. Cacciottola, L., Donnez, J., Dolmans, M., Cacciottola, L., Donnez, J., & Dolmans, M. (2021).. (International Journal of Molecular Sciences, 22(13).)
37. Expression of Free Radicals and Reactive Oxygen Species in Endometriosis: Current Knowledge and Its Implications.. Lee, J., Yeo, S. G., Lee, J. M., Kim, S. S., Lee, W., Chung, N., & Park, D. C. (2025).. (Antioxidants, 14(7), 877.)
38. New roles for glutathione: Modulators of bacterial virulence and pathogenesis.. Ku, J. W. K., & Gan, Y. (2021).. (Redox Biology, 44, 102012.)
39. Unraveling the Multifaceted Role of Glutathione in Sepsis: A Comprehensive Review.. Tandon, R., & Tandon, A. (2024).. (Cureus, 16(3), e56896.)
40. Glutathione and Adaptive Immune Responses against Mycobacterium tuberculosis Infection in Healthy and HIV Infected Individuals.. Guerra C, Morris D, Sipin A, Kung S, Franklin M, Gray D, et al. (2011). (PLoS ONE 6(12): e28378.)
41. Inhibition of influenza infection by glutathione.. Cai, J., Chen, Y., Seth, S., Furukawa, S., Compans, R. W., & Jones, D. P. (2003).. (Free Radical Biology and Medicine, 34(7), 928-936.)
42. Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease.. Labarrere, C. A., & Kassab, G. S. (2022).. (Frontiers in Microbiology, 13, 979719.)
43. Role of glutathione in immunity and inflammation in the lung.. Ghezzi, P. (2011).. (International Journal of General Medicine, 4, 105.)