Glutathione: A Samsonian life-sustaining small molecule that protects against oxidative stress, ageing and damaging inflammation Original paper

What was reviewed?

This review explained how glutathione (GSH) controls redox balance, limits oxidative stress, and shapes inflammatory and immune responses across major diseases. The authors described GSH biology, including synthesis from glutamate, cysteine, and glycine, its reduced and oxidized forms (GSH and GSSG), and how the GSH:GSSG ratio signals cellular redox function. They also linked GSH depletion to persistent inflammation, “inflammaging,” and severe outcomes in chronic lung disease, atherosclerosis, and SARS-CoV-2 infection. They emphasized the Keap1–Nrf2–ARE pathway as a key regulator that drives antioxidant and immune gene programs, and they discussed therapies that raise GSH or activate Nrf2, such as cysteine donors like N-acetylcysteine and selenium support for glutathione peroxidase activity.

Who was reviewed?

The paper reviewed evidence from human and experimental work across several disease settings rather than one defined cohort. It discussed patients with chronic obstructive pulmonary disease, acute respiratory distress syndrome, cystic fibrosis, idiopathic pulmonary fibrosis, coronary artery disease, acute coronary syndrome, ischemic stroke, and COVID-19, plus supporting mechanistic models in cells and animals. The review also covered airway and vascular compartments where immune cells act, including alveolar epithelial cells, macrophages, neutrophils, monocytes, endothelial cells, and platelets. It treated these populations as contexts where redox stress, innate immune sensing, and inflammatory signaling interact, which matters when clinicians interpret oxidative stress markers or consider antioxidant strategies.

Most important findings

The authors argued that GSH depletion sits near the center of a loop that links oxidative stress to chronic inflammation. They described how reactive oxygen species rise in lung and vascular disease, then amplify cytokine signaling through pathways that include NF-κB. At the same time, low GSH weakens peroxide clearance and allows tissue injury to continue. In COPD, they noted that bronchoalveolar lavage GSH can rise in stable states but can drop during severe exacerbations, and they linked low GSH with neutrophil influx and higher IL-8. In ARDS, they highlighted low epithelial lining fluid glutathione and reported that N-acetylcysteine improved antioxidant biomarkers and oxygenation in some settings. In cystic fibrosis, they connected low airway GSH to defective CFTR-linked transport and high γ-glutamyltransferase activity, which can degrade inhaled GSH and limit benefit. In atherosclerosis, the review tied oxidative stress markers such as malondialdehyde to lower GSH and lower glutathione peroxidase activity, then linked this redox state to endothelial dysfunction and plaque inflammation. For SARS-CoV-2, they described a pattern where infection increases ROS, boosts neutrophil extracellular traps, and drives cytokine production (including IL-1β, IL-6, IL-8, and TNF-α), while impaired antioxidant defenses worsen tissue damage.

Key implications

Clinicians can treat this review as a mechanistic guide that links low GSH to a redox state that drives exaggerated innate immune activation, cytokine release, and tissue injury across lung, vascular, and viral inflammatory disease. It supports careful evaluation of GSH status and related pathways, including Nrf2 activity and glutathione peroxidase capacity, when inflammation persists or worsens. It also frames GSH-raising strategies as adjuncts that may reduce oxidative stress load.