Sepsis is a complex condition characterized by an uncontrolled inflammatory response to infection, which can trigger multi-organ dysfunction and is associated with high mortality rates. In this context, oxidative stress plays a key role in the progression of tissue damage. Reduced glutathione (GSH), the primary non-enzymatic intracellular antioxidant, serves as a fundamental pillar in redox defense, acting as a key modulator of immune response, endothelial barrier integrity, and mitochondrial metabolism. This review explores the multifaceted role of GSH in the pathophysiology of sepsis, with emphasis on its biphasic effect on both innate and adaptive immunity, as well as its involvement in vascular alterations and mitochondrial dysfunction. The molecular mechanisms of GSH depletion during sepsis are analyzed, including excessive consumption by reactive species, disruption of its synthesis, and its intracellular compartmentalization. Additionally, the available clinical evidence in humans regarding the functional consequences of GSH loss is reviewed, particularly concerning organ failure—understood more as a bioenergetic and functional disruption than a structural one—and mortality, highlighting the methodological limitations and heterogeneity of the reported findings. Altogether, this analysis intends to provide a comprehensive view of the role of glutathione in redox dysregulation and the pathophysiological mechanisms underlying sepsis. Furthermore, it seeks to consolidate current pathophysiological and clinical knowledge to emphasize the potential role of glutathione as a prognostic marker and possible target for future therapeutic strategies in addressing this complex condition.
Gomar et al. (Fri,) studied this question.