Glutathione-driven redox decisions in cell survival and death

Glutathione (GSH), the most abundant low-molecular-weight thiol in mammalian cells, is a key regulator of cellular redox homeostasis and metabolic adaptation. Traditionally regarded as a cytoprotective antioxidant, GSH buffers oxidative stress, supports biosynthesis, and preserves cellular integrity under both physiological and pathological conditions. However, this notion is increasingly recognized as incomplete, as disturbances in GSH homeostasis can also modulate cellular susceptibility to death in a context-dependent manner. In this review, we examine how GSH metabolism intersects with major regulated cell death pathways, including apoptosis, pyroptosis, necroptosis, ferroptosis, and cuproptosis, and summarize the physiological and pathological settings in which GSH supports cell survival or, when disrupted, predisposes cells to death. We further discuss how subcellular compartmentalization and metabolic context shape these divergent outcomes. A deeper understanding of the dynamic regulation of GSH may provide new insights into cell fate control and guide therapeutic strategies in cancer, neurodegeneration, and inflammatory disease.