Glutathione in brain oxidative stress: from redox chemistry to clinical imaging

Glutathione (GSH), a tripeptide composed of glutamate, cysteine, and glycine, is the most abundant intracellular low-molecular-weight thiol and serves as a central regulator of cellular redox homeostasis. In addition to its well-established roles in antioxidant defense and detoxification, GSH is essential for maintaining mitochondrial function and cellular viability. Since its discovery more than a century ago, extensive research has progressively revealed the diverse biological functions of GSH. More recently, growing evidence from experimental and clinical studies has demonstrated that disruption of GSH homeostasis is a common feature of multiple neurodegenerative diseases. Because the central nervous system consumes large amounts of oxygen, contains abundant oxidizable lipids, and possesses limited regenerative capacity, maintenance of neuronal GSH homeostasis is indispensable for protecting the brain against oxidative injury. Recent advances have further demonstrated that neuronal GSH synthesis is tightly regulated through specialized mechanisms, including astrocyte-neuron metabolic coupling and excitatory amino acid carrier 1-dependent cysteine transport. This review summarizes the historical development of GSH research, current understanding of the molecular mechanisms regulating brain GSH homeostasis, and how these mechanisms are disrupted in major neurodegenerative diseases. Finally, we discuss promising therapeutic strategies aimed at restoring endogenous neuronal GSH homeostasis and highlight the potential of brain GSH as both a biomarker and therapeutic target for oxidative stress-related neurodegenerative diseases.