Glutathione depletion (GSH depletion)

Glutathione depletion refers to the reduction of intracellular glutathione levels, where glutathione (GSH) is the most abundant low molecular weight thiol and major redox determinant in animal cells. GSH normally reaches concentrations up to 10 mM in some cells and is involved in antioxidant defense, drug detoxification, signaling, and proliferation[1]. Glutathione depletion is an early hallmark in the progression of cell death in response to apoptotic stimuli and has been associated with activation of plasma membrane transport mechanisms rather than oxidation by reactive oxygen species[1]. The condition is implicated in numerous chronic diseases including cancer, neurodegenerative diseases, cardiovascular disease, metabolic syndrome, and mitochondrial disorders[2][6][8]. In cancer cells, paradoxically elevated GSH levels contribute to chemoresistance[2]. Glutathione depletion can trigger ferroptosis, autophagy, and premature senescence[5], and directly modulates permeability transition pore formation and caspase 3 activation during apoptosis[1]. The condition can be monitored using the biomarker GGT (gamma-glutamyl transferase), which is inversely correlated with GSH levels and has been shown in large prospective studies to predict chronic disease development[6].

Other names

GSH lossGlutathione deficiencyGSH effluxIntracellular glutathione depletion

Not applicable as a therapeutic target; the mechanisms by which GSH depletion occurs include: Plasma membrane transport/efflux via organic anion transporters; ATP-dependent multidrug resistance proteins (ABCC/MRPs); Death receptor (Fas)-induced transport activation; GSH/organic anion exchange.