Distinct from glutathione_metabolism (synthesis arm: γ-GCS → γ-GC + glycine → GSH) and transsulfuration_cysteine_glutathione (precursor arm: homocysteine → cysteine → GSH). This pathway covers the **redox cycling** arm — how reduced GSH is consumed to neutralize peroxides and how the oxidized GSSG is regenerated to maintain antioxidant reserve. Step 1: glutathione peroxidase (GPx, selenoenzyme — selenocysteine in the active site) reduces H₂O₂ → H₂O + GSSG. Step 2: glutathione peroxidase 4 (GPx4) reduces phospholipid hydroperoxides → the canonical defense against lipid peroxidation; GPx4 deficiency drives ferroptosis. Step 3: glutathione reductase (GR, FAD-flavoenzyme) reduces GSSG → 2 GSH consuming NADPH. Step 4: NADPH is supplied by the pentose phosphate pathway (G6PD, the rate-limiting step — G6PD-deficient patients are susceptible to hemolytic crisis with oxidative stressors like sulfa drugs / fava beans because they cannot regenerate GSH). Step 5: peroxiredoxins (Prx1-6, abundant thiol-peroxidases) operate in parallel + crosstalk with GSH redox. Step 6: GSH/GSSG ratio (normally ~100:1 in cytosol, ~10:1 in mitochondria) is a master redox-state indicator — falling ratio triggers Nrf2 activation, sirtuin modulation, and apoptotic priming. Therapeutic relevance: selenium deficiency → diminished GPx capacity; vitamin E (chain-breaking lipid antioxidant) cooperates with GPx4 to prevent peroxide propagation; astaxanthin + carotenoids extend the GSH/GPx antioxidant chain. Cross-links: glutathione metabolism, transsulfuration cysteine glutathione, ros oxidative stress, nrf2 keap1 antioxidant response (GSH/GSSG redox state is the canonical input to Keap1 cysteine sensing), pentose phosphate pathway (NADPH supply).
Organ Systems
immune-hematologic
cardiovascular
nervous
Pathway Steps
2 GSH + H₂O₂ → GSSG + 2 H₂O — via glutathione peroxidase (GPx1-3, selenocysteine-active-site selenoenzyme). Glutathione peroxidases (GPx) use two molecules of reduced glutathione (GSH) to reduce hydrogen peroxide to water, oxidizing GSH to the disulfide GSSG. This is the cell’s main enzymatic defense against H₂O₂, complementing catalase and the peroxiredoxins — a key node in redox homeostasis.
GSH + phospholipid-OOH → GSSG + phospholipid-OH — via GPx4 — canonical defense against lipid peroxidation; GPx4 deficiency = ferroptosis. The same GPx system (notably the membrane-acting GPx4) reduces lipid hydroperoxides in phospholipids to harmless alcohols, again consuming GSH. This lipid-repair function protects membranes from peroxidative damage — and its failure is precisely what drives ferroptotic cell death.
GSSG + NADPH + H+ → 2 GSH + NADP+ — via glutathione reductase (GR) — FAD flavoenzyme; NADPH-dependent recycling. GSSG is recycled back to GSH by glutathione reductase, which uses NADPH as the electron donor. This regeneration keeps the GSH:GSSG ratio very high (reducing), letting the system buffer continuous oxidant production — so NADPH supply is the ultimate limit on antioxidant capacity.
glucose-6-phosphate + NADP+ → 6-phosphogluconolactone + NADPH — via G6PD (rate-limiting NADPH supply; PPP-dependent). The NADPH powering GSH regeneration comes largely from the pentose phosphate pathway: glucose-6-phosphate dehydrogenase (G6PD) oxidizes G6P while reducing NADP⁺ to NADPH. This is why G6PD deficiency causes oxidant-induced hemolysis — red cells cannot regenerate GSH to defend against oxidative stress.
GSH/GSSG ratio falls → Nrf2 release from Keap1 → ARE transcription — via redox-sensing — cysteine thiols on Keap1 modified by GSSG. The GSH/GSSG couple is also a signal: when the ratio falls (oxidative stress), oxidation of sensor cysteines on Keap1 releases Nrf2 to drive ARE-dependent antioxidant genes. So the glutathione system both buffers oxidants directly and triggers an adaptive transcriptional defense.
Known Modulators
glutathione (substrate) — GSH pool — oral bioavailability limited; liposomal/sublingual forms preferred