Fig. 1. Glutathione (GSH) dynamics of cancer stem cells (CSCs) in tumor microenvironment (TME). In the TME, the CSCs dynamically modulate their GSH regeneration capacity for survival. (A) Cytosolic nicotinamide adenine dinucleotide phosphate (NADPH) was mainly supplied via the pentose phosphate pathway (PPP). Under oxidative stress, glyceraldehyde 3-phosphate dehydrogenase is inactivated via the oxidation of cysteine thiol residues at its active site, and glucose 6-phosphate dehydrogenase (G6PD) is activated by ataxia-telangiectasia mutated serine/threonine kinase (ATM), leading to the potentiation of PPP. (B) Cytosolic GSH synthesized from glutamate, cysteine, and glycine can scavenge reactive oxygen species (ROS) via glutathione peroxidase (GPX) and can be regenerated by glutathione reductase (GSR) with NADPH, leading to the generation of a redox buffering cycle. (C) In the mitochondrial matrix, mitochondrial ROS (mtROS) are produced via superoxide dismutase 2 (SOD2) acetylation by GCN5L1 and can be removed by mitochondrial GSH and NADPH pools. (D) Plasma membrane is protected by GPX4 from lipid peroxidation and ferroptosis. GSH and oleic acid present in the lymphatic vessels inhibit CSCs’ ferroptosis. (E) Cytosolic NADPH is produced by isocitrate dehydrogenase 1 (IDH1). (F) Mitochondrial NADPH is supplied by IDH2 which transforms isocitrate to α-ketoglutarate (α-KG) as a reaction of the citric acid cycle. α-KG is also produced by mitochondrial glutaminase (GLS) and the glutamine transamidase reaction. (G, H) Cytosolic NADPH is produced by malic enzyme 1 (ME1, G) and the folate pathway (H). (I) CSCs derived-DKK1 inhibits Wnt signaling and increases SLC7A11 expression, leading to the inhibition of ferroptosis. Cys2: cysteine, DHA: dehydroascorbate, F1,6BP: fructose 1,6-bisphosphate, G3P: glyceraldehyde 3-phosphate, G6P: glucose 6-phosphate, GSSG: glutathione disulfide, OAA: oxaloa-cetate, THF: tetrahydrofolate.