Cystine-glutamate transporter (System xc-) (System xc-)

The Cystine-glutamate transporter, commonly referred to as System xc-, is a heterodimeric amino acid transporter consisting of the light chain subunit SLC7A11 (xCT) and the heavy chain subunit SLC3A2 (CD98hc) (UniProt: Q9UPY5). Its primary physiological role is the 1:1 exchange of extracellular cystine for intracellular glutamate, providing the essential precursor for glutathione (GSH) synthesis, the cell's primary antioxidant (PMID: 11553011). By maintaining intracellular redox balance, the transporter protects cells from oxidative damage and prevents ferroptosis, an iron-dependent form of regulated cell death (PMID: 22591915). In oncology, many tumors overexpress SLC7A11 to survive high levels of metabolic stress and resist chemotherapy, making it a high-priority therapeutic target (PMID: 33064942). However, because the transporter also regulates extracellular glutamate levels in the brain, its modulation is linked to neurodegenerative diseases and epilepsy (PMID: 26163355). Pharmacological inhibition of the transporter, using agents like sulfasalazine or erastin, aims to deplete glutathione and induce ferroptosis in tumor cells. Despite its potential, therapeutic development faces challenges regarding the selectivity of inhibitors and the risk of systemic oxidative stress. Additionally, the role of System xc- in the immune system, particularly in T-cell activation, suggests that its inhibition might have complex effects on anti-tumor immunity (PMID: 30610151). Current research is focused on developing more potent and specific small-molecule inhibitors and identifying biomarkers for patient stratification. Overall, the Cystine-glutamate transporter represents a critical node in cellular metabolism and a promising target for treating various cancers and neurological disorders.

Other names

xCTSLC7A11Cysteine-glutamate antiporterCystine/glutamate exchangerSolute carrier family 7 member 11

Inhibition of the transporter prevents the uptake of cystine, leading to the depletion of intracellular glutathione and the subsequent accumulation of lipid peroxides, which induces ferroptotic cell death.