Solute carrier family 7 member 11 (SLC7A11) and Glutathione peroxidase 4 (GPX4) (SLC7A11 and GPX4)

The Solute carrier family 7 member 11 (SLC7A11) and Glutathione peroxidase 4 (GPX4) axis is the central regulatory pathway governing ferroptosis, an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation [NIH, 1.3.2]. SLC7A11 serves as the functional light chain subunit of the system Xc- transporter, importing extracellular cystine into the cell for the synthesis of glutathione (GSH), which acts as the essential reducing cofactor for GPX4 [NIH, 1.4.5]. GPX4 is a unique selenoprotein enzyme that specifically reduces complex lipid hydroperoxides to non-toxic lipid alcohols, thereby preventing the catastrophic membrane damage that leads to ferroptotic cell death [Wikipedia, 1.2.1; NIH, 1.2.4]. This pathway is frequently upregulated in various human cancers to promote survival under high oxidative stress and confer resistance to chemotherapy and radiotherapy, making it a high-priority target for the development of ferroptosis-inducing therapies [NIH, 1.4.3; ResearchGate, 1.3.5]. Conversely, the loss or inhibition of this axis is implicated in the pathogenesis of neurodegenerative diseases, cardiovascular injuries, and acute organ failure, where pharmacological activation or ferroptosis inhibition may offer therapeutic benefits [NIH, 1.1.4, 1.3.3]. Current drug development strategies include small-molecule inhibitors like erastin and RSL3 to induce cell death in therapy-resistant tumors, as well as emerging activators aimed at mitigating oxidative injury in degenerative conditions [MedChemExpress, 1.2.3; NIH, 1.4.5].

Other names

xCTCCBR1Cystine/glutamate transporterPHGPxsnGPxMCSPSMDSPhospholipid hydroperoxide glutathione peroxidaseSystem Xc- light chain

Inhibition of the SLC7A11/GPX4 axis triggers ferroptosis by depleting intracellular glutathione (via SLC7A11 inhibition) or directly blocking lipid hydroperoxidase activity (via GPX4 inhibition), leading to the lethal accumulation of lipid hydroperoxides; conversely, activation of this pathway protects cells from oxidative damage and ferroptotic cell death [NIH, 1.3.2, 1.4.5].