Glutathione peroxidase 4 (GPX4) (GPX4)

Glutathione peroxidase 4 (GPX4) is a unique antioxidant enzyme that plays a pivotal role in maintaining membrane integrity by reducing lipid hydroperoxides to their corresponding alcohols (UniProt P36969). It is distinguished from other glutathione peroxidases by its ability to reduce complex lipid substrates, such as phospholipid hydroperoxides, directly within biological membranes. GPX4 is the master negative regulator of ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation (Dixon et al., 2012, Cell). The enzyme utilizes a catalytic selenocysteine residue to perform its redox function, a site that is also the primary target for covalent small-molecule inhibitors like RSL3 (Yang et al., 2014, Cell). In the context of cancer, GPX4 is often upregulated in therapy-resistant mesenchymal-state cells, making its inhibition a strategy to overcome drug resistance (Viswanathan et al., 2017, Nature). Conversely, the loss of GPX4 activity is linked to neurodegenerative diseases and organ damage, highlighting its essential role in protecting healthy tissues from oxidative stress (Bao et al., 2021, MedComm).

Other names

Phospholipid hydroperoxide glutathione peroxidasePHGPxGSHPx-4MCSPSnGPx

Direct covalent inhibition of the selenocysteine residue (Sec46) in the catalytic pocket, which prevents the reduction of lipid hydroperoxides, leading to their accumulation and subsequent ferroptotic cell death (Yang et al., 2014, Cell).