GPX4

GPX4 (glutathione peroxidase 4) is a selenium-dependent phospholipid hydroperoxidase that maintains cellular redox homeostasis by reducing complex lipid hydroperoxides to their corresponding lipid alcohols using glutathione as a cofactor, thereby preventing membrane lipid peroxidation and oxidative damage^[1][2][3]. Mechanistically, GPX4 functions as the central regulator and major endogenous suppressor of ferroptosis, an iron-dependent form of regulated cell death driven by the accumulation of phospholipid hydroperoxides, and loss of GPX4 activity promotes lipid peroxide accumulation and ferroptotic cell death^[2][4][5][6]. Through this lipid peroxide detoxification pathway, GPX4 contributes to the maintenance of cellular viability, immune homeostasis, and tissue integrity, while impaired GPX4 function has been associated with cancer, neurodegenerative disorders, inflammation, ischemia-reperfusion injury, and other ferroptosis-related pathologies^[1][7][8]. Compared with other glutathione peroxidase family members, GPX4 possesses a unique ability to directly reduce phospholipid hydroperoxides and oxidized complex lipids, distinguishing it as a specialized phospholipid repair enzyme and a master regulator of ferroptosis^[2][9][10]. Distinct cytosolic, mitochondrial, and nuclear GPX4 isoforms have been described, with cytosolic GPX4 identified as essential for embryonic development and cell survival^[7][8]. For experimental applications, pharmacological GPX4 inhibitors such as RSL3 and ML162 are widely used to induce ferroptosis, enabling mechanistic studies of lipid peroxidation, redox regulation, cancer vulnerability, and ferroptosis-targeted therapeutic strategies^[11][12].