Peroxisome proliferator-activated receptor alpha–Glutathione peroxidase 4 (PPARα–GPX4) transcriptional axis (PPARα–GPX4 axis)

The Peroxisome proliferator-activated receptor alpha–Glutathione peroxidase 4 (PPARα–GPX4) transcriptional axis is a critical regulatory pathway that links lipid metabolism with the control of ferroptosis, an iron-dependent form of regulated cell death. Peroxisome proliferator-activated receptor alpha (PPARα), a ligand-activated nuclear receptor and transcription factor, directly binds to the promoter of the glutathione peroxidase 4 (GPX4) gene to upregulate its expression. GPX4 is the primary enzyme responsible for neutralizing lipid hydroperoxides, thus protecting cell membranes from oxidative damage and preventing ferroptotic death. This axis is particularly relevant in tissues with high metabolic activity, such as the liver, heart, and kidneys. Dysregulation of the PPARα–GPX4 axis is implicated in various pathologies, including metabolic-associated fatty liver disease (MAFLD), ischemia-reperfusion injury, and certain cancers where ferroptosis resistance is a hallmark. Therapeutic strategies often involve the use of PPARα agonists, such as fibrates, to enhance GPX4 levels and provide cytoprotection in degenerative or inflammatory conditions, while inhibition of the axis is explored as a means to sensitize tumor cells to ferroptosis-inducing therapies.

Other names

PPARα-GPX4 signaling pathwayPPARα/GPX4 axisPPAR alpha-GPX4 axisPPARα-mediated GPX4 regulation

PPARα functions as a ligand-activated transcription factor that, upon activation, forms a heterodimer with the Retinoid X Receptor (RXR) and binds to Peroxisome Proliferator Response Elements (PPRE) within the promoter region of the GPX4 gene. This binding induces the transcription of GPX4, an essential antioxidant enzyme that reduces lipid hydroperoxides to non-toxic lipid alcohols, thereby preventing the accumulation of lipid reactive oxygen species (ROS) and inhibiting ferroptosis.