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

The Peroxisome proliferator-activated receptor alpha–Glutathione peroxidase 4 (PPARα–GPX4) signaling axis is a critical molecular pathway that regulates cellular susceptibility to ferroptosis, an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation [1][2]. PPARα, a member of the nuclear receptor superfamily, functions as a transcription factor that directly upregulates the expression of GPX4, the primary enzyme responsible for neutralizing lipid hydroperoxides within cellular membranes [2][3]. This axis plays a pivotal role in maintaining metabolic homeostasis and protecting tissues from oxidative damage, particularly in the liver, heart, and kidneys [4][5]. In the context of disease, the impairment of this axis is linked to acute organ injuries and neurodegeneration, while its overactivation in various cancers contributes to therapeutic resistance and tumor progression by evading ferroptotic triggers [5][6]. Therapeutic intervention strategies include the use of PPARα agonists, such as fibrates, to bolster antioxidant defenses in inflammatory or ischemic conditions, and the development of GPX4 inhibitors to sensitize cancer cells to treatment [1][7]. Consequently, the PPARα–GPX4 axis represents a significant target for drug discovery across oncology and regenerative medicine [2][8].

Other names

PPARa-GPX4 pathwayPPARalpha-GPX4 signaling axisPPARα/GPX4 axisPPARα-GPX4 regulatory loop

The mechanism involves the ligand-dependent activation of the transcription factor PPARα, which subsequently binds to the peroxisome proliferator response elements (PPRE) in the promoter region of the GPX4 gene, leading to increased GPX4 protein synthesis and the enzymatic reduction of toxic lipid hydroperoxides into non-toxic lipid alcohols [1][2][3].