Nuclear factor erythroid 2-related factor 2–Antioxidant Response Element pathway with downstream Glutathione peroxidase 4 and Ferroptosis suppressor protein 1 (Nrf2–ARE–GPX4–FSP1 axis)

The Nrf2–ARE–GPX4–FSP1 axis is a fundamental cellular defense network that maintains redox balance and protects cells from ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation. Nuclear factor erythroid 2-related factor 2 (Nrf2) serves as the central transcription factor that, in response to oxidative stress, binds to Antioxidant Response Elements (ARE) to upregulate a battery of cytoprotective genes. Among its most critical downstream effectors are Glutathione peroxidase 4 (GPX4) and Ferroptosis suppressor protein 1 (FSP1), which constitute the two primary, parallel pathways for neutralizing toxic lipid peroxides. GPX4 utilizes glutathione to detoxify membrane lipids, while FSP1 operates independently of glutathione by regenerating ubiquinol to trap lipid radicals. This signaling axis is a major focus in drug development due to its dual role in human health. In oncology, many tumors overexpress Nrf2, GPX4, or FSP1 to evade ferroptosis and resist chemotherapy or radiation, making the inhibition of this pathway a promising strategy for sensitizing therapy-resistant cancers. Conversely, in neurodegenerative and cardiovascular diseases, pharmacological activation of the Nrf2-ARE pathway is being pursued to enhance cellular resilience against oxidative damage and prevent premature cell death. For instance, Nrf2 activators like omaveloxolone have been approved for treating Friedreich's ataxia, highlighting the therapeutic potential of modulating this axis to mitigate oxidative stress-induced pathology.

Other names

NFE2L2–ARE signaling axisNrf2-mediated ferroptosis defense pathwayNrf2-GPX4-FSP1 axisKEAP1-Nrf2-ARE pathwayAIFM2-dependent ferroptosis suppression

The Nrf2–ARE pathway functions as a master regulator of the cellular antioxidant response. Upon activation (often via KEAP1 inhibition), Nrf2 translocates to the nucleus and binds to Antioxidant Response Elements (ARE) to induce the transcription of GPX4 and FSP1. GPX4 reduces lipid hydroperoxides to non-toxic lipid alcohols using glutathione (GSH) as a cofactor, while FSP1 (AIFM2) acts as an oxidoreductase that reduces Coenzyme Q10 to ubiquinol, which directly scavenges lipid peroxyl radicals. Together, these parallel systems prevent the iron-dependent lipid peroxidation that drives ferroptotic cell death.