Kelch-like ECH-associated protein 1–Nuclear factor erythroid 2-related factor 2–Antioxidant Response Element signaling system (Keap1–Nrf2–ARE)

The Keap1–Nrf2–ARE signaling system is a master regulatory pathway that governs the cellular response to oxidative and electrophilic stress [1]. It consists of the sensor protein Kelch-like ECH-associated protein 1 (Keap1), the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), and the Antioxidant Response Element (ARE) DNA sequences [2]. Under homeostatic conditions, Keap1 targets Nrf2 for ubiquitination and proteasomal degradation; however, stress-induced modification of Keap1 cysteines allows Nrf2 to stabilize and translocate to the nucleus [3]. Once in the nucleus, Nrf2 binds to AREs to induce the expression of a battery of cytoprotective genes involved in antioxidant defense, detoxification, and metabolic regulation [4]. This system is a major therapeutic target for diseases characterized by oxidative stress and inflammation, such as multiple sclerosis and chronic kidney disease [5]. While Nrf2 activation is generally protective, its constitutive activation in certain cancers can promote tumor survival and resistance to therapy, presenting a complex challenge for drug development [6]. Current pharmacological interventions include electrophilic molecules like dimethyl fumarate and omaveloxolone that covalently modify Keap1 to boost the endogenous antioxidant response [7].

Other names

Nrf2 pathwayKeap1-Nrf2 pathwayNFE2L2-KEAP1 signalingAntioxidant response pathwayNrf2-ARE signaling axis

Activation of the Nrf2 transcription factor by disrupting its interaction with the Keap1-Cul3 E3 ubiquitin ligase complex, preventing its degradation and allowing nuclear translocation to induce antioxidant response element (ARE)-driven genes.