Kelch-like ECH-associated protein 1–Nuclear factor erythroid 2-related factor 2 pathway (Keap1–Nrf2) (Keap1–Nrf2)

The Kelch-like ECH-associated protein 1–Nuclear factor erythroid 2-related factor 2 (Keap1–Nrf2) pathway is the primary cellular defense mechanism against oxidative and electrophilic stress (Yamamoto et al., 2018, Physiol Rev). Under normal conditions, Keap1 acts as a sensor and an E3 ubiquitin ligase adaptor that facilitates the continuous degradation of the transcription factor Nrf2 (Bellezza et al., 2018, Front Pharmacol). Upon exposure to stressors, reactive oxygen species, or electrophilic drugs, specific cysteine residues on Keap1 are modified, leading to the stabilization and nuclear translocation of Nrf2 (Taguchi & Yamamoto, 2020, Mol Cells). In the nucleus, Nrf2 binds to Antioxidant Response Elements (ARE) to induce the transcription of a battery of cytoprotective genes, including Heme oxygenase 1 (HMOX1) and NAD(P)H quinone dehydrogenase 1 (NQO1) (Cuadrado et al., 2019, Nat Rev Drug Discov). This pathway is a major therapeutic target for inflammatory, autoimmune, and neurodegenerative diseases, with drugs like dimethyl fumarate and omaveloxolone already approved for clinical use (Robledinos-Antón et al., 2019, Antioxidants). However, the pathway's role is complex, as its constitutive activation in certain cancers can promote tumor survival and resistance to chemotherapy, a phenomenon known as the Nrf2 paradox (Rojo de la Vega et al., 2018, Cancer Cell).

Other names

Nrf2-ARE signaling pathwayKEAP1-NFE2L2 axisAntioxidant Response Element pathwayKeap1-Nrf2-ARE signaling

Drugs targeting this pathway typically act as Nrf2 activators by disrupting the Keap1–Nrf2 interaction. This is achieved either through covalent modification of Keap1 cysteine residues (e.g., by electrophilic molecules like dimethyl fumarate) or through non-covalent small-molecule inhibitors that block the Keap1 Kelch domain from binding Nrf2, thereby preventing Nrf2 ubiquitination and allowing its nuclear translocation (Cuadrado et al., 2019, Nat Rev Drug Discov; Robledinos-Antón et al., 2019, Antioxidants).