Host oxidative stress pathway proteins

The host oxidative stress pathway proteins constitute a complex network of enzymes and transcription factors dedicated to maintaining cellular redox homeostasis [PMID: 25911333]. The central regulator of this pathway is the Nuclear factor erythroid 2-related factor 2 (Nrf2), which, under normal conditions, is sequestered and targeted for degradation by Kelch-like ECH-associated protein 1 (KEAP1) [Nature Reviews Drug Discovery, 2014]. Upon exposure to oxidative stress or electrophiles, Nrf2 translocates to the nucleus and binds to the Antioxidant Response Element (ARE) to induce the expression of protective genes such as Heme oxygenase-1 (HO-1) and Superoxide dismutase (SOD) [PubMed, 2021]. Additionally, downstream enzymes like Glutathione peroxidase and Catalase play critical roles in neutralizing reactive oxygen species directly [NIH, 2023]. Dysregulation of this pathway is implicated in a wide range of pathologies, including neurodegenerative diseases, chronic inflammation, and cancer [Frontiers in Pharmacology, 2020]. Pharmacological modulation typically involves Nrf2 activators, such as Dimethyl fumarate or Bardoxolone methyl, that disrupt the KEAP1-Nrf2 interaction, thereby enhancing the cell's endogenous antioxidant capacity [PubChem]. However, chronic activation must be carefully managed, as it can promote the survival of malignant cells and lead to drug resistance in oncology settings [Science Signaling, 2018]. Therapeutic strategies also include the use of mimetic compounds that supplement the activity of these endogenous enzymes to mitigate tissue damage in acute settings [Journal of Medicinal Chemistry, 2019].

Other names

Antioxidant response element (ARE) pathwayNrf2-KEAP1 signaling pathwayRedox homeostasis proteinsPhase II detoxifying enzyme system

Activation of the Nrf2 transcription factor by inhibiting its negative regulator KEAP1, leading to the upregulation of antioxidant and phase II detoxification enzymes; direct scavenging of reactive oxygen species by enzyme mimetics.