Nuclear factor erythroid 2-related factor 2-Heme oxygenase 1 pathway (Nrf2-HO-1 pathway) (Nrf2-HO-1 pathway)

The Nuclear factor erythroid 2-related factor 2-Heme oxygenase 1 (Nrf2-HO-1) pathway is a primary cellular defense mechanism against oxidative and electrophilic stress (Source: PubMed, PMID: 29061141). Nrf2, a transcription factor, remains sequestered in the cytoplasm by Keap1 under basal conditions; however, upon exposure to stressors or pharmacological activators, Nrf2 translocates to the nucleus to induce the expression of various cytoprotective genes, most notably Heme oxygenase 1 (HO-1) (Source: UniProt, Q16236). HO-1 catalyzes the degradation of heme into biliverdin, carbon monoxide, and free iron, which collectively exert potent antioxidant, anti-inflammatory, and anti-apoptotic effects (Source: PubMed, PMID: 16407468). This pathway is a significant therapeutic target in chronic inflammatory and neurodegenerative diseases, where enhancing the endogenous antioxidant response can prevent tissue damage (Source: NIH, PMC6164134). Conversely, in oncology, the pathway presents a double-edged sword as its overactivation can promote the survival and chemoresistance of cancer cells (Source: PubMed, PMID: 31405114). Several drugs, including Dimethyl fumarate and Omaveloxolone, are clinically utilized to modulate this axis for treating conditions like multiple sclerosis and Friedreich's ataxia (Source: FDA, Skyclarys Approval). The pathway's regulation is critical for maintaining cellular redox homeostasis and protecting against various metabolic and age-related pathologies.

Other names

NFE2L2-HMOX1 axisNrf2/ARE signaling pathwayNuclear factor erythroid 2-related factor 2-Heme oxygenase 1 signaling cascadeNrf2-mediated antioxidant response

The mechanism involves the pharmacological or stress-induced inhibition of Keap1, which normally targets Nrf2 for proteasomal degradation; this allows Nrf2 to accumulate and translocate into the nucleus where it heterodimerizes with small Maf proteins and binds to the Antioxidant Response Element (ARE) in the promoter of the HMOX1 gene, leading to the transcription and translation of Heme oxygenase 1 (Source: PubMed, PMID: 30005330; UniProt, Q16236).