Targeting the NRF2 pathway for disease modification in neurodegenerative diseases: mechanisms and therapeutic implications

Summary

This narrative review examines NRF2 (nuclear factor-erythroid 2-related factor 2) as a therapeutic target for neurodegenerative disease modification. The authors synthesise evidence on NRF2's role in regulating antioxidant, anti-inflammatory, and mitochondrial defence pathways—all implicated in neurodegeneration—and critically appraise existing pharmacological activators and their limitations, whilst exploring alternative therapeutic approaches. The review positions NRF2 activation as a disease-modifying strategy rather than symptomatic treatment, addressing a significant unmet clinical need.

Regional applicability

This is a mechanistic and pharmacological review with no specific geographical focus; its applicability to United Kingdom clinical and research settings depends on translational validation of the reviewed approaches in human trials. The underlying biology and therapeutic rationale are internationally relevant, though implementation would require adaptation to UK regulatory and NHS frameworks.

Key measures

NRF2 pathway activation mechanisms; effectiveness of pharmacological interventions targeting NRF2; relevance to protein aggregation, oxidative stress, neuroinflammation, and mitochondrial dysfunction in neurodegeneration

Outcomes reported

The paper reviews the role of NRF2 transcription factor in regulating cellular defence mechanisms (antioxidant, anti-inflammatory, and mitochondrial pathways) and describes current and alternative pharmacological approaches to activate this pathway for disease modification in neurodegenerative disorders.

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