Nrf2 Modulation by Natural Compounds in Aging, Neurodegeneration, and Neuropathic Pain

TL;DR

This review explores how Nrf2, a key regulator of antioxidant responses, is linked to aging, neurodegeneration, and neuropathic pain, and how natural compounds can modulate it.

Contribution

The paper highlights Nrf2 as a unifying target for aging-related conditions and evaluates natural modulators and their translational challenges.

Findings

Reduced Nrf2 activity is associated with oxidative stress and inflammation in aging and neurodegenerative diseases.

Nrf2 modulation by natural compounds shows promise but faces challenges like poor bioavailability and safety concerns.

Future research should focus on improving delivery systems and evaluating Nrf2 modulators in combination with standard therapies.

Abstract

This review summarizes the role of nuclear factor erythroid 2–related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders—including Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis—evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management.

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