# Nrf2-Activating Natural Compounds in Neurodegenerative Diseases: Targeting Oxidative Stress and Protein Aggregation

## TL;DR

This paper reviews natural compounds that activate Nrf2 to combat oxidative stress and protein aggregation in neurodegenerative diseases.

## Contribution

The paper highlights Nrf2-inducing natural compounds as multi-target neuroprotective agents for diseases like Alzheimer’s and Parkinson’s.

## Key findings

- Nrf2 activation is critical for antioxidant and proteostatic responses in neurodegenerative diseases.
- Natural compounds from plants, fungi, and marine sources show neuroprotective potential via Nrf2 pathways.
- These compounds may complement existing therapies by targeting multiple disease mechanisms.

## Abstract

Neurodegenerative diseases (NDs) are among the leading causes of disability and mortality worldwide and are characterized by multifactorial pathogenesis involving interconnected mechanisms, such as oxidative stress, protein misfolding and aggregation, neuroinflammation, and mitochondrial dysfunction. Dysregulation of transcription factors, governing cellular defense responses, particularly nuclear factor erythroid 2–related factor 2 (Nrf2), a key regulator of antioxidant and proteostatic pathways, plays a critical role in neurodegenerative processes. Currently, available pharmacological treatments for NDs are largely symptomatic, as no disease-modifying therapies exist. Natural bioactive compounds have emerged as promising multi-target agents, demonstrating antioxidant, anti-aggregative, and anti-apoptotic properties, frequently mediated through activation of the Nrf2 signaling pathways. These compounds may represent valuable supportive strategies alongside conventional drug treatments, potentially contributing to the modulation of multiple pathogenic mechanisms. This review summarizes key oxidative stress- and protein aggregation-driven mechanisms underlying Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. It further examines the neuroprotective potential of plant-, fungi-, and marine-derived natural compounds, with particular emphasis on Nrf2 activation. Beyond redox regulation, the broader role of Nrf2 in maintaining proteostasis is discussed. Overall, the review highlights Nrf2-inducing nutraceuticals as promising complementary, multi-target approaches for neuroprotection in NDs.