Nrf2 Activation in Inflammatory Diseases: A Review of Natural and Synthetic Modulators

TL;DR

This review explores how activating the Nrf2 pathway can help reduce inflammation and oxidative stress in diseases, but also warns of potential risks in cancer.

Contribution

The paper provides a comprehensive review of Nrf2 modulators and their mechanisms in inflammatory diseases.

Findings

Nrf2 activation reduces oxidative damage and inflammation in diseases like rheumatoid arthritis and diabetes.

Natural and synthetic Nrf2 activators work through diverse molecular mechanisms.

Prolonged Nrf2 activation may promote cancer cell survival and resistance to treatment.

Abstract

The nuclear factor erythroid 2–related factor 2 (Nrf2) pathway is a central regulator of the cellular antioxidant response, playing a key role in modulating inflammation and defending against oxidative stress‐induced damage. A range of natural and synthetic compounds, including dimethyl fumarate, bardoxolone, oltipraz, RTA‐408, ursodiol, curcumin, sulforaphane, and resveratrol, have been shown to activate Nrf2 via distinct molecular mechanisms, thereby enhancing the expression of cytoprotective and antioxidant genes. These mechanisms include direct dissociation from Keap1, activation of AMP‐activated protein kinase, and modulation of signaling pathways relevant to cellular stress and immune regulation. In inflammatory diseases such as rheumatoid arthritis, periodontitis, diabetes mellitus, and inflammatory bowel diseases, Nrf2 activation has been associated with attenuation of oxidative damage, suppression of proinflammatory mediators, and improved tissue homeostasis. However, sustained or dysregulated activation of Nrf2 may promote tumor cell survival, proliferation, and chemoresistance, particularly in oncologic contexts. This narrative review synthesizes mechanistic insights and preclinical and clinical evidence on the role of Nrf2 in inflammatory diseases and evaluates the therapeutic potential of its key activators. The dual nature of Nrf2, as both a cytoprotective and potentially oncogenic factor, highlights the importance of context‐specific and temporally controlled modulation. A better understanding of these dynamics is essential for optimizing clinical applications and minimizing therapeutic risks.

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