# Therapeutic Agents Targeting the Nrf2 Signaling Pathway to Combat Oxidative Stress and Intestinal Inflammation in Veterinary and Translational Medicine

## TL;DR

This review explores how activating the Nrf2 pathway can protect the gut from inflammation and oxidative stress using natural and synthetic compounds.

## Contribution

The paper provides a comprehensive review of Nrf2-targeting therapeutic agents for intestinal inflammation in both veterinary and human medicine.

## Key findings

- Nrf2 activation enhances antioxidant defenses and suppresses inflammation in the gut.
- Natural compounds and probiotics modulate Nrf2 to improve intestinal barrier function and microbiota.
- Nrf2 pathway modulation offers a multi-targeted strategy for treating intestinal inflammatory disorders.

## Abstract

The gut plays a critical role in animal and human health, with inflammatory conditions causing significant welfare and economic concerns. This review examines how the Nrf2 signaling pathway protects the intestine from damage caused by oxidative stress and inflammation. We explore various natural compounds (polyphenols, terpenoids, alkaloids), probiotics, and nutritional interventions that activate Nrf2 to enhance antioxidant defenses, suppress inflammatory responses, strengthen intestinal barriers, and beneficially modulate gut microbiota. The evidence demonstrates that Nrf2 activation represents a promising multi-targeted therapeutic strategy for managing intestinal inflammatory disorders in both clinical and livestock settings.

This review synthesizes research on nuclear factor erythroid 2-related factor 2 (Nrf2) in intestinal health across human, livestock, and mouse models. The Nrf2 signaling pathway serves as a master regulator of cellular antioxidant defenses and a key therapeutic target for intestinal inflammatory disorders, including ulcerative colitis and Crohn’s disease. The interplay between oxidative stress, Nrf2 signaling, and NF-κB inflammatory cascades represents a critical axis in the pathogenesis and resolution of intestinal inflammation. Under normal physiological conditions, Nrf2 remains sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (Keap1), which facilitates its ubiquitination and proteasomal degradation. However, during oxidative stress, reactive oxygen species (ROS) and electrophilic compounds modify critical cysteine residues on Keap1, disrupting the Keap1-Nrf2 interaction and enabling Nrf2 nuclear translocation. Once in the nucleus, Nrf2 binds to antioxidant response elements (ARE) in the promoter regions of genes encoding phase II detoxifying enzymes and antioxidant proteins, including heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase. This comprehensive review synthesizes current evidence demonstrating that activation of Nrf2 signaling confers protection against intestinal inflammation through multiple interconnected mechanisms: suppression of NF-κB-mediated pro-inflammatory cascades, enhancement of cellular antioxidant capacity, restoration of intestinal barrier integrity, modulation of immune cell function, and favorable alteration of gut microbiota composition. We systematically examine a diverse array of therapeutic agents targeting Nrf2 signaling, including bioactive peptides, natural polyphenols, flavonoids, terpenoids, alkaloids, polysaccharides, probiotics, and synthetic compounds. The mechanistic insights and therapeutic evidence presented underscore the translational potential of Nrf2 pathway modulation as a multi-targeted strategy for managing intestinal inflammatory conditions and restoring mucosal homeostasis.