Targeting NRF2 With Isoeugenol - A Promising Small Molecule for Neurodegenerative, Metabolic, and Chronic Inflammatory Disorders

Sep 29, 2026

Oxidative stress from redox imbalance drives chronic disorders including cancer, diabetes, neurodegenerative disease, and aging. The NRF2–KEAP1 pathway coordinates transcription of cytoprotective genes, and pharmacological NRF2 activation is viewed as a strategy to reduce oxidative-stress–related pathology. Isoeugenol, a phenylpropanoid from essential oils, shows antioxidant, anti-inflammatory, and neuroprotective actions and may modulate metabolic diseases. This review analyzes how isoeugenol activates NRF2—via KEAP1 cysteine modification, AKT activation with GSK3β inactivation, and glutathione depletion with ROS generation—and discusses translational implications and future clinical optimization.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

The KEAP1–NRF2 Pathway

Wiley Oxidative Medicine and Cellular Longevity Volume 2025, Article ID 7695056, 12 pages [https://doi.org/10.1155/omcl/7695056](https://doi.org/10.1155/omcl/7695056) Review Article Targeting NRF2 With Isoeugenol: A Promising Small Molecule for Neurodegenerative, Metabolic, and Chronic Inﬂammatory Disorders Ana Silva , 1,2,3,4 Sónia Silva ,2,3 Beatriz Rodrigues , 1,3,4,5 Gonçalo Simões, 1,3,4 Inês Dinis,2 Mafalda Freitas,2 Rosa Resende , 1,3,4 Joana Bicker ,2,6 Ana Fortuna ,2,6 Maria M. Silva , 1,2,3,4 Armanda E. Santos , 1,2,3,4 Sónia A. Pinho , 1,3,4 Bruno Neves ,7 Cláudia Fragão Pereira, 1,3,4,8 and Maria Teresa Cruz 1,2,3,4 1Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3000-548, Portugal 2Faculty of Pharmacy, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3000-548, Portugal 3CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3000-548, Portugal 4CAC-CHUC, Clinical Academy Center of Coimbra Hospital and University Center, Coimbra, Portugal 5CEMMPRE—Centre for Mechanical Engineering, Materials and Processes, Coimbra, Portugal 6CIBIT/ICNAS-Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra, Azinhaga de Santa Comba, Coimbra 3000-548, Portugal 7iBiMED, Department of Medical Sciences and Institute of Biomedicine, University of Aveiro, Aveiro 3810-193, Portugal 8Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal Correspondence should be addressed to Ana Silva; [anacrs@cnc.uc.pt](anacrs@cnc.uc.pt) and Maria Teresa Cruz; [trosete@ff.uc.pt](trosete@ff.uc.pt)[ ](trosete@ff.uc.pt)Received 4 March 2025; Revised 29 July 2025; Accepted 16 October 2025 Academic Editor: Sandra Moreno Copyright © 2025 Ana Silva et al. Oxidative Medicine and Cellular Longevity published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Oxidative stress, driven by an imbalance between oxidants and antioxidants, disrupts redox homeostasis and contributes to the development of chronic diseases, including cancer, diabetes, neurodegenerative disorders, and aging. The NRF2-KEAP1 pathway is a pivotal cellular defense mechanism against oxidative stress, regulating the transcription of cytoprotective genes. Pharmacological NRF2 activation has emerged as a promising strategy to mitigate oxidative stress-related pathologies; however, challenges regarding target speciﬁcity, pharmacodynamics, efﬁcacy, and safety remain unresolved. Isoeugenol, a phenylpropanoid found in essential oils, has traditionally been recognized as a skin allergen but is now gaining attention for its potential as an NRF2 activator. Emerging evidence suggests that isoeugenol exerts antioxidant, anti-inﬂammatory, and neuroprotective effects and modulates metabolic disorders such as diabetes mellitus. Despite its therapeutic potential, the direct correlation between isoeugenol’s effects and NRF2 activation remains underexplored. Existing studies indicate that isoeugenol may activate NRF2 through multiple mechanisms, including covalent modiﬁcation of KEAP1 cysteine residues, increased AKT activation and GSK3β inactivation, and glutathione depletion leading to reactive oxygen species (ROS) generation. Understanding these activation pathways is critical for leveraging isoeugenol as a therapeutic agent. This review provides a comprehensive analysis of isoeugenol’s role in modulating NRF2 activity and its implications for treating oxidative stress-driven diseases. By integrating current ﬁndings, this review highlights new insights into the therapeutic potential of isoeugenol in translational medicine. We propose future research directions to optimize its application in clinical settings, paving the way for more targeted and effective NRF2-based interventions

FAQs

What role does the NRF2–KEAP1 pathway play in oxidative stress?

It is a key cellular defense mechanism that regulates transcription of cytoprotective genes, helping counter oxidative-stress damage.

Why is NRF2 activation considered a promising therapeutic approach?

Pharmacological activation can mitigate oxidative-stress–related pathologies, though issues such as specificity, pharmacodynamics, efficacy, and safety still need resolution.

How might isoeugenol activate NRF2 according to the review?

It may activate NRF2 through covalent modification of KEAP1 cysteine residues, increased AKT activation with GSK3β inactivation, and glutathione depletion that generates ROS.

Sep 29, 2026

Upload by Mafia Boss