Health position paper and redox perspectives – Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases

Antonio Cuadrado; Eduardo Cazalla; Anders Bach; Boushra Bathish; Sharadha Dayalan Naidu; Gina M. DeNicola; Albena T. Dinkova-Kostova; Raquel Fernández-Ginés; Anna Grochot-Przeczek; John D. Hayes; Thomas W. Kensler; Rafael León; Karen T. Liby; Manuela G. López; Gina Manda; Akshatha Kalavathi Shivakumar; Henriikka Hakomäki; Jessica A. Moerland; Hozumi Motohashi; Ana I. Rojo; Gerasimos P. Sykiotis; Keiko Taguchi; Ángela M. Valverde; Masayuki Yamamoto; Anna Liisa Levonen

doi:10.1016/j.redox.2025.103569

Health position paper and redox perspectives – Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases

Antonio Cuadrado (Lead / Corresponding author), Eduardo Cazalla, Anders Bach, Boushra Bathish, Sharadha Dayalan Naidu, Gina M. DeNicola, Albena T. Dinkova-Kostova, Raquel Fernández-Ginés, Anna Grochot-Przeczek, John D. Hayes, Thomas W. Kensler, Rafael León, Karen T. Liby, Manuela G. López, Gina Manda, Akshatha Kalavathi Shivakumar, Henriikka Hakomäki, Jessica A. Moerland, Hozumi Motohashi, Ana I. RojoGerasimos P. Sykiotis, Keiko Taguchi, Ángela M. Valverde, Masayuki Yamamoto, Anna Liisa Levonen (Lead / Corresponding author)

Cancer Research

Research output: Contribution to journal › Review article › peer-review

3 Citations (Scopus)

9 Downloads (Pure)

Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.

Original language	English
Article number	103569
Number of pages	40
Journal	Redox Biology
Volume	81
Early online date	3 Mar 2025
DOIs	https://doi.org/10.1016/j.redox.2025.103569
Publication status	Published - Apr 2025

Keywords

Drug repurposing
GSK-3
KEAP1
NRF2 diseasome
β-TrCP

ASJC Scopus subject areas

Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.redox.2025.103569Licence: CC BY-NC-ND

Final published version
Available online 3 March 2025 2213-2317/© 2025 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Final published version, 10.5 MBLicence: CC BY-NC-ND

Cite this

Cuadrado, A., Cazalla, E., Bach, A., Bathish, B., Naidu, S. D., DeNicola, G. M., Dinkova-Kostova, A. T., Fernández-Ginés, R., Grochot-Przeczek, A., Hayes, J. D., Kensler, T. W., León, R., Liby, K. T., López, M. G., Manda, G., Shivakumar, A. K., Hakomäki, H., Moerland, J. A., Motohashi, H., ... Levonen, A. L. (2025). Health position paper and redox perspectives – Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases. Redox Biology, 81, Article 103569. https://doi.org/10.1016/j.redox.2025.103569

@article{dbc7e3b689064a479a13c3de584849de,

title = "Health position paper and redox perspectives – Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases",

abstract = "Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.",

keywords = "Drug repurposing, GSK-3, KEAP1, NRF2 diseasome, β-TrCP",

author = "Antonio Cuadrado and Eduardo Cazalla and Anders Bach and Boushra Bathish and Naidu, \{Sharadha Dayalan\} and DeNicola, \{Gina M.\} and Dinkova-Kostova, \{Albena T.\} and Raquel Fern{\'a}ndez-Gin{\'e}s and Anna Grochot-Przeczek and Hayes, \{John D.\} and Kensler, \{Thomas W.\} and Rafael Le{\'o}n and Liby, \{Karen T.\} and L{\'o}pez, \{Manuela G.\} and Gina Manda and Shivakumar, \{Akshatha Kalavathi\} and Henriikka Hakom{\"a}ki and Moerland, \{Jessica A.\} and Hozumi Motohashi and Rojo, \{Ana I.\} and Sykiotis, \{Gerasimos P.\} and Keiko Taguchi and Valverde, \{{\'A}ngela M.\} and Masayuki Yamamoto and Levonen, \{Anna Liisa\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = apr,

doi = "10.1016/j.redox.2025.103569",

language = "English",

volume = "81",

journal = "Redox Biology",

issn = "2213-2317",

publisher = "Elsevier",

}

Cuadrado, A, Cazalla, E, Bach, A, Bathish, B, Naidu, SD, DeNicola, GM, Dinkova-Kostova, AT, Fernández-Ginés, R, Grochot-Przeczek, A, Hayes, JD, Kensler, TW, León, R, Liby, KT, López, MG, Manda, G, Shivakumar, AK, Hakomäki, H, Moerland, JA, Motohashi, H, Rojo, AI, Sykiotis, GP, Taguchi, K, Valverde, ÁM, Yamamoto, M & Levonen, AL 2025, 'Health position paper and redox perspectives – Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases', Redox Biology, vol. 81, 103569. https://doi.org/10.1016/j.redox.2025.103569

TY - JOUR

T1 - Health position paper and redox perspectives – Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases

AU - Cuadrado, Antonio

AU - Cazalla, Eduardo

AU - Bach, Anders

AU - Bathish, Boushra

AU - Naidu, Sharadha Dayalan

AU - DeNicola, Gina M.

AU - Dinkova-Kostova, Albena T.

AU - Fernández-Ginés, Raquel

AU - Grochot-Przeczek, Anna

AU - Hayes, John D.

AU - Kensler, Thomas W.

AU - León, Rafael

AU - Liby, Karen T.

AU - López, Manuela G.

AU - Manda, Gina

AU - Shivakumar, Akshatha Kalavathi

AU - Hakomäki, Henriikka

AU - Moerland, Jessica A.

AU - Motohashi, Hozumi

AU - Rojo, Ana I.

AU - Sykiotis, Gerasimos P.

AU - Taguchi, Keiko

AU - Valverde, Ángela M.

AU - Yamamoto, Masayuki

AU - Levonen, Anna Liisa

PY - 2025/4

Y1 - 2025/4

N2 - Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.

AB - Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.

KW - Drug repurposing

KW - GSK-3

KW - KEAP1

KW - NRF2 diseasome

KW - β-TrCP

UR - http://www.scopus.com/inward/record.url?scp=86000365094&partnerID=8YFLogxK

U2 - 10.1016/j.redox.2025.103569

DO - 10.1016/j.redox.2025.103569

M3 - Review article

C2 - 40059038

AN - SCOPUS:86000365094

SN - 2213-2317

VL - 81

JO - Redox Biology

JF - Redox Biology

M1 - 103569

ER -

Health position paper and redox perspectives – Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

The Role of Nrf2 in the Tumour Microenvironment of IDH Wild-Type Glioma (Joint with University of Edinburgh)

Defining the Oxidative Stress-Related Mechanisms by which Activation of the Transcription Factor Nrf2 Arrests and Resolves Liver Fibrosis

Cite this

Health position paper and redox perspectives – Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

The Role of Nrf2 in the Tumour Microenvironment of IDH Wild-Type Glioma (Joint with University of Edinburgh)

Defining the Oxidative Stress-Related Mechanisms by which Activation of the Transcription Factor Nrf2 Arrests and Resolves Liver Fibrosis

Cite this