Recent advancements in NRF2-regulated ferroptosis modulation for targeted cancer therapy.

Authors

Ozge Cemiloglu Ulker, Antonella Capozzi, Nisa Nur Sari-Goktas, Maurizio Sorice, Luciano Saso, Brigitta Buttari

Published in

Molecular biology reports. Volume 53. Issue 1. Sep 05, 2026. Epub Sep 05, 2026.

Abstract

The nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway is a major regulator of cellular response to oxidative stress. While NRF2 protects the normal cells against oxidative stress, its abnormal signaling activity in the context of cancer helps tumor cells evade oxidative stress, survive, proliferate, and develop resistance to treatment. Increasing evidence has established the tight connection between NRF2 signaling and ferroptosis, a type of programmed cell death based on iron-dependent lipid oxidation. In this review, the role of NRF2 in regulating important pathways as glutathione metabolism, lipid peroxidation, and iron homeostasis that contribute to the process of ferroptosis is discussed. This review highlights the latest progress that has been made in therapies that are designed to target the NRF2-ferroptosis pathway in cancers, by providing an overview of the mechanism involved as well as relevant pre-clinical and current clinical studies. The latest advancements regarding the NRF2 modulators and ferroptosis inducers, both natural and synthetic, along with new studies regarding the ability of such compounds to overcome drug resistance and increase antitumor effectiveness are reviewed.In addition, it is addressed current studies in biomarker discovery, precision medicine, drug targeting in terms of future direction. Moreover, the existing limitations related to clinical application of NRF2 and ferroptosis modulation therapies are also described, including tumor heterogeneity, treatment selectivity, biomarker validation, and possible toxicity of such therapy to normal tissue.Overall, these developments provide the rationale for the clinical application of the NRF2-ferroptosis pathway as a therapeutic target in overcoming drug resistance.

PMID:
42700331
Bibliographic data and abstract were imported from PubMed on 06 Sep 2026.

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