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

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.

Key Findings

• NRF2 signaling regulates glutathione metabolism, lipid peroxidation, and iron homeostasis, which are critical pathways contributing to ferroptosis.
• Abnormal NRF2 activity in cancer cells promotes survival, proliferation, and treatment resistance by evading oxidative stress.
• Therapies targeting the NRF2-ferroptosis pathway, including natural and synthetic NRF2 modulators and ferroptosis inducers, show promise in overcoming drug resistance and enhancing antitumor efficacy.
• Current challenges for clinical application include tumor heterogeneity, treatment selectivity, biomarker validation, and potential toxicity to normal tissues.
• Ongoing research in biomarker discovery and precision medicine aims to improve targeting and effectiveness of NRF2-ferroptosis modulation therapies.

Clinical Significance

Citation

Ulker Ozge Cemiloglu, Capozzi Antonella, Sari-Goktas Nisa Nuret al.. Recent advancements in NRF2-regulated ferroptosis modulation for targeted cancer therapy. Molecular biology reports. 2026-Sep-05.