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Updated: May 22, 2025

A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells
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Activation, interaction and intimation of Nrf2 pathway and their mutational studies causing Nrf2 associated cancer

Mridul Sahu1, Utkarsh Jain1

  • 1School of Health Sciences and Technology (SoHST), UPES, Bidholi, Dehradun - 248007, India.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|March 15, 2025
PubMed

Insights

Molecular hydrogen activates the Nrf2 pathway, a key defense against oxidative stress and disease. This process involves molecular hydrogen interacting with Keap1, stabilizing Nrf2 and reducing harmful reactive oxygen species.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Signaling

Background:

  • Infection responses generate cytokines, leading to reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage cellular components and contribute to diseases like cancer.
  • The Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is a critical cellular defense mechanism against oxidative stress.

Purpose of the Study:

  • To elucidate the mechanism by which molecular hydrogen activates the Nrf2 pathway.
  • To understand how Nrf2 activation mitigates oxidative damage and prevents disease.

Main Methods:

  • The study focuses on the molecular interactions within the Nrf2-Keap1 pathway.
  • Investigated the role of specific motifs (DLG, ETGE) in Nrf2-Keap1 binding and Nrf2 degradation.
  • Examined the effect of molecular hydrogen on Keap1 and subsequent Nrf2 stabilization.

Main Results:

  • Under oxidative stress, Keap1 undergoes conformational changes, stabilizing Nrf2.
  • Nrf2 translocates to the nucleus, inducing the transcription of antioxidant genes (SOD, GSH, CAT).
  • Molecular hydrogen activates Nrf2 by oxidizing iron porphyrin, which acts as an electrophile interacting with Keap1 cysteine residues, thereby preventing oxidative stress.

Conclusions:

  • Molecular hydrogen serves as a therapeutic agent by activating the Nrf2 pathway.
  • Nrf2 pathway activation is crucial for cellular protection against oxidative damage and disease development.
  • Targeting the Nrf2-Keap1 interaction with agents like molecular hydrogen offers a promising strategy for disease prevention.
Keywords:
Antioxidant response elementKeap1Molecular hydrogenNrf2Reactive oxygen species

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