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Related Experiment Video

Updated: Apr 5, 2026

Protocol for the Differentiation of Human Induced Pluripotent Stem Cells into Mixed Cultures of Neurons and Glia for Neurotoxicity Testing
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Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation.

Jeong Su Park1, Dong Hoon Kang2, Da Hyun Lee1

  • 1Severance Biomedical Science Institute, Republic of Korea; Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea.

Biochemical and Biophysical Research Communications
|August 19, 2015
PubMed
Summary

Fenofibrate triggers cell death by inducing reactive oxygen species (ROS). The study reveals p62 protein prevents this by mediating the Nrf2-Keap1 pathway activation, crucial for cellular defense against oxidative stress.

Keywords:
AutophagyFenofibrateKeap1Nrf2PPARαp62

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Area of Science:

  • Cellular biology
  • Biochemistry
  • Pharmacology

Background:

  • Peroxisome proliferator-activated receptor α (PPARα) agonists like fenofibrate treat hyperlipidemia but can induce cell death via reactive oxygen species (ROS).
  • The Nrf2-Keap1 pathway is vital for cellular defense against oxidative stress, but its role in fenofibrate-induced cell death is unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism of the Nrf2-Keap1 pathway in fenofibrate-induced cell death.
  • To investigate the role of p62 in regulating this pathway and cellular response to fenofibrate.

Main Methods:

  • Investigated fenofibrate's effect on Keap1 degradation and Nrf2 activation in liver cells.
  • Utilized autophagy-related assays to assess fenofibrate-mediated Keap1 degradation.
  • Employed p62 knockout models to evaluate its role in fenofibrate toxicity and ROS accumulation.

Main Results:

  • Fenofibrate treatment led to Keap1 degradation and subsequent Nrf2 activation.
  • Keap1 degradation was partially dependent on autophagy and primarily mediated by the adaptor protein p62.
  • Ablation of p62 exacerbated fenofibrate-induced cell death and ROS accumulation.

Conclusions:

  • p62 plays a critical role in the autophagic degradation of Keap1, thereby activating Nrf2.
  • This p62-mediated pathway is essential for cellular protection against fenofibrate-induced oxidative stress and apoptosis.