Related Experiment Video

Updated: Aug 19, 2026

Revealing the Ferroptotic Phenotype of Medulloblastoma
04:01

Revealing the Ferroptotic Phenotype of Medulloblastoma

Published on: March 15, 2024

A targetable ALDH3A2-NRF2 axis mediates KEAP1-mutant tumour development via ferroptosis inhibition

Li Yang1, Xiao Zhuang2, Jing Han3

  • 1Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China.

Cell Death and Differentiation
|August 18, 2026
PubMed

Insights

Aldehyde dehydrogenase 3A2 (ALDH3A2) activates nuclear factor erythroid 2-related factor 2 (NRF2), inhibiting ferroptosis and stabilizing NRF2. This discovery reveals a new NRF2 pathway and targets KEAP1-mutant tumors.

Area of Science:

  • Cellular biology
  • Molecular oncology
  • Biochemistry

Background:

  • Nuclear factor erythroid 2-related factor 2 (NRF2) regulates antioxidant responses, ferroptosis, and tumor progression.
  • Kelch-like ECH-associated protein 1 (KEAP1) mutations are common in tumors and affect NRF2 activity.

Purpose of the Study:

  • Identify novel regulators of NRF2.
  • Investigate the role of aldehyde dehydrogenase 3 family member A2 (ALDH3A2) in NRF2 activation and ferroptosis.
  • Explore ALDH3A2 as a therapeutic target in KEAP1-mutant tumors.

Main Methods:

  • Aldehyde dehydrogenase (ALDH) family shRNA screen.
  • In vitro and in vivo experiments assessing NRF2 activation, ferroptosis, and protein stabilization.
  • Analysis of glycogen synthase kinase 3 beta (GSK3β) and beta-transducin repeat-containing protein (BTRC) interactions with NRF2.

Main Results:

  • ALDH3A2 was identified as a potent NRF2 activator that inhibits ferroptosis.
  • ALDH3A2 stabilizes NRF2 by inhibiting GSK3β phosphorylation and blocking BTRC recruitment, independent of its enzymatic activity.
  • ALDH3A2 activates NRF2 in both wild-type and mutant KEAP1 tumor cells.

Conclusions:

  • A novel NRF2 regulatory pathway involving ALDH3A2 was discovered.
  • ALDH3A2 represents a promising druggable target for KEAP1-mutant tumors due to its ability to suppress ferroptosis and stabilize NRF2.

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