ALDH3A1-dependent Nrf2/HO-1/GPX4 pathway supports AHR as a promising therapeutic target for ferroptosis and promotes imperatorin-mediated lung protection

  • Cell Death Discov. 2026 Jan 9;12(1):16. doi: 10.1038/s41420-025-02860-8.
Xiaominting Song  1 ,  Wenya Yang  1 ,  Hang You  1  2 ,  Shan Qian  3 ,  Xiaoxue Hu  1 ,  Ao Zhang  1 ,  Jia Li  1 ,  Yuzhi Li  1 ,  Huachao Bin  4 ,  Cheng Peng  1 ,  Jin Pei  5 ,  Zhixing Cao  6
Affiliations
  • 1. State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
  • 2. Department of Pharmaceutical Engineering, College of Food and Bioengineering, Xihua University, Chengdu, China.
  • 3. Department of Pharmaceutical Engineering, College of Food and Bioengineering, Xihua University, Chengdu, China. [email protected].
  • 4. Institute of Herbgenomics, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
  • 5. State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China. [email protected].
  • 6. State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China. [email protected].
PMID: 41513604 DOI: 10.1038/s41420-025-02860-8
Abstract

The Aryl Hydrocarbon Receptor (AHR) is a transcription factor prominently expressed at barrier sites, while aldehyde dehydrogenase 3 family member A1 (ALDH3A1) is a metabolic enzyme implicated in oxidative stress. However, their roles in Ferroptosis remain poorly understood. Imperatorin (IMP) is a bioactive compound derived from traditional Chinese medicine. Here, we demonstrate that IMP is a natural agonist of AHR, inhibiting LPS-induced Ferroptosis, inflammation, and barrier damage in lung epithelial cells by promoting AHR nuclear translocation and activation. Mechanistically, IMP-activated AHR stimulated the Nrf2/HO-1/GPX4 axis and enhanced ALDH3A1 expression, thereby inhibiting ferroptosis-related Fe2+ accumulation, ROS production, and lipid peroxidation. The in vivo results showed that oral IMP activated the AHR/ALDH3A1 and Nrf2/HO-1/GPX4 pathways in lung tissue, thus improving lung dysfunction and inflammation in acute lung injury (ALI) mice induced by LPS. Notably, ALDH3A1 is a key downstream signaling protein of AHR. An AHR inhibitor reversed the IMP-induced upregulation of ALDH3A1, whereas an ALDH3A1 inhibitor blocked the anti-ferroptotic Nrf2/HO-1/GPX4 pathway and diminished the lung-protective effects of IMP-activated AHR both in vitro and in vivo. These findings indicate that the AHR/ALDH3A1 axis may represent a previously unrecognized therapeutic target for Ferroptosis and provide insight into IMP as a therapeutic strategy to prevent and treat ALI.

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