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

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

SUBMITTER: Song X 

PROVIDER: S-EPMC12789433 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature