The tryptophan metabolite 3-hydroxyanthranilic acid alleviates hyperoxia-induced bronchopulmonary dysplasia via inhibiting ferroptosis
Qiqi Ruan, Yingqiu Peng, X. Yi, Jingli Yang, Qing Ai, Xiaochen Liu, Yu He, Yuan Shi
Abstract
Bronchopulmonary dysplasia (BPD) is a prevalent chronic respiratory condition in preterm infants with increasing incidence, severely affecting their survival rate and quality of life. Exploring the underlying mechanisms of BPD helps to develop novel effective therapeutic strategies. In this study, integrated metabolomic analyses of tracheal aspirates (TAs) from BPD infants and non-BPD infants, along with lung tissues from hyperoxia-induced experimental BPD neonatal rats and control rats, demonstrated that BPD was associated with a significant reduction in 3-hydroxyanthranilic acid (3-HAA), which was confirmed to be partly caused by tryptophan-metabolizing enzyme disorders. In vivo and in vitro models were subsequently developed to assess the efficacy and underlying mechanisms of 3-HAA in relation to BPD. Compared with the BPD group, 3-HAA nebulization improved lung development and suppressed inflammation in rats. Limited proteolysis-small molecule mapping (LiP-SMap) proteomics analysis revealed the involvement of the ferroptosis pathway in the underlying mechanism by which 3-HAA alleviated hyperoxia-induced BPD damage. Ferroptosis was identified by detecting Fe 2+ levels, malondialdehyde (MDA), 4-HNE, total aldehydes, mitochondrial morphology, ferroptosis-associated protein expression and mRNA expression, and this dysregulation was indeed ameliorated by 3-HAA nebulization in vivo. Furthermore, a combination of LiP-SMap, molecular docking, SPR and Co-IP analyses confirmed that 3-HAA can bind directly to FTH1 and disrupt the nuclear receptor coactivator 4 (NCOA4)-FTH1 interaction. In conclusion, our study is the first to reveal that BPD is linked to the reduction of 3-HAA, which could inhibit the ferroptosis pathway by targeting FTH1, thereby alleviating hyperoxia-induced damage in rats and alveolar type II epithelial cells, highlighting the potential of targeting 3-HAA and ferroptosis for clinical applications in BPD. • BPD is associated with dysregulation of tryptophan metabolism and a significant reduction in its metabolite 3-hydroxyanthranilic acid (3-HAA). • 3-HAA protects against hyperoxia-induced damage by inhibiting ferroptosis in lung tissue and alveolar type II epithelial cells (AECII). • 3-HAA inhibits the ferroptosis pathway by targeting FTH1 and disrupting the NCOA4-FTH1 interaction, thereby alleviating hyperoxia-induced damage in AECII. • This study is the first to reveal the dysregulation of tryptophan metabolism in BPD and explore the underlying mechanism of 3-HAA in alleviating BPD, indicating the potential of targeting 3-HAA and ferroptosis for clinical applications in BPD.