Ipriflavone From Aquilaria malaccensis Lam. Exosome‐Like Nanoparticles Targets Prolyl Hydroxylase Domain Protein 2 (PHD2) to Enhance Hypoxia‐Inducible Factor‐α (HIF‐α) Hydroxylation Thereby Alleviating Hypoxia‐Induced Gastrointestinal Mucosal Ferroptosis

ABSTRACT The major challenge in the clinical treatment of gastrointestinal mucosal injury caused by high‐altitude hypoxic environments lies in its unclear underlying mechanisms. In the previous study, we found that hypoxia‐induced gastric and small intestinal damage was mainly attributable to ferroptosis mediated by hypoxia‐inducible factor‐α (HIF‐α; mainly HIF‐1α and HIF‐2α). Both plant exosome‐like nanoparticles and Aquilaria malaccensis Lam. have been reported to have antioxidant properties. In the present study, orally delivered A. malaccensis Lam. exosome‐like nanoparticles (AELNs) reduced HIF‐1α expression and alleviated gastric and small intestinal mucosal ferroptosis induced by hypoxia. We analyzed the compositions of AELNs and hypothesized that ipriflavone was the effector component, as it showed the highest abundance of metabolites. Subsequent experiments demonstrated that ipriflavone downregulated polyunsaturated fatty acid‐phospholipids, NADPH oxidase 4 (NOX4), and arachidonate 5‐lipoxygenase (ALOX5) by inhibiting HIF‐α, consequently alleviating hypoxia‐induced gastric and small intestinal mucosal ferroptosis. Ipriflavone was found to inhibit HIF‐α by targeting prolyl hydroxylase domain protein 2 (PHD2) to induce it to hydroxylate HIF‐α. This study highlights that ipriflavone, a potent HIF‐α inhibitor, significantly ameliorates the gastric and small intestinal mucosal damage caused by hypoxia and has promise in clinical applications for treating disorders characterized by high levels of HIF‐α.