Ferrous Iron Metabolism Modulator for Immune Stress Regulation and Its Application in Skin Allograft Models

The dysregulation of ferrous iron (Fe²⁺) metabolism, which is closely linked to immune stress, plays a pivotal role in driving pathological processes such as ferroptosis and hyperinflammation. Therefore, it is crucial to modulate Fe²⁺ metabolism to alleviate iron overload and immune stress. However, current iron chelators, which are commonly used as iron metabolism modulators, primarily target ferric ions (Fe³⁺), the downstream oxidation product of Fe²⁺. This approach not only limits their modulation efficacy but also poses a risk of disrupting Fe³⁺ homeostasis in healthy tissues. Herein, a novel Fe²⁺ metabolism modulator, DHU-Feex1, was developed by optimizing the electronic structure of iron chelators through theoretical calculations. DHU-Feex1 preferentially recognized Fe²⁺ and effectively inhibited the iron-mediated Fenton reaction. Additionally, by responding to hydroxyl radicals and sequentially scavenging Fe³⁺, DHU-Feex1 mitigated the harmful effects of ferroptosis. <i>In vivo</i> validation using a mouse skin allograft model demonstrated the therapeutic potential of DHU-Feex1. The modulator remarkably prolonged graft survival and reduced immune rejection by precisely regulating immune responses. Gene and protein expression analyses further revealed that DHU-Feex1 effectively regulated ferroptosis-related pathways and suppressed inflammation, confirming its role as an immunomodulatory agent. In summary, this study presents DHU-Feex1 as a promising strategy for modulating immune responses, particularly in diseases associated with Fe²⁺ metabolism disorders.