用於誘發鐵死亡具時空可控及光觸發螯合劑之開發

Abstract

生物體中過多的鐵會催化脂質過氧化物的生成，進而誘導細胞進行一種稱為「鐵死亡」的新型細胞死亡方式。然而，常見的鐵死亡觸發藥物在生理環境下普遍缺乏精確的空間與時間控制性。在此，我們設計了光觸發的鐵螯合分子oNPE-(HQ)2，可作為時空可控的鐵死亡觸發工具。經過光照後oNPE-(HQ)2表現出對鐵的螯合力呈現斷崖式下跌(至少差距14,454倍)，隨後光解產物上的側鏈酰胺基團在生理條件下表現出能顯著加速芬頓反應的特性。此外，原始的oNPE-(HQ)2能有效補捉內源性的鐵，而預先錯合的Fe(Ⅲ)-oNPE-(HQ)2錯合物則透過調降GPX4蛋白的表達進而導致鐵死亡的發生。總體而言，我們提供了一種非侵入性的化學生物學工具，可應用於研究鐵死亡中胞器之間的動態交互作用。我們希望在未來光控金屬釋放的策略，可進一步延伸至銅、鎳、鋅等其他過渡金屬，爲更廣泛的金屬生物學研究奠定基石。

Iron catalyzes lipid peroxide generation, inducing a novel form of cell death called ferroptosis. However, conventional small-molecule ferroptosis inducers are constrained by a lack of precise spatial and temporal control under physiological conditions. Herein, we report the design of a phototriggerable chelator, oNPE-(HQ)2, acting as a phototriggerable ferroptosis inducer. Upon photoirradiation, oNPE-(HQ)2 exhibits a dramatic decrease (at least 14,454-fold) in iron-binding affinity. Subsequently, the pendant amide on the photolyzed counterpart accelerates the Fenton reaction under physiological conditions. Furthermore, the pristine oNPE-(HQ)2 captures endogenous iron, and the preformed Fe(Ⅲ)-oNPE-(HQ)2 complex triggers ferroptosis via the GPX4 downregulation pathway. Overall, this work offers a non-invasive chemical biology tool for investigating organelle-level interactions during the ferroptotic process. Through our strategy, phototriggerable metal release can be extended to alternative transition metals, such as copper, nickel, and zinc, to investigate broader metallobiological processes.