铁稳态失调是多种病理学的基础，从缺血再灌注损伤到上皮间质转化和耐药“持续”癌细胞状态。在这里，我们介绍了二价铁可激活荧光素-1 (FeAL-1)，这是一种小分子探针，用于对表达荧光素酶的细胞和动物中的不稳定铁库 (LIP) 进行生物发光成像。我们发现，FeAL-1 可以检测补充铁、耗尽铁或用铁调素（哺乳动物生理学中全身铁的主要调节剂）治疗后细胞中 LIP 的波动。利用 FeAL-1 和双荧光素酶报告系统，我们量化了小鼠肝脏和三种不同原位胰腺导管腺癌肿瘤中的 LIP。我们观察到，与健康肝脏（哺乳动物铁储存的主要器官）相比，异种移植肿瘤中的 FeAL-1 生物发光信号增加了 10 倍。正如预测的那样，用铁调素治疗小鼠进一步升高了肝 LIP。这些研究揭示了肿瘤 LIP 和肝脏 LIP 之间的治疗指数，并提出了一种使肿瘤对 LIP 激活疗法敏感的方法。版权所有 © 2023 Elsevier Ltd。保留所有权利。

Dysregulated iron homeostasis underlies diverse pathologies, from ischemia-reperfusion injury to epithelial-mesenchymal transition and drug-tolerant "persister" cancer cell states. Here, we introduce ferrous iron-activatable luciferin-1 (FeAL-1), a small-molecule probe for bioluminescent imaging of the labile iron pool (LIP) in luciferase-expressing cells and animals. We find that FeAL-1 detects LIP fluctuations in cells after iron supplementation, depletion, or treatment with hepcidin, the master regulator of systemic iron in mammalian physiology. Utilizing FeAL-1 and a dual-luciferase reporter system, we quantify LIP in mouse liver and three different orthotopic pancreatic ductal adenocarcinoma tumors. We observed up to a 10-fold increase in FeAL-1 bioluminescent signal in xenograft tumors as compared to healthy liver, the major organ of iron storage in mammals. Treating mice with hepcidin further elevated hepatic LIP, as predicted. These studies reveal a therapeutic index between tumoral and hepatic LIP and suggest an approach to sensitize tumors toward LIP-activated therapeutics.Copyright © 2023 Elsevier Ltd. All rights reserved.