Ferroptosis modulation is a powerful therapeutic option for pancreatic ductal adenocarcinoma (PDAC) with a low 5-year survival rate and lack of effective treatment methods. However, due to the dual role of ferroptosis in promoting and inhibiting pancreatic tumorigenesis, regulating the degree of ferroptosis is very important to obtain the best therapeutic effect of PDAC. Biothiols are suitable as biomarkers of imaging ferroptosis due to the dramatic decreases of biothiol levels in ferroptosis caused by the inhibited synthesis pathway of glutathione (GSH) and the depletion of biothiol by reactive oxygen species. Moreover, a very recent study reported that cysteine (Cys) depletion can lead to pancreatic tumor ferroptosis in mice and may be employed as an effective therapeutic strategy for PDAC. Therefore, visualization of biothiols in ferroptosis of PDAC will be helpful for regulating the degree of ferroptosis, understanding the mechanism of Cys depletion-induced pancreatic tumor ferroptosis, and further promoting the study and treatment of PDAC. Herein, two biothiol-activable near-infrared (NIR) fluorescent/photoacoustic bimodal imaging probes (HYD-BX and HYD-DX) for imaging of pancreatic tumor ferroptosis were reported. These two probes show excellent bimodal response performances for biothiols in solution, cells, and tumors. Subsequently, they have been employed successfully for real-time visualization of changes in concentration levels of biothiols during the ferroptosis process in PDAC cells and HepG2 cells. Most importantly, they have been further applied for bimodal imaging of ferroptosis in pancreatic cancer in mice, with satisfactory results. The development of these two probes provides new tools for monitoring changes in concentration levels of biothiols in ferroptosis and will have a positive impact on understanding the mechanism of Cys depletion-induced pancreatic tumor ferroptosis and further promoting the study and treatment of PDAC.

中文翻译：

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使用生物硫醇激活探针对胰腺癌铁死亡进行近红外荧光/光声双峰成像

铁死亡调节是胰腺导管腺癌 (PDAC) 的一种强大的治疗选择，但其 5 年生存率较低且缺乏有效的治疗方法。然而，由于铁死亡具有促进和抑制胰腺肿瘤发生的双重作用，调节铁死亡程度对于获得PDAC的最佳治疗效果非常重要。生物硫醇适合作为铁死亡成像的生物标志物，因为谷胱甘肽（GSH）合成途径受到抑制以及活性氧物质消耗生物硫醇导致铁死亡中生物硫醇水平急剧下降。此外，最近的一项研究报告称，半胱氨酸 (Cys) 耗竭可导致小鼠胰腺肿瘤铁死亡，并可作为 PDAC 的有效治疗策略。因此，对PDAC铁死亡中生物硫醇的可视化将有助于调节铁死亡的程度，了解Cys耗竭导致胰腺肿瘤铁死亡的机制，进一步推动PDAC的研究和治疗。在此，报道了两种用于胰腺肿瘤铁死亡成像的生物硫醇可激活的近红外（NIR）荧光/光声双峰成像探针（HYD-BX和HYD-DX）。这两种探针对溶液、细胞和肿瘤中的生物硫醇表现出优异的双峰响应性能。随后，它们已成功用于实时可视化 PDAC 细胞和 HepG2 细胞铁死亡过程中生物硫醇浓度水平的变化。最重要的是，它们已进一步应用于小鼠胰腺癌铁死亡的双模态成像，并取得了令人满意的结果。这两种探针的开发为监测铁死亡中生物硫醇浓度水平的变化提供了新的工具，将对理解Cys耗竭诱导胰腺肿瘤铁死亡的机制、进一步推动PDAC的研究和治疗产生积极影响。