铁死亡对环磷酰胺诱导的出血性膀胱炎发挥作用。
Ferroptosis contributes to cyclophosphamide-induced hemorrhagic cystitis.
发表日期：2023 Sep 08
作者：
Zhimin Mao, Kun Zhong, Xiaojun Liu, Xuhui Zeng
来源：
CHEMICO-BIOLOGICAL INTERACTIONS
摘要：
环磷酰胺（CYP）广泛用于肿瘤治疗，但其对膀胱的毒性作用限制了其临床应用。由于CYP诱导的膀胱炎被认为是脂质过氧化产物丙烯醛（ACR）介导的，丙烯醛触发铁死亡，我们假设铁死亡可能是CYP诱导的膀胱炎的一个重要分子机制。本研究旨在验证这一假设。CYP腹腔注射导致膀胱出血和水肿，伴随着氧化、炎症和细胞损伤的增加。进一步分析发现这些变化与膀胱中的铁死亡标志物如FPN1、ACSL4、SLC7A11和GPX4有关，表明铁死亡的存在。给予铁死亡抑制剂达克拉唑（DXZ）改善了铁死亡，并防止了CYP诱导的膀胱病理变化。总体而言，我们的研究揭示了铁死亡是CYP诱导的膀胱炎的一个重要机制，并且可以开发针对铁死亡的治疗策略来治疗CYP诱导的膀胱炎。版权所有 © 2023 Elsevier B.V. 发布。
Cyclophosphamide (CYP) is extensively used in tumor therapy, but its clinical application is limited by its toxic effects on the bladder. Since CYP-induced cystitis is believed to be mediated by acrolein (ACR), a product of lipid peroxidation that triggers ferroptosis, we hypothesized that ferroptosis might be an essential molecular mechanism underlying CYP-induced cystitis. The purpose of this study was to test this hypothesis. Intraperitoneal injection of CYP led to bladder hemorrhage and edema, along with increased oxidation, inflammation, and cell injury. Further analysis revealed these changes were associated with altered ferroptosis markers in the bladder, such as FPN1, ACSL4, SLC7A11, and GPX4, indicating the existence of ferroptosis. Administration of ferroptosis inhibitor dexrazoxane (DXZ) improved ferroptosis and prevented CYP-induced pathological changes in the bladder. Collectively, our study revealed that ferroptosis is an important mechanism underlying CYP-induced cystitis, and therapeutic approaches targeting ferroptosis could be developed to treat CYP-induced cystitis.Copyright © 2023. Published by Elsevier B.V.