Mao Zhimin, Zhong Kun, Liu Xiaojun, Zeng Xuhui
Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, Jiangsu, China.
Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, Jiangsu, China.
Chem Biol Interact. 2023 Oct 1;384:110701. doi: 10.1016/j.cbi.2023.110701. Epub 2023 Sep 9.
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.
环磷酰胺（CYP）广泛应用于肿瘤治疗，但其临床应用受到其对膀胱毒性作用的限制。由于CYP诱导的膀胱炎被认为是由丙烯醛（ACR）介导的，ACR是一种引发铁死亡的脂质过氧化产物，我们推测铁死亡可能是CYP诱导膀胱炎的关键分子机制。本研究的目的是验证这一假设。腹腔注射CYP导致膀胱出血和水肿，同时氧化、炎症和细胞损伤增加。进一步分析显示，这些变化与膀胱中铁死亡标志物的改变有关，如FPN1、ACSL4、SLC7A11和GPX4，表明存在铁死亡。给予铁死亡抑制剂地拉罗司（DXZ）可改善铁死亡并预防CYP诱导的膀胱病理变化。总的来说，我们的研究表明铁死亡是CYP诱导膀胱炎的重要机制，并且可以开发针对铁死亡的治疗方法来治疗CYP诱导的膀胱炎。
