Tao Qiqi, Li Yifei, Zhang Weizhi, Zhang Minghong, Li Xinmiao, Jin Hui, Zheng Jianjian, Li Yeping
Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Int J Biol Macromol. 2025 Apr;304(Pt 1):140602. doi: 10.1016/j.ijbiomac.2025.140602. Epub 2025 Feb 6.
Ferroptosis is a novel, iron-dependent regulated cell death mode. The biochemical features of ferroptosis include iron accumulation, lipid peroxidation, inhibition of glutathione peroxidase 4 (GPX4) and antioxidant glutathione (GSH) decrease through inhibition of the system xc transporter. Zinc finger NFX1 type-containing 1 (ZNFX1) antisense RNA 1 (ZFAS1) is a long non-coding RNA that has been identified as an oncogene in various types of cancers. However, its regulatory role and molecular mechanisms in clear cell renal cell carcinoma (ccRCC) ferroptosis remain unclear. In this study, the ferroptosis inducers (FINS) (erastin and RSL3) were found to increase ZFAS1 expression through the facilitation of SP1 binding to the ZFAS1 promoter. ZFAS1 increased mRNA and protein levels of solute carrier family 25 member 28 (SLC25A28) via functioning as a miR-185-5p sponge. Overexpressed SLC25A28 increased the production of ROS and caused a decrease in NADPH and GSH in cells treated with FINS. In addition, overexpression of ZFAS1 enhanced ferroptosis both in vitro and in vivo. Altogether, this study demonstrates that ZFAS1 is a crucial element of ferroptosis in ccRCC, as it is responsible for the regulation of miR-185-5p and SLC25A28. Introducing ferroptosis could be a beneficial approach to treat ccRCC patients with high ZFAS1 levels.
铁死亡是一种新型的、铁依赖性调节性细胞死亡模式。铁死亡的生化特征包括铁蓄积、脂质过氧化、谷胱甘肽过氧化物酶4（GPX4）受抑制以及通过抑制系统xc转运体导致抗氧化剂谷胱甘肽（GSH）减少。含锌指NFX1型1（ZNFX1）反义RNA 1（ZFAS1）是一种长链非编码RNA，已被确定为多种癌症中的癌基因。然而，其在透明细胞肾细胞癌（ccRCC）铁死亡中的调节作用和分子机制仍不清楚。在本研究中，发现铁死亡诱导剂（FINS）（埃拉斯汀和RSL3）通过促进SP1与ZFAS1启动子结合来增加ZFAS1表达。ZFAS1通过充当miR-185-5p海绵增加溶质载体家族25成员28（SLC25A28）的mRNA和蛋白质水平。过表达的SLC25A28增加了活性氧的产生，并导致用FINS处理的细胞中烟酰胺腺嘌呤二核苷酸磷酸（NADPH）和GSH减少。此外，ZFAS1的过表达在体外和体内均增强了铁死亡。总之，本研究表明ZFAS1是ccRCC铁死亡的关键因素，因为它负责调节miR-185-5p和SLC25A28。引入铁死亡可能是治疗ZFAS1水平高的ccRCC患者的一种有益方法。
