Jiang Yong, Zhou Han-Zhu, Zhang Jun-Xuan, Li Kai-Qi, Wang Jia-He
School of Laboratory Medicine, Jilin Medical University, No. 5 Jilin Street, Jilin, 132013, Jilin, China.
School of Clinical Medicine, Jilin Medical University, Jilin, 132013, China.
Mol Biotechnol. 2025 Apr 28. doi: 10.1007/s12033-025-01441-5.
LINC00926 has been identified as an upregulated lncRNA in patients with coronary heart disease (CHD) through high-throughput sequencing. This study aimed to explore the biological role of LINC00926 in vascular endothelial cell ferroptosis and its underlying mechanisms. For in vitro experiments, HUVECs were exposed to hypoxic conditions. Our results showed an upregulation of LINC00926 expression, a decrease in GPX4 and GSH levels, and an increase in MDA and ROS levels in hypoxia-treated HUVECs. Furthermore, the ferroptosis inhibitor (ferrostatin-1) reversed the decrease in cell viability induced by hypoxia, suggesting that hypoxia treatment triggered GPX4-mediated ferroptosis in HUVECs. These variations were further exacerbated when LINC00926 was overexpressed, but were partially mitigated when LINC00926 was silenced. Notably, LINC00926 had no effect on GPX4 mRNA levels. Our data proved that LINC00926 modulated the ubiquitination and degradation of GPX4 via STUB1, thereby promoting hypoxia-induced HUVEC ferroptosis. Additionally, ChIP and luciferase reporter gene assays confirmed that TCF12 protein enhanced the transcriptional activity of LINC00926 promoter, hinting TCF12 is an upstream regulator of LINC00926. Besides, LINC00926 also enhanced the stability of TCF12 mRNA to promote TCF12 expression. Moreover, TCF12 acted as a regulator of ferroptosis in hypoxia-induced HUVECs. Finally, rescue experiments determined the role of the TCF12/LINC00926/GPX4 axis in ferroptosis of HUVECs upon hypoxic stimulation. In conclusion, this study demonstrated that the TCF12/LINC00926/GPX4 axis plays a regulatory role in hypoxia-induced ferroptosis of HUVECs, offering a promising target for the treatment of CHD.
通过高通量测序，LINC00926已被鉴定为冠心病（CHD）患者中上调的长链非编码RNA。本研究旨在探讨LINC00926在血管内皮细胞铁死亡中的生物学作用及其潜在机制。在体外实验中，将人脐静脉内皮细胞（HUVECs）置于缺氧条件下。我们的结果显示，缺氧处理的HUVECs中LINC00926表达上调，谷胱甘肽过氧化物酶4（GPX4）和谷胱甘肽（GSH）水平降低，丙二醛（MDA）和活性氧（ROS）水平升高。此外，铁死亡抑制剂（铁抑素-1）逆转了缺氧诱导的细胞活力下降，表明缺氧处理触发了HUVECs中GPX4介导的铁死亡。当LINC00926过表达时，这些变化进一步加剧，但当LINC00926沉默时，这些变化部分得到缓解。值得注意的是，LINC00926对GPX4 mRNA水平没有影响。我们的数据证明，LINC00926通过含 Stub1结构域的E3泛素连接酶1（STUB1）调节GPX4的泛素化和降解，从而促进缺氧诱导的HUVECs铁死亡。此外，染色质免疫沉淀（ChIP）和荧光素酶报告基因分析证实，转录因子12（TCF12）蛋白增强了LINC00926启动子的转录活性，提示TCF12是LINC00926的上游调节因子。此外，LINC00926还增强了TCF12 mRNA的稳定性，以促进TCF12表达。此外，TCF12在缺氧诱导的HUVECs铁死亡中起调节作用。最后，挽救实验确定了TCF12/LINC00926/GPX4轴在缺氧刺激下HUVECs铁死亡中的作用。总之，本研究表明TCF12/LINC00926/GPX4轴在缺氧诱导的HUVECs铁死亡中起调节作用，为冠心病的治疗提供了一个有前景的靶点。
