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Updated: May 9, 2025

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
LINC00926, Regulated by TCF12, Modulates the Ubiquitination of GPX4 to Regulate Ferroptosis by Interacting with STUB1
Yong Jiang1, Han-Zhu Zhou2, Jun-Xuan Zhang2
1School of Laboratory Medicine, Jilin Medical University, No. 5 Jilin Street, Jilin, 132013, Jilin, China. jiangyongpost@sina.com.
Abstract:
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.
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