circFBXO7 promotes ferroptosis in vascular endothelial cells exposed to high glucose through enhancing proteasomal degradation of TFCP2.
TL;DR
Findings identify a novel circFBXO7-TFCP2 regulatory axis linking metabolic stress to endothelial ferroptosis, providing new insight into the molecular basis of diabetic vascular dysfunction.
Abstract
High-glucose (HG) stress induces dysfunction of vascular endothelium, a key factor contributing to diabetic vascular complications, in part through ferroptosis. However, the mechanisms governing ferroptosis under these conditions remain partially understood. Herein, we identified circFBXO7 as a novel circular RNA that promotes ferroptosis and endothelial injury in human umbilical vein endothelial cells (HUVECs) and immortalized human aortic endothelial cells (iHAECs) treated with HG. Transcriptomic profiling revealed that circFBXO7 was markedly upregulated upon HG exposure and positively correlated with ferroptosis-related genes. Functional experiments showed that silencing circFBXO7 alleviated HG-induced cell death, restored migration and tube formation, and reduced oxidative stress, lipid peroxidation, Fe2+ accumulation, and mitochondrial damage. Mechanistically, circFBXO7 interacted with the transcription factor cellular promoter 2 (TFCP2) and promoted its ubiquitination and proteasomal degradation. Rescue experiments demonstrated that TFCP2 inhibition abolished the protective effects of circFBXO7 knockdown and sensitized endothelial cells to HG-induced ferroptosis. Overexpression of TFCP2 inhibited ferroptosis caused by HG treatment. Collectively, these findings identify a novel circFBXO7-TFCP2 regulatory axis linking metabolic stress to endothelial ferroptosis, providing new insight into the molecular basis of diabetic vascular dysfunction.