Background: Growth arrest specific 5 (GAS5) is a long noncoding RNA (lncRNA) that regulates the function of cardiovascular cells in various cardiovascular diseases. The current study delved into the regulation of GAS5 on the function of endothelial progenitor cells (EPCs) and its potential regulatory mechanism in coronary heart disease (CHD).

Methods: Reverse transcription-quantitative polymerase chain reaction was used to detect GAS5 expression in the blood samples and EPCs from CHD patients and healthy controls. Cell Counting Kit-8, colony formation, flow cytometry, and transwell assays were performed to evaluate cell phenotype of EPCs. Ferroptosis was detected by the measurement of Fe2+, malondialdehyde, GSH, and reactive oxygen species (ROS) levels. Glycolysis was determined by extracellular acidification rate (ECAR), oxygen consumption rate (OCR), glucose uptake and lactate production.

Results: Growth arrest specific 5 was downregulated in the blood samples and EPCs from CHD patients. Growth arrest specific 5 deficiency suppressed EPC proliferative capacity, migration, invasion and facilitated EPC apoptosis while GAS5 overexpression showed contrary effects. Moreover, GAS5 silencing inhibited the glucose metabolic reprogramming, as evidenced by the reduced ECAR, glycolysis capacity, ATP, glucose uptake and lactate production, and elevated OCR. Additionally, GAS5 overexpression attenuated the erastin-induced ferroptosis of EPCs. Growth arrest specific 5 could bind to IGF2BP1 to enhance the mRNA stability of glycolysis transcriptional regulator SIX1. Growth arrest specific 5 interacted with miR-23a-3p to regulate SLC7A11 expression. GAS5 promoted glucose metabolic reprogramming of EPCs by upregulating SIX1 and inhibited EPC ferroptosis by elevating SLC7A11.

Conclusion: Growth arrest specific 5 promotes glucose metabolic reprogramming and represses ferroptosis of EPCs via the IGF2BP1/SIX1 and miR-23a-3p/SLC7A11 dual-regulatory pathways in CHD.