Superenhancer-driven circRNA Myst4 involves in pulmonary artery smooth muscle cell ferroptosis in pulmonary hypertension.

ABSTRACT

The abnormal expression of circular RNAs (circRNAs) is emerging as a critical cause in regulation of pathological changes of hypoxic pulmonary hypertension (PH), in which ferroptosis is a new pathological change reported recently. However, how circRNAs regulate ferroptosis remains unclear. Here, we proved a significant decrease in circMyst4 expression in hypoxia. In vitro assays revealed that circMyst4 alleviated hypoxic pulmonary artery smooth muscle cell (PASMC) ferroptosis through directly combing with DDX5 in the nucleus to promote GPX4 mRNA processing and inhibiting the formation of the Eef1a1/ACSL4 complex in the cytoplasm. Additionally, superenhancer (SE) was verified to drive the generation of circMyst4. In vivo assays revealed that circMyst4 inhibited the progression of hypoxic PH. Overall, SE-driven circMyst4 may be a new potential therapeutic target for mediating PASMC ferroptosis through promoting DDX5-regulated GPX4 mRNA processing and inhibiting the binding between Eef1a1 and ACSL4.