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

Area of Science:

• Molecular Biology
• Cardiovascular Research
• Cellular Pathology

Background:

• Abnormal circular RNA (circRNA) expression is linked to hypoxic pulmonary hypertension (PH).
• Ferroptosis, a form of regulated cell death, is a recently identified pathological feature in PH.
• The precise mechanisms by which circRNAs regulate ferroptosis in PH remain largely unknown.

Purpose of the Study:

• To investigate the role of circRNAs, specifically circMyst4, in regulating ferroptosis within the context of hypoxic PH.
• To elucidate the molecular mechanisms underlying circMyst4's function in pulmonary artery smooth muscle cells (PASMCs).
• To explore the therapeutic potential of circMyst4 in treating hypoxic PH.

Main Methods:

• Quantitative analysis of circMyst4 expression in hypoxia.
• In vitro studies using PASMCs to assess circMyst4's effects on ferroptosis.
• Investigation of circMyst4's molecular interactions with DDX5 and Eef1a1/ACSL4 complex.
• Identification of superenhancer (SE) involvement in circMyst4 generation.
• In vivo experiments in a hypoxic PH model.

Main Results:

• circMyst4 expression was significantly decreased under hypoxic conditions.
• circMyst4 alleviated ferroptosis in hypoxic PASMCs by promoting GPX4 mRNA processing via DDX5 interaction and inhibiting Eef1a1/ACSL4 complex formation.
• Superenhancers (SEs) were confirmed to drive circMyst4 biogenesis.
• In vivo administration of circMyst4 inhibited the progression of hypoxic PH.

Conclusions:

• SE-driven circMyst4 plays a protective role against ferroptosis in PASMCs.
• circMyst4 represents a novel therapeutic target for hypoxic PH by modulating PASMC ferroptosis through specific molecular pathways.
• The findings highlight a new mechanism involving circRNAs in the pathogenesis of PH.