FOXO3 regulates Smad3 and Smad7 through SPON1 circular RNA to inhibit idiopathic pulmonary fibrosis

Area of Science:

• Molecular Biology
• Cell Biology
• Pulmonary Medicine

Background:

• Idiopathic pulmonary fibrosis (IPF) is characterized by excessive fibroblast activation and extracellular matrix deposition.
• Forkhead box protein O3 (FOXO3) shows potential in inhibiting these processes, but its regulatory mechanism in pulmonary fibrosis is not fully understood.

Purpose of the Study:

• To elucidate the mechanism by which FOXO3 regulates pulmonary fibrosis through F-spondin 1 (SPON1) and its derived circular RNA (circSPON1).
• To investigate the role of circSPON1 in fibroblast activation and extracellular matrix deposition in the context of pulmonary fibrosis.

Main Methods:

• Analysis of FOXO3 binding to the SPON1 promoter.
• Assessment of circSPON1 expression and its impact on HFL1 cells.
• Investigation of circSPON1 interaction with Smad3 and its effect on nuclear translocation.
• Study of circSPON1 binding to microRNAs (miR-942-5p and miR-520f-3p) and its influence on Smad7 expression.

Main Results:

• FOXO3 activates SPON1 transcription, selectively promoting circSPON1 expression over mRNA.
• circSPON1 is implicated in extracellular matrix deposition in HFL1 cells.
• cytoplasmic circSPON1 inhibits fibroblast activation by preventing Smad3 nuclear translocation.
• circSPON1 upregulates Smad7 expression by sponging miR-942-5p and miR-520f-3p.

Conclusions:

• This study reveals a novel FOXO3-circSPON1 pathway crucial for regulating pulmonary fibrosis development.
• circSPON1 acts as a key mediator, inhibiting fibroblast activation and extracellular matrix deposition.
• The findings provide potential circRNA-based therapeutic targets and diagnostic insights for idiopathic pulmonary fibrosis.