# Circular RNA FCHO2 promotes airway remodeling in COPD via regulating nuclear translocation of PTBP1 to repress the splicing of GRN pre-mRNA

## TL;DR

This study shows that a circular RNA called circFCHO2 contributes to airway remodeling in COPD by affecting gene splicing and signaling pathways.

## Contribution

The study reveals a novel mechanism by which circFCHO2 regulates airway remodeling in COPD through PTBP1 and GRN pre-mRNA splicing.

## Key findings

- circFCHO2 expression is elevated in COPD cell and mouse models and human lung tissues.
- circFCHO2 promotes EMT and ECM remodeling by inhibiting GRN pre-mRNA splicing via PTBP1.
- circFCHO2 knockdown reverses COPD-related airway remodeling in mice.

## Abstract

Circular RNAs (circRNAs) have emerged as key regulators in human diseases, yet their mechanisms of action in chronic obstructive pulmonary disease (COPD) remain largely unknown. In this study, the conserved mammalian circRNA circFCHO2 was shown to play critical roles in COPD. The expression level of circFCHO2 was significantly increased in COPD cell models, mouse models, and human lung tissue samples. Moreover, we demonstrated that circFCHO2 promotes epithelial‒mesenchymal transition (EMT) in bronchial epithelial cells and extracellular matrix (ECM) remodeling. Mechanistically, circFCHO2 binds to and facilitates the nuclear translocation of PTBP1, thereby inhibiting the splicing of GRN pre-mRNA, which reduces PGRN protein expression levels and activates the NF-κB pathway. This activation of the NF-κB signaling pathway regulates the expression of EMT and ECM remodeling-related proteins, leading to the occurrence of airway remodeling. circFCHO2 knockdown reverses cigarette smoke-induced emphysema and airway remodeling of COPD in mice. Overall, our study advanced the understanding of the molecular mechanisms by which circRNAs contribute to airway remodeling in COPD patients.