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ADAR1-HNRNPL-Mediated CircCANX Decline Promotes Autophagy in Chronic Obstructive Pulmonary Disease
Ting-Ting Chen1,2, Yuan-Yuan Wei1,2, Jia-Ying Kang1,2
1Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230022, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|March 17, 2025
Summary
This study identifies circCANX, a circular RNA that decreases in chronic obstructive pulmonary disease (COPD). Lower circCANX levels worsen COPD by increasing inflammation, suggesting circCANX as a potential therapeutic target.
Area of Science:
- Molecular Biology
- Pulmonology
- Biochemistry
Background:
- Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory airway disease with limited treatment options.
- Circular RNAs (circRNAs) are emerging as key regulators in diseases, including COPD, offering potential therapeutic targets.
- Identifying novel molecular mechanisms in COPD is crucial for developing effective interventions.
Purpose of the Study:
- To identify and characterize novel circular RNAs involved in the pathogenesis of COPD.
- To investigate the role of circCANX in COPD progression and inflammation.
- To explore the potential of circCANX as a biomarker and therapeutic target for COPD.
Main Methods:
- Identification and quantification of circRNAs in COPD patient samples and cell/animal models.
- Investigation of the regulatory mechanisms controlling circCANX expression, including pre-mRNA splicing factors.
- Functional studies using in vitro and in vivo models to assess the impact of circCANX on COPD-related inflammation, autophagy, and stress granule formation.
- Mechanistic studies to elucidate how circCANX regulates gene expression via the nonsense-mediated mRNA decay (NMD) pathway.
Main Results:
- A nuclear circRNA, circCANX, was identified and found to be significantly decreased in COPD.
- The decline in circCANX is attributed to enhanced linear splicing of CANX pre-mRNA, mediated by the ADAR1-HNRNPL interaction.
- Higher circCANX expression correlated with better lung function (FEV1/FVC) in COPD patients.
- CircCANX was shown to suppress autophagy and stress granule formation, thereby mitigating COPD inflammation.
- Mechanistically, circCANX forms a complex with P53 mRNA and UPF1, promoting P53 mRNA degradation through NMD.
Conclusions:
- CircCANX plays a protective role in COPD by suppressing inflammation through the regulation of autophagy and stress granule formation.
- The circCANX-P53 mRNA-UPF1-NMD axis represents a novel regulatory pathway in COPD pathogenesis.
- CircCANX holds promise as a potential diagnostic biomarker and a therapeutic target for COPD drug development.
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