ADAR1‐HNRNPL‐Mediated CircCANX Decline Promotes Autophagy in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a characteristic chronic airway inflammatory disease that worsens over time, however, there are currently limited clinical therapeutics to suspend its progression. Circular RNAs (circRNAs), which have emerged as functional regulators in various diseases, including COPD, may server as new pharmacological targets in COPD. Here, it is identified a nuclear circRNA, circCANX, that is preferentially decreased in COPD. The linear splicing of CANX pre-mRNA, enhanced by the ADAR1-HNRNPL interaction, is responsible for the circCANX decline. Clinically, the higher circCANX expression is associated with a worse lung function index of FEV₁/FVC among patients with COPD. CircCANX suppresses autophagy and stress granule (SG) formation to strengthen inflammation of COPD in vivo and in vitro. Mechanistically, circCANX recruits the tumor suppressor protein P53 (P53) mRNA and RNA helicase upstream frameshift 1 (UPF1) to form a ternary complex, which mediates P53 mRNA degradation through nonsense-mediated mRNA decay (NMD) process. Together, this study reveals an important circCANX-mediated regulatory mechanism in COPD, and provides new insights into the potential of circRNA-based drug and biomarker development for COPD.