Circular RNA circDhx32 promotes cardiac inflammatory responses in mouse cardiac ischemia-reperfusion injury via binding to FOXO1 competed with AdipoR1

作者：Wei Si, Chun-lei Wang, Ling-Hua Zeng, Qiao-yue Zhao, Yating Xie, Yang Yang, Hongtao Diao, Jing-lun Song, Han Wu, Feng Zhang, Zhuo Wang, Xue Kong, Weitao Jiang, Xinyue Zhang, Ke-ying Lin, Fangyin Yao, Yüting Xiong, Tengfei Pan, Ping Pang, Baofeng Yang, Yu Bian · 发表于：Acta Pharmacologica Sinica · 年份：2025 · DOI：10.1038/s41401-025-01593-9 · 被引用次数：4 · 研究领域：Circular RNAs in diseases、RNA modifications and cancer、Cancer-related molecular mechanisms research

Abstract Ischaemic heart disease is an important cause of death in humans, and resupply of blood to damaged myocardium can exacerbate the risk of cardiac I/R injury. Circular RNAs (circRNAs) play an important role in cardiovascular disease. In this study we investigated the regulatory role of circDhx32 in the progression of I/R injury. Cardiac I/R model was established in mice by ligating the left anterior descending coronary artery (LAD) for 45 min, followed by blood reperfusion for 24 h or 2 weeks. For in vitro study, neonatal mouse ventricular cardiomyocytes were subjected to hypoxia-reoxygenation (H/R) assault. CircDhx32 was significantly upregulated in I/R-treated mice and H/R-treated cardiomyocytes. Cardiomyocyte-specific knockdown of circDhx32 ameliorated the pathological outcomes of cardiac I/R injury including improved cardiac function, reduced infarct size and reduced release of cardiac injury biomarkers. The protective effects of circDhx32 silencing were also observed in cardiomyocytes after H/R. We demonstrated that ALKBH5 functioned as an m 6 A demethylase, removing the m 6 A modification sites of circDhx32. Reduced m 6 A modification inhibited recognition and bindin g by the m 6 A readers YTHDF2 and YTHDC1, leading to circDhx32 degradation and diminished nucleoplasmic export under pathological conditions. Elevated circDhx32 inhibited the transcriptional activation of AdipoR1 by binding to FOXO1. Conversel y , circDhx32 deficiency alleviated the inflammatory resp...